The foetus and breastfed infant is totally dependent on maternal nutrient status for growth and development. Recent research has shown that maternal dietary deficiencies of docosahexaenoic acid (DHA), vitamin D, folic acid and iodine are associated with a variety of poor foetal and/or infant health outcomes mostly impacting brain development and/or function in infancy and often throughout life. Therefore, adequate maternal nutrient intake is critical when planning to conceive and during pregnancy and lactation.
A review of current literature was undertaken to summarize the potential benefits of maternal supplementation with DHA, vitamin D, folic acid and iodine during pregnancy and/or breast feeding for foetal and/or infant brain development and/or function. A systematic search was performed in MEDLINE for English-language articles published between January 2000 and February 2012 using broad search criteria including DHA and pregnancy, DHA and lactation, docosahexaenoic acid and pregnancy, docosahexaenoic acid and lactation, vitamin D and pregnancy, vitamin D and lactation, folic acid and pregnancy, folic acid and lactation, iodine and pregnancy and iodine and lactation. Additional studies including some prior to January 2000 were identified within the Cochrane Central Register of Controlled Trials and by reviewing reference lists from included studies and review articles. Titles and abstracts were reviewed and reports were selected for inclusion in the review if they were systematic reviews, meta-analyses, randomised controlled trials, cohort studies, cross-sectional or case-control studies and if they reported benefits and/or harms associated with maternal supplementation with DHA, vitamin D, folic acid or iodine during pregnancy and/or lactation. Studies that reported neither benefit nor harm were not included.
Data was reviewed and summarized to discuss the relevance of dietary DHA, vitamin D, folic acid and iodine to foetal and infant brain development and function, to present evidence demonstrating dietary deficiency of these nutrients in many populations, to highlight the potential benefits of maternal supplementation during pregnancy and/or lactation on foetal and/or infant outcomes and to include safe intake recommendations.
Over the past three decades our diets have changed enormously. We have been encouraged to reduce fat intake while at the same time detrimental trans fatty acids have been introduced into the food chain. In response, many people have reduced intake of all dietary fat without realizing that there is a requirement for certain fats especially for women during pregnancy and while breast feeding, in particular the omega-3 fatty acid, docosahexanoic acid (DHA).
Clinically established as a nutrient essential for the development of an infant’s brain and central nervous system, DHA occurs naturally in breast milk, and is added to infant formula [1
]. In the last trimester of pregnancy, the foetal brain increases in size while rapidly accumulating DHA [2
]. As reported in this review, foetal and infant DHA deficiencies are associated with poor growth, and brain and eye development and function. Numerous observational studies have identified a link between maternal DHA intake during pregnancy and while breast feeding, and enhanced foetal and infant development and function. In addition, intervention trials have measured significant benefits for both the mother and baby.
1.1.1. Importance of Fatty Acids in Brain Development and Function
Fatty acids such as DHA are found in dietary fat and are components of every cell membrane in the body. The types of fatty acids in the diet influence body composition, and ultimately its function and health.
Fatty acids are grouped into various categories: for example saturated fatty acids tend to be solid at room temperature and are abundant in butter. Polyunsaturated fatty acids (PUFAs) are liquid at room temperature and are the main components of vegetable oils such as corn, sesame and evening primrose, and are also found in fish and fish oils. PUFAs are often called “good fats” because eating a higher proportion of them compared to saturated fats can improve health. These are subdivided into two main categories, omega-6 and omega-3. Various long chain polyunsaturated fatty acids (LC-PUFAs) within these two categories can be synthesized de novo starting with dietary essential fatty acids (EFAs), the omega-6 linoleic acid (LA) and the omega-3 alpha-linolenic acid (ALA) respectively, through a multi-step process that is very slow and inefficient in humans [3
]. Typically, only about 0.1% of dietary ALA is converted to DHA in normal healthy adults eating a Westernized diet [5
], making routine dietary intake of DHA a necessity in extraordinary circumstances, such as in pregnancy and during lactation.
About 60% of the dry weight of brain tissue is fat. The most abundant LC-PUFAs in the brain and those which are critical for proper brain, nervous system and eye development and function are DHA and the omega-6 arachidonic acid (AA). DHA and AA are highly concentrated in membrane phospholipids of the retina and brain, where they accumulate rapidly during foetal and infant growth spurts [6
]. DHA is the main structural fatty acid in nerve cells and its presence helps to ensure nerve cell message transmission through its effects on ion channels, response to neurotransmitters [8
], and formation of secondary messengers [9
]. It may also protect against loss of scaffolding proteins [10
] and lipid peroxidation [12
] thereby maintaining the physical structure of the brain. DHA is also extremely important for vision since it is the main membrane constituent in the photoreceptor cells of the eye. These cells are responsible for transmitting light messages to nerves that supply the brain and their proper function is essential for vision.
1.1.2. Maternal Nutrition: During Preconception, Gestation and Lactation
The parent EFAs and their derived LC-PUFAs are vitally important structural elements of all cell membranes, so they are absolutely essential for formation of new tissue as occurs throughout foetal development. During pregnancy and while breast feeding, mothers are the sole provider of these important nutrients to the growing fetus and baby. Consequently, maternal fatty acid status is critical to ensure optimal supply to the offspring, and maternal dietary intake must be sufficient to satisfy her requirements as well as those of her growing baby.
LC-PUFAs are required during all reproductive stages. Before pregnancy, they ensure that the mother’s body is well nourished before she conceives so that the pregnancy begins in a healthy state. During pregnancy they are required for growth of the mammary glands, placenta, uterus and fetus. In the last three months of pregnancy, there is rapid accumulation of DHA in the eyes and brain of the foetus () [2
] and its brain weight increases, making it increasing important that the mother has an adequate DHA intake at this time.
Figure 1 Docosahexaenoic acid (DHA) accumulation in foetal brain .
After birth, the baby’s nervous system continues to grow very rapidly and DHA supplied primarily through breast milk, is required as a structural component. Consequently, maternal body stores can become depleted resulting in health risks for her including post natal depression [14
During the last trimester, a foetus accrues about 67 mg of DHA per day from the mother, and during breast feeding the need increases to 70–80 mg daily [17
]. This huge demand for DHA particularly during breast feeding depletes maternal stores to below pre-pregnancy levels and this deficit can take months to even partially correct.
In addition, the LC-PUFA content of breast milk can vary widely from mother to mother depending on her diet and how efficiently she is able to make these nutrients from the parent EFAs ().
A number of dietary and environmental factors can affect the fatty acid status of the mother. Vegetarians have lower than normal DHA status () [27
] because a strict vegetarian diet does not contain any DHA.
Also, mothers who have given birth in rapid succession and those who have given birth to twins, triplets or other multiples have lower than normal levels of DHA [30
]. This was initially deduced from a population study completed at Maastricht University, The Netherlands, where the fatty acid status of 98 mothers of singletons and 146 mothers of twins, triplets or other multiples was determined during pregnancy and after delivery. During this study, the fatty acid status of their infants was also assessed immediately following birth. Results showed the infant’s DHA status was progressively lower as the number of infants per pregnancy increased and as the number of singleton births increased (i.e.
, a first born had higher DHA levels than a second born, etc.
). Consequently, the mother’s DHA status becomes reduced after each successive pregnancy, restricting the supply of this nutrient to the growing fetus and results in low DHA status in the infant ().
Figure 4 DHA status in successful pregnancies .
However, dietary supplementation can increase maternal plasma and breast milk DHA which can be passed on to the growing baby.
1.1.3. Infant Supplementation Studies
The idea that LC-PUFAs may be important for early brain development and function came from comparison studies between infants fed mother’s milk which contains LC-PUFAs and those fed formula without LC-PUFAs. These studies [32
], plus intervention trials [36
] that included formula supplemented with LC-PUFAs, have reported enhanced eye development and function in infants, in particular visual acuity [41
], and less conclusively enhanced infant brain development and function pertaining to problem solving ability [41
]. These results furnished a compelling argument that LC-PUFAs may also be important for the growing foetus.
1.2. Vitamin D
Vitamin D is a fat soluble vitamin found in some foods including fish and eggs, and can also be manufactured in skin upon exposure to ultraviolet B rays from sunlight. Vitamin D is required to maintain pregnancy, for skeletal development, and to promote normal brain development. There is evidence of widespread sub-clinical vitamin D deficiency [44
] that is aggravated by long hours of work indoors and avoidance of sunshine aimed at reducing skin cancer risk [45
Vitamin D exists in several different forms including D1, D2, D3, D4 and D5 that differ primarily in their side chains. The two major forms are vitamin D2 or ergocalciferol, and vitamin D3 or cholecalciferol. These are known collectively as calciferol. The majority of circulating vitamin D, known as serum 25-hydroxyvitamin D [25(OH)D] that is necessary to maintain health and function of the immune, reproductive, muscular, skeletal and integumentary system, originates from vitamin D3 (cholecalciferol) and reflects endogenous synthesis from exposure to sunlight as well as intake from the diet [46
There are very few dietary sources of vitamin D. Oily fish such as herring, mackerel, pilchards, sardines and tuna are rich sources but their consumption in some countries is low. The only other useful sources are eggs, fortified margarines (required in some countries by law to contain vitamin D) and some fortified yoghurts and breakfast cereals. However, a recent global review of vitamin D status has shown that its intake is often too low to sustain healthy circulating 25(OH)D in countries without mandatory staple food fortification and is even too low in countries that do fortify due to low milk consumption, vegetarianism, non-supplement use and low fish intake [46
]. Supplement use contributed 6%–47% of the average vitamin D intake in some countries. As reported in 2005, the average dietary intake of vitamin D was in the range of 3 μg/day in most countries and did not exceed 9 μg/day in any of the countries surveyed including the United States, Canada, the United Kingdom, Ireland, Scotland, Australia, Europe, Japan and various other countries.
Vitamin D deficiency is defined as serum 25(OH)D of less than 25–50 nmol/L. Approximately one billion people worldwide are estimated to be vitamin D deficient with people living in Europe, the Middle East, China and Japan at particular risk [47
]. Deficiency is more common in women than men (9.2% vs.
6.6%) and pregnancy is known to represent a particularly high-risk situation [45
]. In addition, pregnant women with darker skin pigmentation are at even greater risk of low vitamin D status as compared to pregnant women with lighter skin pigmentation [49
Vitamin D is important during pregnancy to:
- Build strong bones—vitamin D ensures foetal supply of calcium for strong bones  including those of the skull. Severe hypocalcaemic is associated with high risk of brain damage . vitamin D insufficiency has been associated with reduction in bone mineral content of the offspring  and perinatal growth restriction .
- Maintain pregnancy—the circulating concentration of maternal active vitamin D rises in the first trimester and doubles by the end of the third trimester . The early rise is believed to be necessary to enable immunological adaptation by the mother that is required to maintain normal pregnancy . These vitamin D induced immunological changes in the mother prevent miscarriage [45,53].
- Promote normal brain development—preliminary research suggests that gestational vitamin D insufficiency has been linked to altered brain development and adult mental health , in particular schizophrenia .
There is also evidence from observational studies suggesting that adequate vitamin D during early life may prevent development of immunological diseases in the offspring later in life such as Type 1 diabetes [55
], allergic diseases [53
] and lower respiratory tract infections, wheezing and asthma [56
]. Therefore at its worst, vitamin D deficiency can be life threatening to the newborn, while lesser deficiency can weaken skull bones risking brain injury during birth and can contribute to a multitude of future health problems.
1.3. Folic Acid
Folic acid is a B vitamin that plays an important role in cell division, and synthesis of amino acids and nucleic acids and is therefore essential for growth [57
]. It is necessary for normal development of the foetal spine, brain and skull, in particular during the first four weeks of pregnancy.
During pregnancy the rate of cell division and erythrocyte formation increases dramatically as the uterus enlarges, the placenta develops, maternal blood volume increases and the embryo develops into a foetus [58
]. In addition, folate is transferred from the mother to the growing foetus [57
] increasing the demand for folate beyond her sole requirements. Women at risk of low folate status include [59
- Those not taking the recommended quantity of folic acid supplement;
- Those on restricted diets (chronic dieters);
- Those with lower socio-economic status;
- Those with limited or uncertain availability of nutritionally adequate and safe food.
Studies have reported a decreased risk of neural tube defects including malformations of the spinal column (spina bifida) and the skull (anencephaly) is associated with both increased maternal folate intake and higher maternal red blood cell folate concentration (greater than 906 nmol/L) [58
]. Neural tube defects occur during the third and fourth week of pregnancy, before the woman knows she is pregnant, and involve failure of the neural tube to close properly. This risk is reduced when the mother takes a daily multivitamin containing folic acid three months before pregnancy and continuing up to the 6th week from the beginning of her last menses [63
Considering this evidence and recognizing that pregnancies are not always planned, the requirement for folic acid in women of child bearing age and during pregnancy has become well established and internationally recognized (see Section 6.3
under Safe Intake Recommendations). Steps to achieve folate sufficiency have included mandatory or voluntary food fortification in some countries such as Canada [63
] and New Zealand [64
], and the promotion of folate supplementation for all women who could become pregnant.
Even with wide spread recognition of the need for folic acid to prevent neural tube defects, it is still not widely used in the general population globally. For example, in 2008 a systematic review of relevant research from 1989 to May 2006 in Europe, the USA, Canada, Australia and New Zealand was used to make recommendations to improve folic acid supplement use in the UK, particularly among low-income and young women. It included 26 systematic reviews and/or meta-analyses identified from the wider public health literature, and 18 studies on the effectiveness of preconception interventions. The results showed that even high-quality public relations campaigns that increase use result in under half of women in the target group taking supplements [65
Iodine is an essential mineral that humans need to produce thyroid hormones throughout life. These hormones are especially needed to ensure normal development of the brain and nervous system during gestation and early life [66
]. Since the foetus is totally dependent in early pregnancy on maternal thyroid hormones for normal brain development, it is very important that pregnant women consume enough iodine [67
]. During lactation, the mammary glands concentrate iodine within breast milk to nourish the newborn [66
] whose iodine requirement is approximately 7 μg/kg of body weight [66
The two thyroid hormones that contain iodine are thyroxine (T4) and triiodothyronine (T3), the later being the biologically active form. T4 has four iodine molecules while T3 has three. Within the body, dietary iodine mixes with circulating iodine originating from iodine molecules removed from thyroid hormones to create a pool of inorganic iodide available for metabolic use [68
]. This pool is in a dynamic equilibrium where the thyroid takes iodide that is required for T3 and T4 synthesis and the kidneys filter and excrete excess iodide in the urine [68
In a healthy non-pregnant woman with adequate iodine intake, the absorbed dietary iodine balances renal iodide clearance and the thyroid maintains a normal iodine store of 15–20 mg [69
]. If iodine intake is inadequate before pregnancy, maternal deficiency may result in inadequate supply of iodine for the unborn baby in later stages of pregnancy [70
]. In addition, when a woman becomes pregnant, her iodine requirement increases more than 50% [69
] to 220–250 μg/day [71
] due to:
- An increase in maternal T4 concentration to maintain her normal thyroid hormone levels while transferring additional thyroid hormone to the foetus early in the first trimester (before the foetal thyroid is functioning) ;
- Iodine transfer to the foetus, particularly towards the end of pregnancy ;
- An increase in iodine urinary excretion .
The rate of maternal thyroid hormone production returns to normal following birth. However, iodine supplementation is also recommended during breast feeding because infants are completely dependent on their food to supply iodine to build their own reserves of thyroid hormone [72
Iodine is stored in the thyroid gland and any excess consumed iodine is excreted in the urine [66
]. Healthy adults can absorb more than 90% of the iodine they consume if required [66
]. When the dietary intake of iodine is adequate, no more than 10% of absorbed iodine is taken up by the thyroid, but in chronic deficiency thyroid absorption can exceed 80% [66
The primary dietary sources of iodine are dairy products, bread, seafood, meat and iodised salt [66
]. However, within any population, the amount of iodine in its food sources varies greatly due to seasonal changes, plant and animal farming practices and processing techniques [66
] and therefore iodine consumption varies considerably [67
]. Iodine consumption also varies widely among individuals within a given population. For example, vegans are likely to have a diet deficient in iodine while those who eat kelp regularly may ingest excessive iodine [67
Iodine deficiency was first shown to cause goitre (thyroid enlargement) in 1917 resulting in addition of iodine to table salt in Switzerland and the United Sates in the early 1920 to prevent the condition [66
]. In 1980, the World Health Organization (WHO) estimated that 20%–60% of the world’s population was iodine deficient with the greatest prevalence in developing countries [66
]. Studies conducted through 1970–1990 showed that supplementation in iodine deficient regions not only prevented goitre, but also eliminated other iodine deficiency disorders including cretinism, reduced infant mortality and improved cognitive function in the population [66
]. Up until 1990, only Switzerland, some of the Scandinavian countries, Australia, the United States and Canada were routinely adding iodine to their table salt [66
]. Since then, more than 70% of households globally use iodised salt thanks to the efforts of a coalition of international organizations including the International Council for the Control of Iodine Deficiency Disorders (ICCIDD), the World Health Organisation (WHO), the Micronutrient Initiative, UNICEF, national deficiency disorder committees and the salt industry [65
]. However, iodine supplementation practices and dietary habits change in populations overtime making regular monitoring essential to identify both low and excessive iodine intakes [66
Iodine status is determined by measuring the concentration of urinary iodine. Ninety percent of ingested iodine is assumed to be excreted in the urine so an individual’s iodine intake can be calculated based on the amount of urinary iodine excreted in a 24 h period. The WHO/UNICEF/ICCIDD recommended intake of 220–250 μg of iodine/day during pregnancy [68
] and new recommendations from WHO suggest that a median urinary iodine concentration 250–500 μg/L indicates adequate iodine intake in pregnancy [71
]. Based on this range, it appears that many pregnant women in Western Europe have inadequate intakes [71
Currently, the WHO estimates that globally approximately 2 billion people have insufficient iodine intake [66
]. Of the countries included in a 2008 survey by the ICCIDD, 11 had deficiency, 1 has moderate deficiency, 10 had mild deficiency, 20 were sufficient [73
]. The top ten iodine deficient countries based on 2011 national median urine iodine concentration of <100 μg/L in school-aged children (i.e.
, children with insufficient iodine intake) in consecutive order from worst to best were Pakistan, Ethopia, Sudan, Russian Federation, Afghanistan, Algeria, Angola, United Kingdom, Mozambique and Ghana [74
]. Numerous studies in various countries have reported iodine deficiency in women of child bearing age, in pregnant women and in pregnant and lactating women even in areas where food fortification is undertaken (see Section 5.1
As a developed country, the UK is an anomaly in the top ten iodine deficient countries mentioned above. Historically, iodine deficiency was widespread in Britain with high rates of goitre and even cretinism in some areas. Goitre was still present in Sheffield and South Wales until the 1960s. Goitre disappeared over the years owing to iodine supplementation in livestock to improve reproductive performance and lactation in the 1930s and iodophor disinfectants used for cleaning. Iodine intake increased for the next 30 years due to iodine contamination of milk through use of these cleaning agents. Also milk consumption increased due to free school milk and advertising by the Milk Marketing Board resulting in a three-fold increase in iodine intake between the 1950s and 1980s. Today, milk is the main source of iodine in the UK diet contributing 40% of the iodine intake [75
]. However, milk consumption has decreased in recent years and iodophors are being replaced by other disinfectants [75
]. At least one study has reported that low milk intake is linked to increased risk of low iodine status [76
]. Contributing to the problem is increased consumption of organic milk over other sources since organic milk is 42.1% lower in iodine content than conventional milk [77
]. Although iodised salt is available in the UK, only one brand with 0.6% market share is available, less than 20% of supermarket shoppers have iodised salt available for purchase, it is six times more expensive than non-iodised versions and 96% of UK pregnant women never or rarely eat iodised salt [78
]. The UK National Diet and Nutrition Survey of 2000/2001 including adults aged 19 to 64 years reported a daily iodine intake of 215 μg/day in men and 159 μg/day in women where 12% of young women were consuming less than 70 μg/day [74
]. Iodine intake had fallen since 1986/1987 and values reported in 2008/2009 showed a further fall [78
The main health concern of mild iodine deficiency during pregnancy and while breastfeeding is its negative effect on the brain and nervous system development in the foetus and infant, in particular reduced intelligent quotient (IQ) [79
]. Iodine deficiency during pregnancy leads to inadequate thyroid hormone production and hypothyroidism during pregnancy [67
]. Thyroid hormone is required for normal neuronal migration, myelination, and synaptic transmission and plasticity during foetal and early postnatal life [68
]. Hypothyroxinemia causes adverse effects on early foetal brain and nervous system development, can lead to irreversible foetal brain damage [72
], and is the world’s most frequent cause of preventable mental retardation in later life [67
]. The consequences depend on the timing and severity of the hypothyroxinemia [68
]. Moderate-to-severe iodine deficiency during pregnancy also increases rates of spontaneous abortion, reduces birth weight, and increases infant mortality [84