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women exposed to famine during any stage of gestation were associated with the following:3 • Lower birth weights. • Glucose intolerance. • Increased incidence of obesity. • Coronary heart disease. • Increased stress responsiveness. • A more atherogenic lipid. • Disturbed blood coagulation profile. Exposure of the mother to famine in early gestation was associated with an increased risk of breast cancer in female offspring, while exposure in mid gestation was associated with more microalbuminuria and obstructive airways disease. Another study found prenatal exposure to famine was associated with double the incidence of schizophrenia.4 A follow-up study of grandchildren of women pregnant during the famine found they may have been smaller in stature than average.5 Therefore, these data suggest that nutrient insufficiency during pregnancy can possibly cause transgenerational epigenetic changes, ie, inherited changes in phenotype that don’t result from alterations in DNA. The ‘foetal origins’ hypothesis published by Dr David Barker based on perinatal nutritional research suggests inadequate nutrition in utero “programs” the foetus to have negative metabolic characteristics that can lead to future disease.6 Thirty years on, the role of epigenetics in human health is now well accepted. The foetus uses maternal nutritional input to prepare itself for the nutritional world it will be born into, and the mother’s nutritional status during pregnancy markedly impacts the foetus as it grows and develops.7 A ‘mismatch’ between human evolutional capacities and modern environments has been used as the basis to explain increases in certain physical and mental conditions.8 Risk of developing conditions such as allergies and immune, metabolic, psychiatric and neurodegenerative disorders can be explained as a ‘mismatch’ of environmental influences in the first 1000 days of life.9,10,11 The American Academy of Paediatrics acknowledges that foetal and infant growth and normal brain development requires more than just calorie intake.11 Its policy states: “Although all nutrients are necessary for brain growth, key nutrients that support neurodevelopment include protein; zinc; iron; choline; folate; iodine; vitamins A, D, B6 and B12; and long-chain polyunsaturated fatty acids. Failure to provide key nutrients during this critical period of brain development may result in lifelong deficits in brain function despite subsequent nutrient repletion. Understanding the complex interplay of micro- and macronutrients and neurodevelopment is key to moving beyond simply recommending a “good diet” to optimising nutrient delivery for the developing child.” Omega-3 fatty acids Omega-3 fatty acids (n-3 LCPUFA – long chain poly-unsaturated fatty acids) include: • Alpha-linolenic acid (ALA). • Eicosapentaenoic acid (EPA). • Docosapentaenoic acid (DPA). • Docosahexaenoic acid (DHA – the principal omega-3 found in mammalian tissues). ALA is considered an essential fatty acid, meaning it must be obtained from the diet, eg, from fatty fish, oils (flax seed), and smaller amounts found in poultry, meats and eggs. The liver can convert some of the ALA from the diet into EPA and then to DHA. However, the rate of conversion is estimated to be around 15 per cent. Consuming foods containing EPA and DHA is therefore the only practical way to reach the ideal levels of these fatty acids. The National Health and Medical Research Council (NHMRC) recommends daily adequate intake (AI) of omega-3 fatty acids during pregnancy of 110-115mg and breastfeeding of 140- 145mg.13 However, the median daily intake via diet alone for women in Australia is only 119mg.14 DHA and other PUFAs are important for the foetus in the following ways: • They are actively transported across the placenta. • They support the high demands for foetal growth. • High DHA concentration rapidly accumulates in the nervous system, particularly in the third trimester.15 • DHA is critical for neural tube closure at day 28 of gestation.16 While the NHMRC recommended daily AI for n-3 LCPUFA during pregnancy and lactation ranges from 110mg to 145mg respectively,13 the Society for the Study of Fatty Acids and Lipids (ISSFAL) recommends at least 200mg of DHA daily in these settings, with DHA constituting about 43 per cent of total n-3 LCPUFA. ISSFAL’s higher recommended intake is based on consensus from the European Commission Perinatal Lipid Intake Working Group and other key stakeholder organisations.17 ISSFAL suggests women of childbearing age can achieve the recommended DHA intake by consuming one to two portions of sea (oily) fish per week. Intakes of up to 1000mg DHA (n-3 LCPUFA 2.7g) don’t increase the occurrence of significant adverse effects in women of reproductive age. Fish oil supplementation during pregnancy has been extensively trialled, with contradictory results depending on the outcome of interest. A meta-analysis of 34 RCTs including 14,106 singleton and 2578 twin births didn’t show that n-3 LCPUFA supplementation statistically significantly prevented:18 • Spontaneous preterm birth. • Pre-eclampsia. • Intrauterine growth restriction. • Gestational diabetes. • Postpartum depression. While data about birth weight, perinatal mortality and childhood cognitive outcome were limited, women with gestational diabetes receiving n-3 LCPUFA had significantly lower serum C-reactive protein concentrations. Also, newborns had lower incidence of hyperbilirubinemia and hospitalisation rates.18 In contrast, a 2018 Cochrane review involving 70 RCTs including 19,927 women from developed countries at low, mixed or high risk of poor pregnancy outcomes, concluded that n-3 LCPUFA supplementation reduced the incidence of preterm birth (<37 weeks) and early preterm birth (<34 weeks) and possibly reduced the risk of perinatal death, neonatal hospital admission and low birth weight. The quality of evidence supporting the reduced risk of preterm birth was considered to be high.18 Another meta-analysis concluded that n-3 LCPUFA supplementation reduced the incidence of pre-eclampsia.19 A 2018 meta-analysis suggested that maternal fish oil supplementation decreased the incidence of egg but not cows’ milk allergy in the infant.21 Despite the important role n-3 LCPUFAs play in neonatal brain development, studies consistently fail to show that maternal supplementation with n-3 LCPUFAs impacts on any cognitive parameters in the offspring.22 The RACGP Handbook of Non-Drug Interventions (HANDI) acknowledges the doses of omega-3s tested in clinical trials are difficult to achieve through diet alone in the real world.23 Most prenatal supplements don’t contain the dose of TO PAGE 62 RETAIL PHARMACY • MAY 2021 CPD ACTIVITY 61