TECHNICAL REPORT

Fish, Shellfish, and Children’s Health: An Assessment of Benefits, Risks, and Sustainability Aaron S. Bernstein, MD, MPH, FAAP,a Emily Oken, MD, MPH,b Sarah de Ferranti, MD, MPH, FAAP,c COUNCIL ON ENVIRONMENTAL HEALTH, COMMITTEE ON NUTRITION

abstract American children eat relatively little fish and shellfish in comparison with other sources of animal protein, despite the health benefits that eating fish and shellfish may confer. At the same time, fish and shellfish may be sources a c Departments of Pediatrics and Cardiology, Boston Children’s Hospital of toxicants. This report serves to inform pediatricians about available and Harvard Medical School, Harvard University, Boston, Massachusetts; and bDepartment of Population Medicine, Harvard research that elucidates health risks and benefits associated with fish and Pilgrim Health Care, Boston, Massachusetts shellfish consumption in childhood as well as the sustainability of fish and This document is copyrighted and is property of the American shellfish harvests. Academy of Pediatrics and its Board of Directors. All authors have filed conflict of interest statements with the American Academy of Pediatrics. Any conflicts have been resolved through a process approved by the Board of Directors. The American Academy of Pediatrics has neither solicited nor accepted any commercial involvement in the development of the content of this publication. Fish and shellfish are, in general, good sources of low-fat protein rich in Technical reports from the American Academy of Pediatrics benefit several essential vitamins and minerals as well as, in certain instances, the from expertise and resources of liaisons and internal (AAP) and external reviewers. However, technical reports from the American essential nutrients omega-3 long-chain polyunsaturated fatty acids (n-3 Academy of Pediatrics may not reflect the views of the liaisons or the LCPUFAs). Some guidance is available and accessible to pediatric health organizations or government agencies that they represent. care providers or families to assist them with navigating fish and shellfish The guidance in this report does not indicate an exclusive course of choices, but most sources focus on consumption by adults or pregnant treatment or serve as a standard of medical care. Variations, taking 1 into account individual circumstances, may be appropriate. women and do not directly address childhood consumption. This report fi All technical reports from the American Academy of Pediatrics provides an overview of the potential risks and bene ts associated with automatically expire 5 years after publication unless reaffirmed, childhood consumption of fish and shellfish. Whenever possible, it draws revised, or retired at or before that time. on research performed with children. However, in instances when such DOI: https://doi.org/10.1542/peds.2019-0999 evidence is not available, it will examine prenatal and adult evidence. Address correspondence to Aaron S. Bernstein, MD, MPH, FAAP. Email: This report also addresses the sustainability of fish and shellfish choices. [email protected] Approximately 90% of fisheries worldwide are exploited at or above PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). maximum sustainable yield. As a result, any guidance on fish consumption Copyright © 2019 by the American Academy of Pediatrics must consider sustainability to protect the viability of fisheries. An overview of the report can be found in Table 1. To cite: Bernstein AS, Oken E, de Ferranti S, AAP COUNCIL ON ENVIRONMENTAL HEALTH, AAP COMMITTEE ON NUTRITION. Fish, Shellfish, and Children’s Health: An Assessment of NUTRIENT VALUE OF FISH CONSUMPTION fi Bene ts, Risks, and Sustainability. Pediatrics. 2019;143(6): All fish are protein dense and have little or no sugar or saturated fat. Many e20190999 species contain high levels of vitamin D and calcium. Some shellfish

Downloaded from www.aappublications.org/news by guest on September 24, 2021 330 FROM THE AMERICAN ACADEMY OF PEDIATRICS PEDIATRICS Volume 143, number 6, June 2019:e20190999 TABLE 1 Technical Report Summary In this report, we cover 4 areas related to seafood: nutrition, potential health benefits, toxicants, and sustainability. An overview of evidence in each of these areas is provided here with the sections of the report providing detail on specific studies. Nutrition • Compared with other animal protein, such as beef, pork, or chicken, fish have a favorable nutrient profile (see Table 2) and are a good source of lean protein, calcium, vitamin D, and n-3 LCPUFAs. Potential Health Benefits Childhood fish consumption has been associated with the following: • prevention of allergic disorders. Fish oil supplement intake in childhood has been associated with the following: • reduced hospitalization and number of pain crises in sickle cell disease, based on limited data. Studies that have evaluated the effects of either childhood fish consumption and/or n-3 LCPUFA intake and had mixed (ie, positive and/or negative) or null results for the following: • treatment of ADHD symptoms; • treatment of depressive symptoms; • treatment of allergic diseases; • prevention or treatment of inflammatory bowel disease flares; • cognitive development, including memory, processing speed, and IQ; • hyperlipidemia; and • prevention or treatment of hypertension. For some diseases, evidence suggests that fish oil supplementation may benefit children who have below average n-3 LCPUFA levels. Studies that have revealed benefits from fish oil supplementation often rely on daily administration of high-dose formulations, which may be difficult for children to comply with. Fish oil supplements sold in the United States are not FDA approved, and as such, their contents may not be as advertised on the product label. Toxicants • Some fish species can be a source of MeHg, which can damage the developing nervous system in utero. • Many accessible resources provide guidance on which species of which to limit intake or avoid (see Resources). • POPs, such as PCBs, can be found in fish, especially in fish caught in freshwater; other animal protein sources may contain as much PCBs and other POPs as many fish and shellfish. • Fish and shellfish captured in freshwater bodies in the United States may have high concentrations of pollutants and populations that regularly consume freshwater fish, and shellfish may be at higher risk of harms from these toxicants. Sustainability • Approximately 30% of global fish stocks are overexploited; a further 60% are harvested at or near their maximum sustainable yield. Medical and governmental organizations have encouraged greater seafood consumption for Americans, which may add pressure to declining wild fisheries and promote unsustainable aquaculture practice. • Shrimp is the most commonly consumed seafood in the United States; much of the shrimp comes from highly unsustainable overseas fi sheries, which exact heavy environmental and human tolls. • US fisheries, wild or farmed, are some of the best managed in the world, even if not all are sustainably harvested. • In comparison with conventional red meat production in the United States, most wild catch fisheries and best practice aquaculture have favorable water, greenhouse gas, and pollution footprints.

species have high iron content. Other consumed in the diet. Humans also neurons in the brain and eye and trace nutrients, such as selenium and can elongate and desaturate short- have anti-inflammatory and iodine, are present in many fish and chain “parent” polyunsaturated fatty immunomodulatory properties, and shellfish species as well. The health acids such as linoleic acid, present in many researchers have investigated benefits of consumption of these nuts and seeds, into LCPUFAs, but the potential benefits of fish or n-3 nutrients have been documented this process is inefficient and unlikely LCPUFA consumption in early life for extensively elsewhere2–7 and will not to result in sufficient levels for neurodevelopmental and atopic be reviewed here, but a summary optimal health among most outcomes, which are summarized in table describing which fish and individuals.8 Fish are the primary later sections of this report. shellfish species provide various natural dietary source for DHA and nutrients is provided in Table 2. EPA. These fatty acids can also be concentrated from algal sources and STUDIES OF FISH CONSUMPTION Some fish are a rich source of the n-3 in this form have been added to infant LCPUFAs, eicosapentaenoic acid formula and foods such as milk, Prevention of Allergic Disease (EPA), and docosahexaenoic acid yogurt, and pasta and increasingly are The majority of observational studies (DHA). n-3 LCPUFAs are essential taken as supplements. n-3 LCPUFAs conducted to date have shown that nutrients and, as such, must be are structural components of maternal fish consumption likely

Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 143, number 6, June 2019 331 TABLE 2 Nutritional and Toxicant Contents for Various Animal Based Foods (Per 100 g Raw, Unless Otherwise Specified) Kcal Protein Total fat (g) Sat fat (g) Cholesterol DHA + EPA Calcium Vitamin Iron Mercury (g) (rounded to nearest (rounded to (mg) omega-3 (mg) D (IU) (mg) meana (CV) whole No.) nearest (mg) mg/kg (ppm)b whole No.) Fish Catfish 95 16 3 1 58 364 14 500 0.3 0.118 (4.97) Atlantic cod 82 18 1 0 43 184 16 36 0.4 0.070 (3.70) Flounder 70 12 2 0 45 245 21 113 0.2 0.119 (3.42) Haddock 74 16 1 0 54 131 11 18 0.2 0.164 (4.59) Halibut (Pacific) 91 19 1 0 49 194 7 190 0.8 0.261 (4.32) Pangasius, swai, or basac 74 15 2 0 36 0 10 54 0.1 d Pollock, Alaskane 70 17 0 0 61 62 15 73 0.22 0.58 (5.93) Rainbow trout (wild) 119 20 3 1 59 587 67 265f 0.7 0.344 (3.00) Salmon (farmed Atlantic) 208 20 13 3 55 1866 9 441 0.3 0.026 (2.91) Salmon (wild Alaskan 187 20 12 2 61 1150 42 425g 0.8 0.067 (1.59) Chinook or King) Sardine, Atlantic canned 208 25 11 2 142 1480 382 193 2.9 0.079 (2.56) in oil, with bone Swordfish 144 20 7 2 66 754 5 558 0.4 0.893 (2.30) Tilapia 96 20 2 1 50 91 10 124 0.6 0.019 (4.99) Tuna (albacore, canned in 128 24 3 1 42 862 14 80h 1.0 0.328 (2.92) water) Tuna (light or skipjack, 116 26 1 0 30 281 11 47 1.5 0.118 (2.55) canned in water) Tuna (yellowfin) 109 24 1 0 39 100 4 69 0.8 0.143 (4.80) Shellfish Blue crab 87 18 1 0 78 549 89 0 0.7 0.110 (5.40) Clamsi 86 15 1 0 30 107 39 1 1.6 0.028 Lobster 77 17 1 0 127 176 84 0 0.3 0.153 (2.06) Scallops 69 12 3 0 24 106 6 1 0.4 0.40 (3.65) Shrimp 85 20 1 0 161 61 64 0 1.62 0.053 (4.03) Other animal protein Bologna (beef) 299 11 26 10 57 4 21 28 1.3 ND Chicken breast with skin 172 21 9 3 64 30 11 16 0.7 0j Chicken leg with skin 214 16 16 4 79 14 8 2 0.7 0f Eggs 143 6 5 3 186 58 56 82 1.8 0f Milk, whole (with vitamin 61 3 3 2 10 0 113 51 0 0f (NA) D supplemented) Pork chops, meat and fat 170 20 9 3 69 0 19 21 0.63 ND Sirloin steak, trimmed to 201 20 13 5 75 0 24 7k 1.61 ND 1/8” fat Nutritional data from US Department of Agriculture Food Composition Database unless otherwise noted (https://ndb.nal.usda.gov/ndb/foods). Typical seafood serving size (84 g/3 oz). Recommended daily allowances: Vitamin D: 600 IU, ages 1–18 years, male or female. Calcium: 0–6 months, 200 mg; 7–12 months, 260 mg; 1–3 years, 700 mg; 4–8 years, 1 g; 9–18 years, 1.3 g. Iron: 0–6 months, 0.27 mg; 7–12 months, 11 g; 1–3 years, 7 mg; 4–8 years, 10 mg; 9–13 years, 8 mg; 14–18 years, 11–15 mg (male or female); pregnant women, 27 mg; lactating women, 10 mg. CV, coefficient of variation; NA, not applicable; ND, no data. a Mercury data from Karimi R, Fitzgerald TP, Fisher NS. A quantitative synthesis of mercury in commercial seafood and implications for exposure in the United States. Environ Health Perspect. 2012;120(11):1512–1519. The FDA has set an action level of 1 ppm per edible portion. Fish that exceed this level may be pulled from the marketplace by the FDA. b More detailed information on mercury content of seafood can be found in Table 3. c Data from UK Department of Health Analysis of Fish and Fish Products, 2013. Available at: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/167923/Nutrie nt_analysis_of_fish_and_fish_products_-_Analytical_Report.pdf. d No reliable data available. Available at: http://www.seafoodhealthfacts.org/description-top-commercial-seafood-items/pangasius for more information on Pangasius. e Omega 3, calcium, vitamin D, and iron data from Canada’s nutrient profile database, as values were unavailable from US Department of Agriculture. Available at: https://food-nutrition. canada.ca/cnf-fce/index-eng.jsp. f Vitamin D data from Canada’s nutrient profile database, as values were unavailable from US Department of Agriculture. Available at: https://food-nutrition.canada.ca/cnf-fce/index-eng. jsp. g Vitamin D content for wild Chinook salmon obtained from Nutrition Canada’s nutrient profile database, as values were unavailable from US Department of Agriculture. Available at: https://food-nutrition.canada.ca/cnf-fce/index-eng.jsp. h Vitamin D data from Canada’s nutrient profile database, as values were unavailable from US Department of Agriculture. Available at https://food-nutrition.canada.ca/cnf-fce/index-eng. jsp. i US Department of Agriculture nutrition information based on “mixed” species. Mercury data for clams includes softshell, Pacific littleneck, cockle, geoduck, and hard. j Data from FDA Market Basket studies 1996–2011. Available at: http://www.fda.gov/downloads/Food/FoodScienceResearch/TotalDietStudy/UCM184301.pdf. k Vitamin D data from Canada’s nutrient profile database as values unavailable from US Department of Agriculture. Available at https://food-nutrition.canada.ca/cnf-fce/index-eng.jsp.

Downloaded from www.aappublications.org/news by guest on September 24, 2021 332 FROM THE AMERICAN ACADEMY OF PEDIATRICS TABLE 3 MeHg Content of Selected Fish (Adapted from Karimi et al) influences risk of atopy in offspring.9 Seafood Item Grand Available research also suggests that fi Mean Hg Samples SDw SEw eating sh early in life can prevent certain allergic diseases, including (ppm) a (Total) b asthma, eczema, and allergic rhinitis. Anchovies (all) 0.103 455 0.197 0.041 Bass (Chilean) 0.357 100 0.185 0.041 In more than a dozen observational Bass (freshwater, all) 0.170 149 0.361 0.059 studies, the associations of fish Bass (saltwater, black, white, striped) 0.288 1660 1.004 0.150 consumption in infancy and Bass, striped (all) 0.285 1367 1.155 0.140 Bass, striped (farmed) 0.028 15 NA NA childhood with atopy risk have been Bass, striped (wild) 0.295 1311 1.147 0.134 evaluated. In a prospective Bluefish 0.351 1019 0.965 0.145 observational study of more than Butterfish 0.054 109 0.112 0.021 4000 Swedish infants who did not Carp (all) 0.156 477 0.521 0.095 fi have eczema or recurrent wheeze in Cat sh (all) 0.118 1757 0.586 0.087 fi 10 Catfish (wild, all species) 0.144 1396 0.513 0.078 the rst year of life, Kull et al found Catfish, channel (wild) 0.120 521 0.253 0.038 a dose-dependent association of Catfish (farmed, all species) 0.012 320 0.073 0.008 greater fish consumption with lower Clams (all) 0.028 1027 0.177 0.032 risks for asthma, eczema, allergic Clams, hard 0.047 181 0.130 0.026 rhinitis, and sensitization, even when Clams, geoduck 0.030 11 0.049 0.021 Clams, cockle 0.054 122 0.404 0.073 controlling for smoking, maternal age, Clams, Pacific littleneck 0.022 18 0.022 0.009 existence of parental allergies, and Clams, softshell 0.016 471 0.249 0.020 breastfeeding. They also found an Cod (all) 0.087 2115 0.358 0.038 inverse association between age at Cod, Atlantic (farmed) 0.034 24 NA NA introduction of fish and atopy risk: Cod, Atlantic (wild) 0.070 1452 0.261 0.017 fi Cod, Pacific 0.144 431 0.260 0.038 children who consumed sh between Crab (all) 0.098 1564 0.453 0.086 3 and 8 months of age had lower risks Crab (blue, king, and snow) 0.095 1087 0.526 0.098 for asthma (adjusted odds ratio [OR], Crab, blue 0.110 864 0.594 0.103 0.73; 95% confidence interval [CI]: Crab, Dungeness 0.120 264 0.225 0.037 0.55 to 0.97), eczema (adjusted OR, Crab, king 0.027 203 0.154 0.032 Crab, snow 0.110 20 0.187 0.073 0.77; 95% CI: 0.64 to 0.92), allergic Crawfish (all) 0.034 206 0.104 0.019 rhinitis (adjusted OR, 0.77; 95% CI: Croaker (all) 0.092 856 0.308 0.058 0.60 to 0.97), and allergic Croaker, Atlantic 0.069 572 0.135 0.025 sensitization (adjusted OR, 0.78; 95% Croaker, white 0.169 193 0.344 0.066 fi CI: 0.64 to 0.95) compared with Cuttle sh 0.134 156 0.275 0.085 fi Eel (all) 0.186 986 0.608 0.111 children introduced to sh at Eel (wild) 0.216 659 0.551 0.110 9 months or older. A subsequent Eel (farmed) 0.066 220 0.163 0.027 study of this cohort found that the Flatfish (flounder, plaice, sole) 0.110 3070 0.417 0.079 benefits of consuming 2 or more fish Flounder (all) 0.119 1687 0.406 0.075 meals per month by age 1 extended to Flounder, summer 0.121 427 0.216 0.042 11 Flounder, windowpane 0.152 84 0.152 0.037 12 years of age. Flounder, winter 0.070 302 0.228 0.039 Further research corroborates the Freshwater perch (all) 0.141 1295 0.745 0.110 fi Grouper (all) 0.417 643 0.804 0.196 potential for early sh consumption Haddock (all) 0.164 226 0.752 0.166 having durable protective effects. Hake (all) 0.146 739 0.489 0.090 Goksör et al12 found that introduction Halibut (all) 0.254 3532 0.703 0.060 of fish before 9 months of age fi Halibut, Paci c 0.261 3111 1.127 0.053 independently reduced the risk Halibut, Greenland 0.183 138 0.630 0.120 Herring (all) 0.043 1277 0.174 0.026 (adjusted OR, 0.6; 95% CI: 0.4 to Herring, Atlantic 0.037 973 0.119 0.015 0.96) of current atopic asthma Herring, Pacific 0.060 194 0.300 0.048 (defined by respiratory symptoms Lingcod 0.363 333 0.952 0.128 plus positive skin prick test result) at Lobster (all) 0.153 344 0.315 0.070 school age. A 2013 meta-analysis of 3 Lobster, American 0.200 142 0.367 0.075 fi Lobster, spiny 0.100 62 0.137 0.035 studies found that sh consumption Mackerel (all) 0.586 2481 3.237 0.450 in infancy was inversely related to Mackerel, Atlantic 0.045 191 0.192 0.037 childhood asthma incidence, with children who ate the most fish having

Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 143, number 6, June 2019 333 TABLE 3 Continued a 25% lower risk of developing Seafood Item Grand asthma than those who ate the 13 Mean Hg Samples SDw SEw least. (ppm) a (Total) b Another prospective cohort of Mackerel, chub 0.099 129 0.166 0.033 Swedish infants found that Mackerel, king 1.101 821 3.470 0.383 introduction of fish between 6 and Mackerel, Spanish 0.440 1168 1.105 0.097 8 months of age substantially reduced Marlin (all) 1.517 821 7.495 1.654 Marlin, blue 2.465 364 9.532 2.120 rates of infantile eczema (OR, 0.6; Marlin, striped 0.861 179 2.356 0.528 95% CI: 0.5 to 0.7; P , .001), and Marlin, white 0.695 56 0.518 0.120 children who did not consume fish Monkfish 0.174 92 0.117 0.024 were 2.7 times more likely to have Mullet 0.050 638 0.152 0.027 eczema than those who ate fish 3 or Mussels (all) 0.028 755 0.106 0.016 Ocean perch 0.117 262 0.421 0.082 more times a week (95% CI: 1.80 to 14 15 Orange roughy 0.513 152 0.569 0.103 4.13; P , .001). Oien et al found Oysters (all) 0.020 5310 0.178 0.013 that infants who ate fish once a week Oysters, Eastern 0.018 4573 0.161 0.009 or more were 38% less likely to have fi Oysters, Paci c 0.039 290 0.171 0.025 eczema at 2 years. In this study, the Pike 0.404 1374 1.328 0.101 fi Plaice 0.148 282 0.576 0.137 mean age of introducing sh was 9 Pollock (all) 0.058 540 0.342 0.059 months. In contrast, in a trial among Pollock, Atlantic 0.160 79 0.330 0.053 123 pregnant women who were Pollock, Pacific/Alaska 0.050 235 0.145 0.027 randomly assigned to consume 2 Porgy 0.065 169 0.143 0.027 fi weekly servings of salmon or their Sable sh 0.243 477 0.620 0.080 fi Salmon (all) 0.048 2818 0.143 0.023 usual diet low in sh, there was no Salmon, Atlantic (farmed) 0.026 145 0.077 0.020 difference in rates of infantile eczema Salmon, Atlantic (wild) 0.058 95 0.083 0.015 at 6 months.16 Salmon, Chinook, farmed 0.017 4 0.024 0.017 Salmon, Chinook, wild 0.067 580 0.106 0.013 Results from other studies (eg, Salmon, chum 0.046 456 0.139 0.018 Hesselmar et al17) support the Salmon, coho 0.044 567 0.065 0.007 potential for early introduction of fish Salmon, pink 0.037 222 0.064 0.009 Salmon, sockeye 0.039 396 0.026 0.004 to prevent other allergic disease, such 14 Salmon (canned) 0.035 61 0.042 0.012 as allergic rhinitis. Alm et al found Sardine (all) 0.079 1007 0.201 0.036 that children who were given fish Scallops (all) 0.040 336 0.148 0.033 before 9 months were half as likely to Seabass, black 0.120 139 0.118 0.032 develop allergic rhinitis by 4.5 years Shad (all) 0.077 93 0.099 0.031 Shad, American 0.067 76 0.095 0.019 of age in a prospective cohort of Shark (all) 0.882 3722 2.504 0.462 Swedish children. Shark, blacktip 0.882 250 1.249 0.274 Shark, blue 0.664 50 1.516 0.480 Of note, some evidence suggests that Shark, mako 1.259 166 1.995 0.464 prenatal shellfish consumption (as Shark, sandbar 0.869 115 1.141 0.301 opposed to finfish) may increase risk Shark, thresher 0.622 119 1.874 0.421 of food allergy. In their analysis of Shrimp (all) 0.053 935 0.212 0.038 18 Shrimp, brown 0.077 72 0.083 0.053 early childhood diet, Pelé et al Shrimp, pink 0.083 49 0.079 0.024 found that maternal prenatal shellfish Shrimp, white 0.057 113 0.136 0.016 intake at least once a month was Skate (all) 0.138 70 0.093 0.036 associated with a higher risk of any Smelt 0.025 175 0.086 0.019 food allergy before age 2 (adjusted Snapper (all) 0.230 1244 0.514 0.104 Snapper, gray 0.233 699 0.595 0.068 OR, 1.62; 95% CI: 1.11 to 2.37) Snapper, red 0.243 279 0.725 0.168 compared with intake less than once Sole 0.086 1101 0.310 0.056 per month while controlling for fish Squid 0.044 728 0.130 0.024 intake. Leermakers et al19 similarly fi Sword sh 0.893 1726 2.052 0.296 found that 1 to 13 g of shellfish Tilapia 0.019 129 0.097 0.027 Tilefish (all) 0.883 109 2.962 0.695 consumption per week, on average, Tilefish, Atlantic 0.171 47 0.195 0.049 during the first trimester of Tilefish, Gulf of Mexico 1.445 61 0.324 0.059 pregnancy marginally increased risk of childhood wheezing and eczema

Downloaded from www.aappublications.org/news by guest on September 24, 2021 334 FROM THE AMERICAN ACADEMY OF PEDIATRICS TABLE 3 Continued reported. Although generally thought Seafood Item Grand to be benign, fish oil supplements Mean Hg Samples SDw SEw may carry certain risks, such as elevated low-density lipoprotein (ppm) a (Total) b (LDL) cholesterol.23 Among possible Trout (freshwater, wild and unknown status) 0.344 2804 1.030 0.087 side effects, weight gain has most Trout, lake 0.349 2748 1.268 0.080 fi Trout (freshwater, farmed) 0.029 178 0.066 0.015 often not been a consequence of sh Tuna (fresh/frozen, all) 0.450 3780 1.619 0.340 oil supplementation, although some Tuna, albacore 0.317 296 0.475 0.103 longitudinal studies, especially of Tuna, Atlantic bonito 0.499 263 2.200 0.359 children born prematurely, have Tuna, bigeye 0.582 376 1.113 0.222 documented greater weight in those Tuna, blackfin 0.856 159 0.972 0.231 Tuna, bluefin (farmed) 0.455 108 0.540 0.156 receiving supplements (for example, 24 Tuna, bluefin (wild) 0.796 514 2.408 0.542 Kennedy et al ). Tuna, skipjack 0.198 341 0.320 0.083 Tuna, yellowfin 0.270 1183 0.797 0.125 A Cochrane systematic review Tuna, albacore (canned) 0.328 1362 0.955 0.113 analyzed data from 8 randomized Tuna, light (canned or packed) 0.118 972 0.300 0.038 controlled trials of pre- and postnatal Tuna, yellowfin (canned) 0.143 298 0.688 0.098 fish oil supplementation for effects on fi Weak sh/seatrout (all) 0.361 2105 1.348 0.193 childhood allergy. These studies Whitefish (all) 0.106 2721 0.707 0.051 Whiting 0.040 27 0.056 0.015 evaluated food allergy, eczema, allergic rhinitis, and/or asthma (or Adapted from Karimi R, Fitzgerald TP, Fisher NS. A quantitative synthesis of mercury in commercial seafood and implications for exposure in the United States. Environ Health Perspect. 2012;120(11):1512–1519. NA, not applicable; SEw, wheeze). The metanalysis conducted weighted SE; SDw, weighted SD. found that among children born to women who consumed fish oil supplements, immunoglobulin E (OR, 1.20; 95% CI: 1.04 to 1.40; OR, Randomized trials in which children (IgE)-mediated food allergy was less 1.18; 95% CI: 1.01 to 1.37, are assigned to fish consumption or likely in children younger than 1 year respectively) after controlling for fish placebo are implausible, but such (relative risk [RR] 0.13; 95% CI: 0.02 intake. trials can be completed with n-3 to 0.95), and any IgE-mediated LCPUFAs delivered via fish oil Regarding the timing of introduction allergy was less likely in children 12 supplements. Such studies can help of fish and the risks related to atopic to 36 months of age (RR 0.66; 95% determine if n-3 LCPUFAs may disease, a 2008 American Academy of CI: 0.44 to 0.98). No benefit was account for allergy prevention as well Pediatrics clinical report revised observed for eczema, allergic rhinitis, as other health outcomes that may be previous guidance, which had or asthma between birth and 3 years associated with fish consumption. recommended delaying consumption of age. Findings did not differ based until 3 years for infants and children on maternal history of asthma or The results of all fish oil trials carry with a strong family history of allergic prenatal or postnatal caveats. First, although the studies disease.20 The 2008 guidance states supplementation of the mother.25 cited here used fish oil supplements that the evidence is not adequate to in which the contents were Since that review, 2 randomized trials delay introduction of foods beyond 4 standardized (although substantially have been published. The first is to 6 months.21 More research is different doses of EPA and DHA were a follow-up to one of the trials needed to clarify the effects of earlier used across studies), no assurance included in the Cochrane review. The introduction of fish and shellfish, exists that over-the-counter original study began in 199026 and particularly to at-risk infants. supplements sold in the United States randomly assigned 533 women to contain fatty acids in the amounts and consume a fish oil supplement, olive STUDIES OF N-3 LCPUFA types specified on the labels. Second, oil, or no oil capsules after 30 weeks’ SUPPLEMENTATION studies tend to use high doses of n-3 gestation. At 24 years’ follow-up, LCPUFAs, which may not be well adults born to mothers who received Prevention of Allergic Disease tolerated by children. A recent review supplementation were less likely to Results of observational studies, such of 75 fish oil supplement studies in need medications for asthma as as those cited previously, have children found dropout rates of 17% compared with individuals born to suggested that fish consumption in and adherence rates of 85%, although mothers who received olive oil early childhood may protect against most studies lacked adequate data on supplements (hazard ratio, 0.54; 95% allergic disease, but they are subject measures of compliance.22 Last, CI: 0.32 to 0.90).27 A second to unmeasured confounding. adverse events are not routinely randomized trial of n-3 LCPUFA

Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 143, number 6, June 2019 335 supplementation among more than children in this study largely received of CYP4F3 and FADS2 genes, which 700 women in the third trimester the same diet, air to breathe, and are both involved in the metabolism of pregnancy found that other potential exposures because of polyunsaturated fatty acids.35 supplementation reduced symptoms they shared the same environment. Metanalyses have not found clinical of asthma at 3 years of age (hazard They were also monitored by nurses benefitoffish oil supplementation for ratio, 0.69; 95% CI: 0.49 to 0.97) and and physicians in the hospital who ulcerative colitis, either for induction especially among children born to assessed them with standardized 32 therapy or maintenance of women who had the lowest serum n- outcome measures. – remission,36 38 although the data in 3 LCPUFA levels at study entry.28 these analyses come exclusively from Inflammatory Bowel Disease If a protective effect against asthma adult studies. and allergy of n-3 LCPUFAs or of fish The anti-inflammatory properties of consumption exists, an outstanding n-3 LCPUFAs have prompted research Neurologic and Cognitive question is when the optimal time of on whether they may ameliorate or Development introduction may be. Studies suggest prevent inflammatory diseases, LCPUFAs, especially DHA, are that introduction before 9 months of including Crohn disease and essential structural components of age may be preferable to postponing ulcerative colitis. A recent Cochrane the brain and eye. Animal studies until 1 year.12,14,29 review evaluated 6 studies on the use have shown that severe deprivation of fish oil supplements to maintain can result in blindness and impaired Treatment of Allergic Disease remission in Crohn disease. When all cognitive development.39 Only 1 The potential of fish and fish oil to studies were considered, a benefit study has directly assessed the value prevent allergic disease raises the was observed of n-3 LCPUFA therapy of childhood consumption of fish or question as to whether they may be for maintenance of remission at shellfish consumption in childhood effective treatments for allergic 12 months (RR, 0.77; 95% CI: 0.61 to for neurodevelopment. In that study, disease. Few studies have 0.98). However, these 6 studies had 232 Norwegian kindergarteners were 2 investigated these questions. Hodge heterogenous results (I = 0.58), randomly assigned to consume fatty et al30 found that among a group of leading the reviewers to perform an fish (herring or mackerel) or meat 39 children 8 to 12 years of age, analysis of the 2 most robust studies (chicken, lamb, and/or beef) 3 times supplementation with n-3 LCPUFA that had less potential bias. With just a week for 16 weeks. When did not affect lung function, day or these 2 studies, the point estimate of controlling for the amount of fish or night symptoms, peak flow rates, or the RR remained below 1, but the meat the children otherwise ate, 33 medication use at 3 or 6 months after 95% CI crossed the null. Of note, in children randomly assigned to the start of the intervention. Similarly, the studies reviewed, only 1 was consume fish scored higher on the no effect on allergic outcomes conducted with children. In this Wechsler Preschool and Primary including sensitization, eczema, study, 38 children were randomly Scale of Intelligence, third edition asthma, or food allergy was found in assigned to receive acetylsalicylic acid (WPPSI-III) (fish 20.4; 95% CI: 17.5 a randomized study of 420 infants along with n-3 LCPUFAs or to 23.3, vs meat 15.2; 95% CI: 12.4 to born to Australian women with acetylsalicylic acid with an olive oil 18.0; P = .0060).40 A separate history of atopy.31 In this study, supplement every day for a year. randomized study evaluated the infants received daily supplements Children receiving n-3 LCPUFAs had effect of fish consumption on from birth to 6 months and dropout lower relapse rates at 1 year (61 vs attention and processing speed 34 rates were substantially higher in the 95%). among adolescents but the study had fish oil supplement arm as compared poor compliance.41 No trials have Costea et al35 recently published an with the placebo arm of the study evaluated longer-term effects of observational analysis of 182 children (28.4% vs 16.8%). childhood fish intake. with Crohn disease in which they In a study of 29 Japanese children assessed whether dietary intake of n- Some observational studies suggest with prolonged hospitalization for 3 and omega-6 (n-6) fatty acids may that maternal prenatal consumption severe asthma, fish oil interact with variants of genes that of fish may benefit supplementation over 10 months regulate fatty acid metabolism to neurodevelopment. Hibbeln et al,42 reduced sensitivity to acetylcholine affect susceptibility to Crohn disease. for example, investigated a cohort of and induced bronchospasm as well as They found that children who 11 875 women who had seafood asthmatic symptoms based on consumed a higher dietary ratio of n- consumption assessed at 32 weeks’ a standardized asthma severity scale. 6/n-3 fatty acids were more gestation. After controlling for Despite the small size of this study, it susceptible to Crohn disease if they confounders, including prenatal had several unique strengths. The were also carriers of specific variants smoking and psychosocial stressors

Downloaded from www.aappublications.org/news by guest on September 24, 2021 336 FROM THE AMERICAN ACADEMY OF PEDIATRICS via a family adversity index,* these during childhood might attenuate the of words as assessed by the Hopkins investigators found that seafood influence of these prenatal Verbal Learning Test (estimated effect intake during pregnancy of less than exposures.46 size, 0.80; 95% CI: 0.15 to 1.45; and 340 g per week was associated with estimated effect size, 1.10; 95% CI: Several other studies have higher risk of children being in the 0.30 to 1.91, respectively). They also investigated the effects of n-3 lowest quartile for verbal IQ (no performed better on the spelling LCPUFA supplementation on seafood consumption compared with portion of the Hopkins Verbal neurodevelopment and cognitive mothers who consumed more than Learning Test (estimated effect size, skills and whether they may be of use 57 340 g per week: OR, 1.48; 95% CI: – 2.81 points; 95% CI: 0.59 to 5.02). to improve academic performance.47 53 1.16 to 1.90; 1–340 g seafood This study contrasts with findings Results of such research are mixed consumption per week compared from a randomized trial of 183 and have been summarized by Joffre with no seafood consumption: OR, children from Jakarta, Indonesia, and et al.54 1.09; 95% CI: 0.92 to 1.29, Adelaide, South Australia, which a nonsignificant result, but for the A study of 154 Arctic Quebecois Inuit found no effect of DHA and EPA overall trend in consumption, children 10 to 13 years of age found supplementation on similar P = .004). Low maternal seafood that those with higher cord blood n-3 outcomes.58 Such opposing results intake was also associated with LCPUFA concentrations had shorter may reflect the baseline levels of DHA increased risk of worse outcomes for FN400 latency and larger late positive and EPA in the population studied, prosocial behavior, fine motor, component amplitude,† findings that with greater benefit to those with communication, and social suggest these children had more lower levels at baseline. development scores.42 robust memory responses to Richardson et al59 have found in stimuli.55 In addition, Oken et al43 found among a randomized trial that a cohort of 25 446 Danish children A randomized controlled crossover supplementation with n-3 LCPUFA that higher maternal prenatal fish trial of 409 Aboriginal Australian (derived from algae) improved intake and greater duration of children aged 6 to 12 years found that reading skills in a cohort of 74 fi breastfeeding were each sh oil supplement administered over healthy children 7 to 9 years of age independently associated with 40 weeks resulted in more advanced from the United Kingdom through improved development in multiple drawings in the Draw-A-Person test supplementation with n-3 LCPUFA domains at 18 months after (a global measure of cognitive (derived from algae) whose baseline controlling for socioeconomic status, maturity and intellectual ability) reading performance was in the smoking, maternal depression, and compared with administration of lowest quintile. a placebo containing palm oil and other relevant covariates. In a notable study that did not show a trace of fish oil to provide odor and a benefit of supplementation, taste consistent with the In the US-based Project Viva cohort, Makrides et al60 conducted a double- 44,45 experimental treatment.56 Oken et al have found that blind, multicenter, randomized fi maternal prenatal sh consumption Another study evaluated 183 second- controlled trial of 2399 Australian above 2 weekly servings was grade children from Northern Cape women to determine if increasing associated with better cognition Province of South Africa randomly DHA during the last half of pregnancy during infancy and early childhood. assigned to consume fish flour-based affects maternal depression or the The best cognitive test scores were spread or placebo made from neurodevelopment of their children. seen among children of mothers who pulverized rusk (twice-baked bread) Mothers received fish oil capsules fi ate more sh but had lower mercury over 6 months. Dropout rates were providing 800 mg/day of DHA or levels. More recently, they followed similar (about 10%) in both groups. matched vegetable oil placebo the same cohort to midchildhood In an intention-to-treat analysis, those without DHA from study entry to – (6 10 years) and saw no evidence of children who consumed the fish flour birth. Children were assessed at fi fi either bene t from prenatal sh spread containing DHA and EPA had 18 months by using the Bayley Scales intake or harm from prenatal better recognition and discrimination of Infant and Toddler Development. mercury exposure, suggesting Maternal supplementation neither perhaps that intervening factors † The FN400 latency refers to a finding on EEG improved depressive symptoms nor associated with the brain’s response to an early childhood language or cognitive * The index is a 38-point battery of questions that external stimulus. A shorter latency implies faster development.60 Follow-up of this cover a broad array of psychosocial variables processing of stimuli input. The late positive including housing security, exposure to crime and component on EEG assesses explicit recognition cohort at 7 years of age likewise violence, substance abuse, maternal mental memory with larger amplitude associated with found no effect of supplementation in health, and income. better memory retrieval. infancy.61,62

Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 143, number 6, June 2019 337 Behavioral and Mental Health resulted in an improvement in symptoms have had mixed results,78, 6 79 Ample evidence from animal studies working memory (pretrial, 97.51 as have trials in which n-3 fi 10.04; posttrial, 101.78 6 11.47; F = LCPUFAs were used in treatment of makes clear that extreme de ciencies 77,80 in n-3 LCPUFA during gestation or 5.54; P = .019) and digit span depression in children. 6 early life can profoundly and (pretrial, 12.46 2.42; posttrial, 6 Sickle Cell Disease adversely affect the developing brain, 14.11 2.78; F = 9.73; P = .003) compared with placebo, as assessed LCPUFAs have been shown to and several observational studies in 69 children have identified low levels of by the HAWIK-IV scale. improve the membrane flexibility of n-3 PUFAs to be associated with Several other more recent studies, red blood cells in animals and 81,82 cognitive and/or behavioral including randomized trials, have humans, prompting interest in – problems.63 65 Despite these findings, produced conflicting results, making whether they may be of benefitto studies of whether n-3 LCPUFA may firm conclusions about the efficacy of patients with sickle cell disease. Two be of value in the management or supplementation for management of studies have examined the potential treatment of a variety of conditions, ADHD difficult.70–72 of n-3 LCPUFAs to ameliorate including attention-deficit/ symptoms of sickle cell disease. hyperactivity disorder (ADHD), Depression Tomer et al83 conducted 66 Tourette disorder, or depression, n-3 LCPUFAs have been studied in the a randomized controlled trial in 2001, have found supplementation to be, at prevention and treatment of showing that supplementation best, of limited value. depression in both adults and reduced the number of pain crises children. The rationale behind n-3 from 7.8 to 3.1 per year in a small ADHD LCPUFAs use is that their anti- sample of sickle cell patients. A larger In 2011, Bloch and Qawasmi67 inflammatory effects, their study of 128 Sudanese children and conducted a meta-analysis to importance to neuroplasticity and adults ranging from 2 to 24 years estimate the potential effect of n-3 neurogenesis, and their ability to found that n-3 LCPUFA LCPUFA supplementation on ADHD affect serotonin and dopamine supplementation more than halved , symptoms. They included 10 trials signaling in the brain, which might pain episodes (4.6 to 2.7 per year, P involving 699 children and identified influence mood.73 A recent meta- .01) and decreased hospitalization for a small effect of n-3 LCPUFA analysis by Grosso et al74 of 11 pain crisis from a median of 1 to 0 per , supplementation for ADHD randomized controlled trials enrolling year (P .0001). Severe anemia was (standardized mean difference [SMD], mostly adult patients with major reduced from 16.4% to 3.2% per year 0.31; 95% CI: 0.16 to 0.47), with depression or depressive symptoms and transfusion from 16.4% to 4.5% 84 higher doses of EPA yielding greater showed that DHA and EPA per year. improvement in ADHD symptoms supplementation resulted in a pooled Lipids (b = .36; 95% CI: 0.01 to 0.72; t = (DHA and EPA) SMD of 0.38 (95% CI: 2.30; P = .04, R2 = 0.37). These 0.18 to 0.59), which suggests A substantial body of research in benefits were modest in comparison a beneficial effect of n-3 fatty acids on adults has evaluated the potential of with those observed with standard depressed mood compared with n-3 LCPUFA supplementation to pharmacotherapy. However, a 2012 placebo. Other meta-analyses have affect lipid profiles and has generally Cochrane review that evaluated 13 not found a beneficial effect and found modest effects of n-3 LCPUFA trials with more than 1000 suggest that positive results are consumption on lipid profiles, participants found no benefit of n-3 attributable to publication bias and especially on triglycerides. A LCPUFA supplementation on ADHD methodologic shortcomings.75 Grosso 2006 meta-analysis by Balk et al85 symptoms in children.68 Bloch and et al74 suggest that such findings may including 21 randomized controlled Qawasmi’s67 meta-analysis and the relate to heterogeneity in symptoms trials of fish oil found that Cochrane review evaluated much of and/or diagnoses in research subjects triglycerides decreased 27 mg/dL the same evidence. and formulations of fatty acid (95% CI: 20 to 33), high-density supplements, which they assert were lipoprotein increased 1.6 mg/dL In a 2014 double-blind randomized better addressed in their study. (95% CI: 0.8 to 2.3), and LDL controlled trial of 95 children with increased 6 mg/dL (95% CI: 3 to 8) in ADHD diagnoses based on Diagnostic Cross-sectional pediatric studies have those who received fish oil versus and Statistical Manual of Mental demonstrated lower erythrocyte DHA controls. Disorders, Fourth Edition criteria, levels in patients with major participants were assigned to n-3 depression.76,77 Trials that have Research on children has been much LCPUFA supplementation or placebo explored whether fish consumption more limited. A study involving 201 over 16 weeks. Supplementation was associated with depressive fifth- and sixth-graders with obesity

Downloaded from www.aappublications.org/news by guest on September 24, 2021 338 FROM THE AMERICAN ACADEMY OF PEDIATRICS from Campeche, Mexico, assigned n-3 LCPUFA supplementation results supplement through 9 months participants to metformin or n-3 in modest decreases in systolic and postterm.24 The difference between LCPUFA supplement (360 mg of EPA diastolic blood pressure. A boys and girls became insignificant, and 240 mg of DHA) 3 times a day for 2014 meta-analysis of 70 randomized however, after controlling for current 12 weeks. Those receiving the fish oil controlled trials found that when weight, which suggests that the supplement had increases in high- compared with placebo, EPA and DHA observed blood pressure difference density lipoprotein (2.12 mg/dL; supplementation reduced systolic may be mediated through weight. Of 95% CI: 0.61 to 3.63) and decreases blood pressure (–1.52 mm Hg; 95% note, in the Asserhøj et al94 study, in triglycerides (–26.35 mg/dL; 95% CI: –2.25 to –0.79) and diastolic blood children receiving fish oil CI: –40.78 to –11.91). No change in pressure (–0.99 mm Hg; 95% CI: supplements had higher BMI at 2.5 LDL or total cholesterol was –1.54 to –0.44).90 This is consistent years, but the higher BMI did not observed.86 Another randomized with another previous meta-analysis persist at 7 years. placebo controlled trial of 4 g of n-3 of 36 double-blinded randomized A multicenter European study, in fi LCPUFA daily in 29 adolescents with trials of sh oil and blood pressure in which 147 children born between 37 fi hypertriglyceridemia, although which high levels of sh oil and 42 weeks’ gestation with birth underpowered, showed decreases in consumption (3.7 g/day) lowered weight between 2500 and 4000 g triglyceride levels that were not systolic blood pressure by 1.7 mm Hg were randomly assigned to receive fi – signi cantly different from placebo (95% CI: 0.3 3.1) and diastolic blood formula supplemented with n-3 and – 6 (experimental group, 54 27 pressure by 1.5 mm Hg (95% CI: n-6 LCPUFAs (DHA, EPA, and – 6 87 – 91 mg/dL; placebo, 34 26 mg/dL). 0.6 2.3). Given the size of blood a-linoleic acid, all sourced from egg A recent randomized, double-blind, pressure change, these effects are yolks) or placebo through age fi crossover trial comparing 4 g of sh unlikely to be clinically relevant. 4 months yielded contrary results. At oil daily for 8 weeks with placebo by age 6 years, supplemented infants 88 Effects of n-3 LCPUFA in childhood on Gidding et al similarly found that in had lower mean blood pressure blood pressure have been less well a group of 42 adolescents with (mean difference, 23.0 mm Hg; 95% studied and results have not been elevated LDL and triglycerides, those CI: 25.4 to 20.5 mm Hg) and consistent, although several have who received supplementation had diastolic blood pressure (mean suggested that supplementation may lower triglycerides than those who difference, 23.6 mm Hg; 95% CI: elevate blood pressure, especially for received placebo, but the difference 26.5 to 20.6 mm Hg) than the fi – 6 boys. This evidence comes from was not signi cant ( 52 16 vs control group.95 These results, and – 6 observational studies92 as well as 16 16 mg/dL). No difference was those from the Asserhøj et al94 study, 88 randomized trials93 of fish oil found in LDL levels. Given these which compared n-3 with n-6 supplementation to infants. The results, changes in lipids are likely to LCPUFA supplementation, raise the studies have revealed elevations in be at best modest and may require question as to whether n-6 LCPUFAs blood pressure. Asserhøj et al94 large (eg, 1000 mg or more) doses of may be responsible for a greater recruited 122 Danish mothers and n-3 LCPUFAs. effect than n-3 LCPUFAs on blood randomly assigned their offspring to pressure in children. Although this Effects of n-3 LCPUFAs for children receive fish oil or olive oil during the specific question has not been with nonalcoholic fatty liver disease first 4 months of lactation. In addressed by other well-designed have also been studied. In a follow-up of 98 children at 7 years, studies, Rytter et al96 followed 180 a randomized trial of 40 children with boys who received fish oil had children born to mothers randomly biopsy-proven nonalcoholic liver unexpectedly higher diastolic and assigned to receive fish oil or olive oil disease, children who received the mean arterial blood pressure (6 supplements in the last trimester of supplement had improvements in mm Hg) than those who received pregnancy at 19 years of age and liver steatosis, improved insulin olive oil. No difference was found found no effect on blood pressure sensitivity, and, consistent with some among girls.94 Higher diastolic blood from prenatal supplementation. of the studies presented above, lower ∼ 89 pressure ( 3 mm Hg) was observed triglycerides. at 10 years of age in girls, but not boys, from a group of children born at POTENTIAL HARMS OF EATING FISH AND Blood Pressure less than 35 weeks’ gestation and SHELLFISH Dozens of randomized controlled with birth weight ,2000 g who were Methylmercury (MeHg) pollution is trials have evaluated fish oil randomly assigned to receive a primary reason for parents to avoid supplementation effects on blood a formula supplemented with n-3 feeding their children some fish and pressure in middle-aged adults and LCPUFA (from tuna oil) and g linoleic for expectant mothers to avoid found that high-dose (eg, $3 g/day) acid or a formula without fatty acid consumption of some fish during

Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 143, number 6, June 2019 339 pregnancy. Available evidence Seychelles and New Zealand studies data from 1990 to 2000 found that indicates that prenatal and, to a lesser did not control for fish consumption, each year more than 300 000 children extent in most cases, postnatal so any benefit of n-3 LCPUFAs on are born in the United States with in mercury exposure has been neurodevelopment may have masked utero exposure to MeHg at levels that associated with decrements in harmful mercury effects.103 This was may cause neurologic harm. The same memory, attention, language, IQ, and demonstrated in the Faroe Islands analysis using data from the visual-motor skills in childhood.97–99 cohort, which had 2000–2010 NHANES found that only Mercury exposure during pregnancy neurodevelopmental outcomes 75 000 children might have been may promote preterm delivery as assessed while controlling for exposed in utero to mercury at levels well.100 Several reviews present the maternal fish consumption and found above the RfD.105 Of note, neither of consequences of mercury exposure in that beneficial effects of fish these analyses accounted for utero.97 consumption concealed the observed trends in maternal blood deleterious effects of MeHg.103 These mercury with increasing age, with Mercury bioaccumulates in marine analyses of the Faroe Island data also older women having higher blood and freshwater food chains. Most of confirmed the beneficial association mercury concentrations.107 In the mercury found in humans comes of fish consumption with child subsequent NHANES research, from contaminated fish. Elemental neurocognitive outcomes. researchers have also identified that mercury enters the environment women living on the Atlantic and primarily through coal combustion Largely based on findings from the Pacific coasts, and to a lesser extent and artisanal and small-scale gold Faroe Islands study, the US Gulf coast, are likely to have higher mining as well as natural emissions, Environmental Protection Agency’s blood mercury concentrations (see for example, from volcanoes. Bacteria reference dose (RfD) for MeHg is 0.1 Fig 1).108 convert elemental to organic (methyl) µg/kg of body weight per day.104 The mercury, a form that is readily RfD for mercury is an estimated daily Beyond this, little research is absorbed after ingestion. Given the intake likely to be without available to inform specific increased use of coal for energy in appreciable risk of harm over recommendations for fish recent decades, especially in Asia, a lifetime, even for the most sensitive consumption in young children to mercury levels in the world’s oceans populations, and employs an prevent harms from mercury have increased and are expected to uncertainty factor of 10 based on exposure. increase substantially, with a possible variability in concentrations of cord doubling by 2050 from 1995 blood and maternal blood and for Persistent Organic Pollutants 101 levels. differences in how MeHg may be Aside from mercury, several other metabolized in different people. The fi The US Food and Drug pollutants commonly found in sh MeHg RfD was calculated with the fi Administration (FDA) and and shell sh have raised concern for intent of preventing fetal neurologic Environmental Protection Agency their detrimental health effects. These harm from maternal consumption. have provided fish consumption include a large group of chemicals The RfD assumes that the fetal brain guidance in the United States aimed known as persistent organic is the organ most sensitive to the at preventing harmful exposure to pollutants (POPs). POPs are organic effects of MeHg, and thus the RfD mercury that is intended for the compounds that resist breakdown should protect everyone, including average American consumer and not and are lipid soluble. These children, from harm. As a result, no necessarily for populations that may properties make it possible for long- governmental guidance for MeHg in have higher consumption of range transport of POPs after they are other populations, including children freshwater fish.102 These released into the environment and and nonpregnant adults, has recommendations are based on also enable them to bioaccumulate been given. cohort studies in the Faroe Islands, within animals and humans and Seychelles Islands, and New Zealand On the basis of representative data biomagnify within food chains. As in which health consequences from from the NHANES, the number of a result, some of the animals with the prenatal mercury exposure have been women in the United States with highest POP burdens live in the Arctic examined, although the diets of these MeHg blood levels reflecting intake circle (for example, polar bears, populations do not represent the above the RfD has decreased which are at the apex of the marine typical American diet. The Faroese, considerably since 1990, and, as food chain). for instance, consume large amounts a result, the number of potentially of whale blubber, and the Seychellois adversely affected children has Polychlorinated Biphenyls eat 12 meals with fish per week. In decreased as well.105 An analysis by Polychlorinated biphenyls (PCBs) are addition, the primary analysis in the Mahaffey et al106 based on NHANES POPs that comprise a group of

Downloaded from www.aappublications.org/news by guest on September 24, 2021 340 FROM THE AMERICAN ACADEMY OF PEDIATRICS a per-weight basis, butter and processed meats may have as much PCBs as fish, if not more.136

Of note, several studies have investigated concentrations of PCBs in fish oil supplements, and 1 recent study examined pediatric supplements in particular. Ashley et al137 analyzed PCBs in 13 over-the- counter children’s fish oil supplements. Every supplement analyzed contained PCBs, with a mean concentration of 9 6 8ng PCBs/g, resulting in a mean daily exposure of 2.5 to 50.3 ng PCBs/day depending on suggested serving size. The trophic level of the fish species or FIGURE 1 purification method used to produce Map of whole blood mercury concentration (geometric mean and 95% CI [mg/L]) in women of childbearing ages by coastal or inland regions for NHANES 1999–2010. (Reprinted with permission the supplement did not predict the from Cusack L, Smit E, Kile ML, Harding AK. Regional and temporal trends in blood mercury amount of PCB it contained, although concentrations and fish consumption in women of child bearing age in the United States using the sample sizes were limited.137 The NHANES data from 1999 to 2010. Environ Health. 2017;16(1):10.) Environmental Protection Agency has established RfDs for several PCB mixtures, including Aroclor 1016 at chemicals that have a biphenyl impairments in gonadal and pubertal 0.00007 mg/kg of body weight per structure with between 1 and 10 development.130,131 Studies on the day. Based on the supplements in the chlorine atoms. Roughly 130 different effects of PCB blood levels on Ashley et al137 study, several of them, PCB molecules, known as congeners, growth have yielded conflicting if taken as directed, would result in have been used commercially, and results.110,132,133 exposures that exceed this RfD. Also, most commercial preparations given the wide range of PCB and n-3 contained mixtures of these Because of health concerns, PCBs LCPUFA content in the samples, they congeners. They most often can be were banned in the United States in might provide more or less PCB/g n-3 found near industrial sites where 1977. However, they have persisted in LCPUFA than wild-caught salmon, they were produced or disposed of the environment, contaminating a fish that usually has high n-3 and can contaminate fish in the water, soil, and air and have made fi LCPUFA and low PCB content.137 surrounding rivers and harbors. their way into sh and, as a result, humans, albeit at declining levels Studies over several decades have 134 found that PCBs can adversely affect with the passage of time. Dioxins the developing fetus and young Fish concentrations of PCBs vary A dioxin is a member of a class of children. In utero PCB exposure has widely. They tend to be highest in organochlorine chemicals that been associated with lower birth fi originate from, among other sources, 109–113 freshwater sh at the top of their weight, acute lymphoblastic local ecosystem’s food chain. The waste incineration, paper bleaching, leukemia and non-Hodgkin’s pesticide production, metal smelting, 114–116 117,118 Environmental Protection Agency lymphoma, obesity, maintains a Web site that provides and production of polyvinyl chloride immune system dysfunction and fi plastics. Dioxins are highly toxic POPs 119–121 122 information on local sh advisories impairment, asthma, motor across the United States that can known to cause reproductive and fi and cognitive developmental de cits identify local water bodies and developmental problems, damage to as assessed on the Bayley Scale and the immune system, and cancer.138 123–127 species with potentially high levels of other instruments, and fi Dioxin levels in the US population 128,129 PCBs (http:// shadvisoryonline.epa. lowered IQ. Research on gov/General.aspx). have declined substantially in recent postnatal exposure is limited. years because of regulations and are Exposure through breastfeeding may Although fish can be a significant expected to continue to fall. both increase and decrease IgE- source of dietary PCBs, most Compared with other pollutants, mediated allergy.119 Children with exposure for Americans is from red dioxins are rarely a cause for higher blood levels of PCBs may have meat and dairy consumption.135 On freshwater fish advisories from the

Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 143, number 6, June 2019 341 Environmental Protection Agency.139 much as 0.57 µg/kg (.5 times RfD) can be found in certain water bodies, In 2010, for example, only 2 of 533 depending on the size, source, and particularly POPs and MeHg. The fish consumption advisories were trophic level of the particular fish Environmental Protection Agency made on the basis of dioxins (not included in the can.143 maintains a database of local fish including dioxin-like PCBs) in the advisories (see Resources) that Increasingly, guidance is available United States. These advisories were provide guidance on when toxicants that provides information on for the Hudson River of New York and may be present in lakes and rivers nutrients, toxicants, and Trinity River of Texas.139 Dioxins are around the nation. Most states have sustainability by fish species. See present in fish and can be at high similar databases available on the Resources for examples. concentrations in freshwater fish; Internet as well. however, the levels are often lower Fish and Shellfish Poisoning For some children, freshwater fish than in beef, butter, and cheese.136 Fish and shellfish, and in particular may be a large part of their diets; therefore, fish consumption may Toxicant Avoidance bivalve shellfish, such as oysters, clams, scallops, and mussels, can carry heightened risk. Some American In general, PCBs and other POPs, become contaminated with toxins Indian children, for instance, have because they are fat soluble, are produced by algae. If these toxins are been found to have high exposure to found at higher concentrations in ingested by humans, they can cause PCBs, other POPs, and mercury fi fi 147,148 fatty sh and are concentrated in several syndromes, some of which through eating freshwater sh. fatty tissue. Removing the fatty skin may be life-threatening, including and broiling or baking rather than amnesic shellfish poisoning, diarrheal SUSHI fi 140,141 frying sh may decrease exposure. shellfish poisoning, neurotoxic Sushi has become an increasingly MeHg, in contrast, tends to be shellfish poisoning, paralytic shellfish popular part of the American diet, stored in protein rather than in fat poisoning, and ciguatera fish including for children. Raw fish and and is distributed throughout the poisoning. Because all of these toxins fl fi shellfish in sushi carry increased risk esh of the sh. Thus, removing the are heat stable, cooking does not for transmitting foodborne illnesses. skin or fatty tissue does not reduce prevent intoxication. In recent On the basis of data reported to the mercury exposure. For both POPs and decades, coastal harmful algal blooms Centers for Disease Control and mercury, the trophic level of the that contained the toxins that cause Prevention, sushi accounted for 0.3% species on the food web is a major these syndromes occurred of all foodborne illnesses in the determinant of pollution burdens nationwide more than 60 times fi fi United States between 1998 and aside from where the sh or shell sh annually. Although shellfish poisoning 2015 (see https://wwwn.cdc.gov/ was raised or lived. syndromes were only rarely reported foodborneoutbreaks/). No evidence to the Centers for Disease Control and Mercury levels in fish are supports guidance on the right age to Prevention between 1990 and proportional to their age, size, and introduce raw fish and shellfish. In 2008,144 estimates of the true trophic level, as well as the amount of places where sushi consumption is incidence are likely 15 000 cases per mercury contamination in the water more common than in the United year or more in the United States for where the fish lived and ate. Although States, parents may introduce sushi ciguatera alone.145 Most ciguatera certain species have generally been containing raw fish as early as cases from fish harvested in US considered to have higher mercury children can eat solid foods or delay waters originate from fisheries in the concentrations in their flesh than until children enter elementary eastern Gulf of Mexico and around the others, variability in mercury levels school. even within the same species can be southern coast of Florida as well as marked.142 For example, the median Hawaii. Caribbean fisheries also may concentration of mercury in canned be affected. Recent research has A NUTRITIONAL COMPARISON light tuna is 0.128 ppm (µg/g), with suggested that climate change may Although some potential toxicants a range from 0 to 0.889 ppm; the increase the risk of ciguatera fish may be more likely to come from 146 concentration in canned albacore poisoning. consumption of certain forms of fish, tuna is 0.338 ppm, ranging from 0 to most fish, with some notable 0.853 ppm. A 25-kg child consuming Freshwater Fish and Vulnerable exceptions, have favorable nutritional 4 oz (113 g) of canned light tuna (a Populations and overall health qualities compared whole can is 5 oz) would, on average, Consuming freshwater fish captured with other forms of animal protein. In consume 0.08 µg of mercury/kg of from US waters carries unique risks the United States, red meat and body weight (approximately 80% of compared with seafood, given the chicken represent the majority of the RfD) but could get none or as high concentrations of pollutants that childhood animal protein

Downloaded from www.aappublications.org/news by guest on September 24, 2021 342 FROM THE AMERICAN ACADEMY OF PEDIATRICS consumption. On average, less than greater fish consumption among and almost all are farm raised.158,159 10% of children’s animal protein Americans. Such guidance, if realized, Shrimp farms in Southeast Asia and intake comes from fish.149 PCBs and may put further pressure on fish Central and South America have dioxins may be found in beef and stocks and promote unsustainable resulted in the loss of millions of other animal products in much higher aquaculture, although specific data to hectares of mangrove forest, and concentrations than in most fish, with describe the relationship are shrimp farms account for roughly the possible exception of farmed lacking.156 one-third of mangrove forest loss salmon or certain freshwater fish.136 worldwide.160 Mangrove forests serve AQUACULTURE many functions to coastal ecosystems, including providing breeding grounds SUSTAINABILITY fi fi A rapid increase in sh and shell sh for wild fish and shellfish. Mangrove Just under 60% of fisheries farming, or aquaculture, in forests also are vital contributors to worldwide are harvested at their industrialized and resource-limited the health of coral reefs and seagrass maximum sustainable yield, and 30% nations, and especially in China, has beds, both among the greatest are overexploited.150 Several recent occurred over the past 2 decades. repositories of marine biodiversity.161 and notable instances of complete Aquaculture now provides for at least Shrimp farms have also been the fi fi collapses of fisheries include the half of the sh and shell sh sources of severe nutrient and 157 Northwest Atlantic cod fishery off the consumed worldwide (see Fig 2). chemical pollution as crowded pens coast of New England and Canada. The Sustainability of Aquaculture generate tremendous amounts of The depletion of fish stocks has had waste and require chemical inputs, major consequences for the nutrition Aquaculture technology and practice such as antibiotics and disinfectants, of coastal populations, especially in has advanced considerably in recent that can harm people exposed to resource-limited nations, where the decades to make aquaculture a much these pollutants.162 In contrast to void left by declining fish stocks has more sustainable enterprise. shrimp farming, much of the other resulted in increased consumption of However, among the aquaculture farm-raised shellfish, such as mussels other animal proteins that may have products in need of improvement are and oysters, are some of the most less healthful profiles, including 2 that have particular importance to sustainably raised seafood available. bushmeat.151 the American diet. Shrimp are the most consumed seafood in the United Fishery practices also have States, with the average American Farmed Salmon implications for those who work in consuming approximately 4 lb per Salmon is the most widely consumed fi them. In the United States, shers and year; 94% of shrimp are imported, noncanned fish in the United States, those working at sea to catch fish have the second-highest on-the-job mortality rate.152 Research has also shown that children may be trafficked into labor in the fisheries workforce, with dire consequences. One study found that 19% of boys trafficked in the Mekong region of southeast Asia were forced to labor in fisheries. Many of these children were found to have witnessed or experienced violence and exposure to violence, and this was associated with increased risk for depression, anxiety, and posttraumatic stress disorder as well as suicidality.153 Shrimp, the most consumed seafood in the United States,154 comes predominantly from this region.155 FIGURE 2 Food and Agricultural Organization of the United Nations’ data on global wild and aquaculture fish Because of potential health benefits production. (Reprinted with permission from Food and Agricultural Organization of the United related to consuming fish and n-3 Nations. The State of World Fisheries and Aquaculture 2016. Contributing to Food Security and LCPUFAs, medical and government Nutrition for All. Rome, Italy; Food and Agricultural Organization of the United Nations; 2016:3.) organizations have encouraged

Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 143, number 6, June 2019 343 and over the past 35 years, the in best practices can be found from managed toward that direction even majority of salmon eaten has shifted a variety of sources (see Resources). if they have not achieved sustainable from wild to farm raised. An Many major retail outlets have harvests to date. The Magnusson influential 2004 study in Science embraced selling seafood that is Stevens Act (Pub Law No. 109–479 reported that farmed salmon had recommended by major ocean [2006]) serves as the foundation of levels of PCBs, dioxins, and other conservation groups.166 the US regulation of fisheries and has POPs severalfold higher than wild- established a framework to promote caught salmon.163 However, critics The Sustainability of Aquaculture the application of the best available have argued that the potential health Compared With Beef, Poultry, and science to fisheries management. As harms of consuming the PCBs in Pork a result, identifying the products of farm-raised salmon are more than Comparing the resource intensity of American fisheries may be the best offset by the health benefits of aquaculture to other animal protein first pass assessment of sustainability. 164 salmon’s nutritional profile. In sources, most farmed fish and Thorough sustainability assessments addition, among other concerns, seafood has a comparable, if not of fish and shellfish have been farmed salmon has been a source of favorable, profile. On a per-calorie conducted by several local pollution from chemical basis, beef is by far the most nongovernmental organizations for additives (eg, antibiotics) and resource-intensive animal protein: it many years. These initiatives are nutrient overload as well as disease takes about 10 times more irrigated summarized in the Resources section spread, given high animal density and water and 4 times more nitrogen of this report. escapes of nonnative salmon species fertilizer and produces about into local ecosystems. Salmon, as 10 times more greenhouse gas CONCLUSIONS carnivores, have also historically been emissions when compared with pork fed fishmeal when farmed, requiring or poultry.167 Many species of farmed Despite the favorable nutritional and, 1.5 to 3 lb of feed for every pound of seafood have a carbon footprint in many cases, sustainability profile of salmon. roughly equivalent to or less than fish and shellfish, children in the United States eat relatively little of Progress has been made in recent pork and poultry, although it can vary them as compared with other animal years to address problems associated greatly, especially with long-distance 168,169 protein sources, and seafood with salmon farming. Some transit. Shrimp eaten in consumption by children has declined operations now approximate 1:1 fish- America mostly comes from every year since 2007 to levels not in to fish-out ratios (ie, 1 lb of wild Southeast Asian nations (Indonesia, seen since the early 1980s.149,174 fish in salmon feed produces 1 lb of India, and Thailand, in particular) and Some evidence suggests that federal farmed salmon), scarcely use has a disproportionately large carbon mercury advisories on fish chemicals, and have greatly reduced footprint, in part because of transport consumption may have pushed disease spread and escapes through but largely because of mangrove people away from eating fish in better monitoring and lower-density forest loss. Shrimp sourced from general and canned tuna in farming.165 Experiments with these regions can have a carbon particular.175 Evidence-based expert vegetarian feeds and other fishmeal footprint an order of magnitude 170,171 guidance has largely advised that and oil substitutes have shown greater than beef. seafood should have a larger place in promise at further reducing reliance Fifty percent or more of salmon is farm the American diet. The recent on wild fish stocks for long-chain raised. Farmed salmon comes mostly Scientific Report of the 2015 Dietary omega-3 fatty acids. Experiments 172 from Canada, Chile, or Norway. Guidelines Advisory Committee, for with vegetarian feeds and Studies of farmed salmon from these instance, stated, “The Committee substituting a yeast for anchovies as countries have found farmed salmon to concurs with the Joint WHO/FAO a source of omega-3 fatty acids have have a carbon footprint of Consultancy that, for the majority of shown promise in further reducing approximately 2 kg carbon dioxide commercial wild and farmed species, reliance on wild fish stocks.118 (Note equivalent/1000 kcal salmon, which is neither the risks of mercury nor that the original source of all n-3 168,173 similartoporkorpoultry. organic pollutants outweigh the LCPUFAs in the oceans are health benefits of seafood phytoplankton). Sustainably Raised and Caught Fish consumption, such as decreased fi Most salmon farms do not yet meet and Shell sh cardiovascular disease risk and cutting-edge standards for production The United States has some of the improved infant neurodevelopment. that limit undesirable environmental best-managed fisheries (wild or However, any assessment evaluates and health impacts. Guidance on farmed) in the world, and although all evidence within a time frame and identifying those operations engaged are not sustainably harvested, all are contaminant composition can change

Downloaded from www.aappublications.org/news by guest on September 24, 2021 344 FROM THE AMERICAN ACADEMY OF PEDIATRICS rapidly based on the contamination health-care.pdf (sustainability, Ellen S. Rome, MD, MPH, FAAP conditions at the location of wild mercury) Sarah J. Schwarzenberg, MD, FAAP catch and altered production practices for farmed seafood.”176 LIAISONS LEAD AUTHORS fi fi Jeff Critch, MD – Canadian Paediatric Society Even if sh and shell sh have Aaron S. Bernstein, MD, MPH, FAAP Janet M. de Jesus, MS, RD – National a favorable nutritional profile Emily Oken, MD, MPH Institutes of Health Sarah de Ferranti, MD, MPH, FAAP compared with other forms of animal Andrea Lotze, MD, FAAP – Food and Drug protein, available research to Administration substantiate specific health benefits Cria G. Perrine, PhD – Centers for Disease COUNCIL ON ENVIRONMENTAL HEALTH, from fish and shellfish consumption Control and Prevention 2017–2018 – in children remains limited. Further Valery Soto, MS, RD, LD US Department of Jennifer Ann Lowry, MD, FAAP, Chairperson Agriculture research is needed to clarify the value Samantha Ahdoot, MD, FAAP of fish and shellfish consumption in Carl R. Baum, MD, FACMT, FAAP childhood to health. Aaron S. Bernstein, MD, FAAP STAFF Aparna Bole, MD, FAAP Debra L. Burrowes, MHA Lori G. Byron, MD, FAAP RESOURCES Philip J. Landrigan, MD, MSc, FAAP ACKNOWLEDGMENT Steven M. Marcus, MD, FAAP An Interactive Map of Freshwater Susan E. Pacheco, MD, FAAP The authors thank Barton Seaver for Fish Advisories in the United States Adam J. Spanier, MD, PhD, MPH, FAAP his review of the sustainability Alan D. Woolf, MD, MPH, FAAP sections of this report. https://fishadvisoryonline.epa.gov/ General.aspx (Note that results can be limited to active advisories. In some LIAISONS ABBREVIATIONS instances, the last update may be John M. Balbus, MD, MPH – National Institute .10 years ago. If this is the case, of Environmental Health Sciences ADHD: attention-deficit/ there is often a link to a state Nathaniel G. DeNicola, MD, MSc – American hyperactivity disorder database to look for newer Congress of Obstetricians and Gynecologists CI: confidence interval Ruth A. Etzel, MD, PhD, FAAP – US information.) DHA: docosahexaenoic acid Environmental Protection Agency Diane E. Hindman, MD, FAAP – Section on EPA: eicosapentaenoic acid Environmental Protection Agency FDA: US Food and Drug fi Pediatric Trainees Fish and Shell sh Advisories and Mary Ellen Mortensen, MD, MS – Centers for Administration Safe Eating Guidelines Disease Control and Prevention/National IgE: immunoglobulin E fi Center for Environmental Health https://www.epa.gov/choose- sh- – LCPUFA: long-chain fi fi Mary H. Ward, PhD National Cancer and-shell sh-wisely/ sh-and- Institute polyunsaturated shellfish-advisories-and-safe-eating- amino acid guidelines LDL: low-density lipoprotein STAFF MeHg: methylmercury Monterrey Bay Aquarium Seafood Paul Spire n-3: omega-3 Watch n-6: omega-6 Seafoodwatch.org COMMITTEE ON NUTRITION OR: odds ratio PCB: polychlorinated biphenyl Mercury in Seafood: A Guide for Steven A. Abrams, MD, FAAP POP: persistent organic pollutant Health Care Professionals George J. Fuchs, III, MD, FAAP Jae Hong Kim, MD, PhD, FAAP RfD: reference dose http://safinacenter.org/documents/ C. Wesley Lindsey, MD, FAAP RR: relative risk 2015/05/mercury-seafood-guide- Sheela Natesh Magge, MD, MSCE, FAAP

FINANCIAL DISCLOSURE: Dr Bernstein has received no funding for this project. Dr de Ferranti has received royalties for UpToDate articles on cholesterol and cardiovascular risk factors in childhood, the New England Congenital Cardiology Foundation, and the National Heart, Lung, and Blood Institute Pediatric Heart Network. Dr Oken has received funding from the National Institutes of Health (P30 ES00002, P30 DK040561, R01 ES016314, K24 HD069408 P30 DK092924, R01AI102960) and royalties for an UpToDate article on Fish Consumption During Pregnancy. Funded by the National Institutes of Health (NIH). FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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