Written by F.E. O’Toole1,2, G. Mealy2, SL. Killeen1,3, A. Murphy-Cruse1,5, B. Soldati1,4, J. Fitzgerald1,5, S. Curran1,3, F.M. McAuliffe1,2, J.M. Walsh1,2
1.National Maternity Hospital, Dublin, Ireland 2. UCD Perinatal Research Centre, School of Medicine, Dublin 3. Department of Dietetics, National Maternity Hospital 4. Pharmacy Department, National Maternity Hospital 5. Department of Haematology, National Maternity Hospital
In Ireland, the two micronutrients recommended for all women as supplements to a healthy diet during preconception and pregnancy are folic acid and vitamin D. Due to increased requirements, iron supplementation is additionally commonly recommended and has important benefits for fetal and maternal health. Most prenatal vitamins have the baseline recommended doses of folic acid, vitamin D and iron.
Folic Acid
All women of reproductive age should be advised to take folic acid supplementation of 400µg a day to reduce the risk of neural tube defects (NTDs) in the event of a pregnancy. NTDs are the most common major congenital malformation of the central nervous system and include spinal bifida, anencephaly, encephalocele and hemivertebrae. They have a profound impact on families and the health service. The incidence of NTDs in Ireland remains higher by European standards.1 Ideally supplementation would be for three months pre-conceptually, with the aim of optimising folate levels before neural tube closure by the 4th week, and can continue throughout pregnancy.
Higher doses of folic acid (5mg once daily orally) are prescribed if there is a personal or family history of neural tube defects, moderate to severe obesity (BMI>34.9), pre-existing diabetes (type 1 or 2) or concurrent medication which interferes with folate metabolism. Folic acid supplementation should be continued throughout the first trimester and there is increasing evidence to suggest a benefit to continuing it through-out the pregnancy.2 The World Health Organization and the International Federation of Obstetrics and Gynaecology recommend continuing low dose folic acid supplementation through-out lactation. This promotes foetal and neonatal development in addition to reducing the risk of anaemia in the mother.3, 4
Vitamin D
Vitamin D is found naturally in oily fish, eggs and fortified sources. Humans can synthesise vitamin D in their cutaneous tissues however in countries with latitudes above 40 degrees such as Ireland, vitamin D cannot be synthesised between October to March as the UV light required to promote synthesis cannot penetrate the atmosphere during this time. Previous observational studies in pregnant women in Ireland have demonstrated significant levels of vitamin D deficiency as well as suboptimal dietary intakes.5, 6 All pregnant and lactating women in Ireland are recommend to take 15µg or 600IU of vitamin D.7 This fat soluble vitamin is essential for the absorption of calcium and supports the immune system. Deficiencies have been associated with adverse pregnancy outcomes including pre-eclampsia, pregnancy-induced hypertension and also may influence bone health and atopy risk in children.8 Maintenance of vitamin D may be particularly important in preventing anaemia, particularly in diseases of inflammation.9 It appears to be a potent regulator in the hepcidin-ferroportin axis which affects iron homeostasis.10
Iron
Irish nutritional guidelines outline that 16-20mg supplemental iron in pregnancy alongside an ironrich diet could help to reduce anaemia. This is typically found in most pregnancy multivitamin formulations. Iron is an essential component of haem and is key to oxygen transport, energy production and DNA synthesis. Pregnancy increases iron requirements due to an increase in maternal red cell mass, foetal and placental growth and blood loss at delivery. The overall iron requirement in pregnancy is approximately 1000mg, and by the second trimester the daily requirements increase to 6.8mg, which is three time that of a non-pregnant woman. Iron stores will deplete through-out pregnancy and women with pre-existing low iron stores are particularly at risk of developing iron deficiency anaemia.
Both iron deficiency and iron deficiency anaemia can cause symptoms of fatigue, palpitations, breathlessness, dizziness, pallor, poor exercise tolerance and may also affect cognitive function, mood, sleep and memory. Iron deficiency anaemia in pregnancy increases the risk of maternal morbidity as well as the risk of poor pregnancy outcomes including intra-uterine growth restriction, prematurity and low birth weight.11, 12 There is an increased risk of perinatal and neonatal mortality in the setting of iron deficiency anaemia in pregnancy and concerns regarding longterm neurodevelopmental and behavioural effects in children.13, 14 Postpartum anaemia has been linked to increased risk of postnatal depression, fatigue, lactation failure and early cessation of breastfeeding.15-17
A diagnosis of iron deficiency anaemia in pregnancy is generally suspected with a haemoglobin level of <11g/dL in the first trimester and <10.5g/ dL in the second and third trimesters while iron deficiency, regardless of haemoglobin, is typically diagnosed with a ferritin level below 30 micrograms/L.18 There are a multitude of possible causes of anaemia, which may overlap. These include acute or chronic blood loss, red blood cell destruction (e.g. haemolytic anaemias, haemoglobinopathies), myelosuppression due to medications or disease, megaloblastic anaemia due to vitamin B12 or folate deficiency, impaired absorption (e.g. bariatric surgery, inflammation due to infection, autoimmune, chronic disease) but by far the most common cause in pregnancy is nutritional iron deficiency. Irish national nutrition surveys indicate
that up to 1/3 of women of child bearing age consume less than the recommended quantity of iron from diet.
Oral iron supplementation in the form of ferrous iron salts are typically commenced first-line as a diagnostic and therapeutic trial. Therapeutic doses of 100mg elemental iron are licensed in Ireland only from the start of the second trimester for the treatment of iron deficiency anaemia. In addition, maternal iron absorption in the first trimester is curtailed and in murine models iron has been demonstrated to show neurotoxicity in the early embryonic period.19
Therapeutic doses of oral iron should not be advised universally to all pregnant women. Ireland has the highest rate of hereditary haemochromatosis in the world, with 1 in 5 people carriers in our population. Several studies suggest an increased risk of gestational diabetes, hypertensive disease and small for gestational age infants in iron-replete women prescribed supplemental iron.20, 21 High haemoglobin concentrations in the third trimester have also been associated with an increased risk of stillbirth.22, 23 It remains unclear if the associations with adverse outcomes are being driven by direct alterations in functional Hb for essential functions or by the indirect underlying causes of anaemia (e.g. iron deficiency) or high Hb (e.g. excess iron vs. failure of plasma volume expansion).24
In terms of optimising absorption of oral iron in pregnancy, advice surrounding method of ingestion is important. Advising women to take their iron supplement in the morning, on an empty stomach if possible and to avoid ingesting with tannins, calcium and phytates in foodstuff is crucial to ensure it is ingested correctly. Gastrointestinal side-effects are common and may worsen pre-existing symptoms of pregnancy such as constipation, haemorrhoidal disease, nausea, vomiting and heartburn.25
Fractional iron absorption is impacted by iron intake, mediated by increase hepcidin levels in the following 48 hours. To overcome this, there is growing scientific evidence for improved absorption of oral iron supplements with alternate day dosing yet this has yet to be confirmed in a pregnancy setting.26, 27 IronMother (EudraCT number:2022-001815-25) is a randomised controlled trial of alternate day versus daily ferrous fumarate for the treatment of confirmed mild to moderate iron deficiency anaemia in pregnancy. This trial is being sponsored by the UCD Clinical Research Centre and has been ethically approved by the National Research Ethics Committee and the Health Products Regulatory Authority and is currently recruiting at the National Maternity Hospital, Dublin.
References available on request
