Background The concept that nutrition during the perinatal period can result in permanent health consequences is perhaps best highlighted by the establishment of the folate requirement to minimise the occurrence of neural tube defects in randomised controlled trials. These data highlighted that folic acid supplementation during early pregnancy, covering the period in which the neural tube closes, will result in a 72% reduction in the incidence of neural tube defects such as spina bifida which are associated with significant morbidity and mortality. Although not every nutritional intervention will result in such clear and specific outcomes, there is increasing recognition that improved nutrition during critical periods of development is important to optimise the development of the brain and nervous system and hence the capacity of future generations. Two specific nutrients of interest are iron and the n-3 (or omega-3) long chain polyunsaturated fatty acids (LCPUFA), called docosahexaenoic acid (DHA, 22:6n-3). Objective To determine whether additional dietary iron or DHA are necessary to enhance neurodevelopment in early childhood using the randomised controlled trials, AMBIT (Adelaide Mothers' and Babies' Iron Trial), DINO (DHA for the Improvement of Neurodevelopment of preterm infants) and DOMInO (DHA to Optimise Mother Infant Outcome). Design In AMBIT, 430 pregnant women were randomly allocated to receive 20mg of iron/day or a placebo tablet from 20 weeks' gestation until birth. The supplement was designed to allow all women to achieve the recommended dietary intake of the time. Neurodevelopment was assessed when children reached 4 years of age. In DINO, 657 preterm infants born <33 weeks' gestation were randomly allocated to receive a diet with 1% total fatty acids as DHA or a control diet with 0.3% of total fatty acids as DHA. The intervention aimed to deliver the DHA level that a fetus would accumulate during the third trimester of pregnancy and was achieved by supplementing women expressing breast milk for their infants as well as supplementing preterm infant formula to allow for breastfeeding, formula feeding and mixed feeding. Neurodevelopment was assessed at 18 months corrected age. In DOMInO, 2399 women with singleton pregnancies were randomly allocated to receive either DHA-rich fish oil capsules providing 800mg of DHA/day or vegetable oil capsules with no DHA from 19 weeks' gestation until birth. Neurodevelopment was assessed when children were 18 months old. Outcomes AMBIT: Routine iron supplementation in pregnancy did not alter any aspect of intelligence quotient (IQ) in 4 year old children from women who were not anaemic during mid-pregnancy. Iron supplementation also resulted in more parental reports of abnormal behaviours, an observation which is now consistent with other reports involving iron supplementation of iron replete individuals. DINO: Supplementation of with high-DHA in the preterm period resulted in a 30% reduction in preterm children with mild cognitive delay and a 50% reduction in preterm children with major cogntive delay at 18 months, although mean scores did not differ between groups. Pre-planned subgroup analyses indicated greater responsiveness of DHA treatment in infants born weighing <1250g and in girls. DOMInO: On the other hand supplementing with DHA during the equivalent time in utero did not result in significant improvements in cognitive scores overall or in boys or girls, although fewer children had delayed cognitive development. Similarly the overall language scores did not differ between groups but the language scores of girls were lower with DHA treatment. Important subgroups of preterm infants will benefit from higher-dose DHA supplementation during the preterm period, while DHA supplementation during pregnancy provides little neurodevelopmental benefit to the off-spring in early childhood. Conclusion Careful consideration is needed to assess risk-benefit balance and to better target interventions to specific population sub-groups.