Metagenics
Pregnancy Care Advanced
Advanced Preconception, Pregnancy and Lactation Support
Designed to meet the nutritional demands in maternal and foetal changes throughout, preconception, pregnancy and lactation.
- Maintains a healthy pregnancy
- Supports maternal energy production
- Promote healthy neonatal outcomes
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BENEFITS
CLINICALLY PROVEN;
Optimises Preconception Health
Contains Methylated folic acid (5-MTHF), an effective infertility treatment
Supports nutritional demand during preconception, pregnancy and lactation
Glycinated minerals and Activated B's for optimal bioavailability
Support Maternal Energy Production
Reduces Miscarriage Risk
Lowers risk of neural tube defects and supports neural tube closure
Improves iron intake, without gastrointestinal side effects
Reduces the severity of morning sickness
Improves blood glucose control
Lowers risk of Preeclampsia
Supports Bone Mass
Protects against birth defects and lowers risk of low birth weight
Supports foetal intracellular communication
Enhances Neonatal cognitive and neural development
Supports prevention of infant psychomotor dysfunctions
Regulates healthy gestational development and genetic expression
Provide Nutritional Support for Lactation
PREGNANCY AND LACTATION NUTRTION REQUIREMENTS
Maternal and neonatal health outcomes are significantly influenced by nutrient availability throughout preconception, pregnancy and lactation. Inadequate nutrition, particularly in relation to zinc, iron, vitamin D, choline, iodine, and folic acid during preconception and pregnancy poses significant risks, including impaired foetal development, preterm birth and low birth weight.[1]
Many women are at risk of inadequate nutritional status during pregnancy, with evidence indicating low dietary intake and lack of nutritional knowledge are contributing factors within global[2] and Australian populations.[3]
Further to this, data indicates that micronutrient deficiencies within Australian[4] and New Zealand soils may negatively influence nutritional adequacy[5]; influencing micronutrient intake.
Beyond nutritional support for infant development, nutrients may also exert protective effects in mothers. For example, lutein, vitamin C and selenium are associated with reduced risk of preeclampsia[6] and gestational diabetes mellitus (GDM).[7],[8] With this is mind, provision of key bioavailable nutrients is important during preconception, pregnancy and lactation for the development of the mother-infant dyad (Figure 1).
Furthermore the preconception period is a critical time when nutritional status can influence gestational outcomes,[9] maternal and infant health.[10]
It is well accepted that pregnant women require a varied diet and nutrient intake to allow for increased needs during pregnancy.[11] However, evidence suggests that many women in the preconception period do not meet their nutritional needs. In a survey of 13,845 women of reproductive age (including pregnant and lactating women, and those planning to conceive) living in a developed country, the majority of participants failed to meet adequate nutritional intake through diet.[12]
It is important to note that whilst some key nutrients garner greater attention during pregnancy, multiple nutrient deficiencies are likely to occur simultaneously when diets are lacking.[19] This highlights the need for nutritional solutions that provide a wide range of micronutrients to promote maternal and foetal wellbeing.
Australian Government RDI Guidelines during Pregnancy and Lactation:
Iodine: 220 µg/d
Zinc, Age 14-18: 10 mg/d
Zinc, Age 19-50: 11mg/d
Iron: 27 mg/d
Folate: 600 µg /d
Vitamin K: 60 µg/d
Vitamin B1: 1.4 mg/d
Vitamin B2: 1.4 mg/d
Vitamin B3: 18 mg/d
Vitamin B5: 5 mg/d
Vitamin B6: 1.9 mg/d
Vitamin B12: 2.6 µg/d
Chromium: 30 µg/d
Selenium: 65 µg/d
Vitamin C, Age 14-18: 55 mg/d
Vitamin C, Age 19-50: 60 mg/d
Magnesium, Age 14-18: 400 mg/d
Magnesium, Age 19-30: 350 mg/d
Magnesium, Age 31-50: 360 mg/d
Calcium, Age 14 - 18: 1300mg/d
Calcium, Age 19 - 50: 1000mg/d
Manganese: 5 mg/d
Choline, Age 14-18: 415 mg/d
Choline, Age 19-50: 440 mg/d
Biotin: 30 µg/d
Molybdenum: 50 µg/d
Vitamin A (Betacarotene), Age 14-18: 4,200 µg/d
Vitamin A (Betacarotene), Age 19-50: 4,800 µg/d
OPTIMISES PRECONCEPTION HEALTH
The supplementation of multiple micronutrients during the periconceptional period has been associated with enhanced fertility outcomes.
These include zinc, iron, vitamin D, vitamin C, iodine, selenium, biotin, vitamin B1, vitamin B2, vitamin B3, vitamin B6, vitamin B12, vitamin K, folic acid and vitamin B5.[104],[105]
To assess the effects of these micronutrients on fertility outcomes, 58 women scheduled to undergo clomiphene-induced ovulation were divided into two groups. Participants received either 400 µg/d folic acid or a multiple micronutrient (MMN) formula over four weeks.[106]
The MMN provided participants with 91% to 150% of the recommended daily intake of iron, zinc, selenium and iodine; 113% to 800% of the recommended intake of vitamins B1, B2, B3, B5, B6, folic acid and B12; 113% of vitamin C requirements; 3 mg/d of beta carotene; 600 IU/d of vitamin D; 60 µg/d of vitamin K and 150 µg/d of biotin plus other micronutrients.
The results indicate that the MMN was associated with a significantly higher pregnancy rate compared to folic acid alone (66.7% vs. 39.3%; p<0.013) and fewer attempts to achieve pregnancy were required compared to women taking folic acid alone (p<0.001).
Additionally, data suggests that 5-MTHF may be more effective in assisting fertility compared to folic acid alone. Research conducted in 30 infertile couples with a history of failed assisted reproductive technology (ART) attempts and previous use of high dose folic acid (5 mg/d) found that supplementing 5-MTHF was associated with pregnancy in 90% of couples.[107]
All couples received 600µg/d of 5-MTHF over a 4-month period before re-attempting conception naturally or via ART. Thirteen-out-of-33 couples conceived naturally, with 17 couples achieving pregnancy through ART. Researchers concluded that 5-MTHF is an effective infertility treatment in couples where at least one partner has one of the two main MTHFR isoforms, C677T or A1298C.
REDUCES MISCARRIAGE RISK
Poor nutritional status has been implicated in miscarriage, particularly in relation to vitamin D, vitamin B6, B12 and folic acid deficiency. In a study of 1,684 pregnant women, vitamin D deficiency (<50 nmol/L) was associated with a two-fold increase in miscarriage in the first trimester.[108]
As such, appropriate vitamin D supplementation to maintain adequacy should be considered during pregnancy. Further data indicates that pregnant women supplemented with 1,000 IU/d of vitamin D from 14 weeks of gestation were more likely to be vitamin D replete at 34 weeks compared to placebo (68.2 ± 21.9 nmol/L vs. 43.4 ± 22.4 nmol/L; p<0.001).[109]
These findings support supplementing 1,000 IU/d of vitamin D during pregnancy.
Dysfunctional Hcy metabolism and impaired methylation status have also been linked to miscarriage, with evidence indicating 20% of women who experience idiopathic recurrent miscarriage (IRM) have elevated Hcy.[110]
A combination of MTHF (5 mg/d), vitamin B6 (50 mg/d) and vitamin B12 (1 mg/week) administered to 16 patients was shown to achieve a statistically significant reduction of plasma Hcy after 6 months (19.4 ± 5.3 µmol/L to 6.9 ± 2.2 µmol/L; p<0.05), resulting in seven full-term pregnancies.[111]
Interestingly, patients included in the study had a history of three or more miscarriages as well as limited folic acid metabolism due to MTHFR genetic mutations, supporting the role of methylating nutrients in patients with recurrent miscarriage.
REDUCES ADVERSE SYMPTOMS AND RISK IN PREGNANCY
The incidence and severity of five complications of pregnancy can be modified using nutritional strategies, namely iron-deficiency anemia (IDA), morning sickness, GDM, PE, and pregnancy-associated osteoporosis.
Iron Support:
IDA: Iron bisglycinate has been shown to prevent IDA in pregnant women, reducing the risk of negative health outcomes in infants. In a clinical trial, 80 women in their second trimester of pregnancy received either 25 mg/d of iron bisglycinate or 50 mg/d of iron sulphate until delivery.[112]
Results revealed that iron bisglycinate improves iron status to the same extent as iron sulphate, however with significantly fewer gastrointestinal side effects (p<0.001), and prevented IDA in 95% of subjects during pregnancy and the post-partum period.
Morning Sickness:
Morning sickness: Vitamin B6 administered within the first trimester of pregnancy has been shown to improve symptom severity. In a randomised-controlled clinical trial, 26 women supplemented with 80 mg/d of vitamin B6 for 4 days were evaluated for severity of nausea and vomiting symptoms compared to women receiving 1,000 mg/d of ginger or placebo.
Vitamin B6 was shown to be as effective as ginger and more efficacious than placebo in reducing the severity of eight items on the Rhodes questionnaire, a validated morning sickness screening tool (p<0.02).[113]
Gestational Diabetes:
GDM: Affects between 3% and 10% of pregnancies, and is associated with birth complications.[114]Supplementation with 30 mg/d elemental zinc for six weeks improved metabolic parameters in 58 pregnant women diagnosed with GDM.[115]
In this randomised, placebo-controlled study, mothers receiving zinc experienced a significant reduction in fasting plasma glucose (−6.6 ± 11.2 vs. +0.6 ± 6.7 mg/dL; p=0.005) and serum insulin levels (1.3 ± 6.6 vs. +6.6 ± 12.2 μIU/mL, p=0.003) compared to the placebo group.
Similarly, vitamin D supplemented at a dose equivalent to 2,400 IU/d for six weeks in GDM patients led to a significant decrease in concentrations of fasting plasma glucose (-17.1 ± 14.8 vs. -0.9 ± 16.6 mg/dL; p<0.001) and serum insulin (-3.08 ± 6.62 vs. +1.34 ± 6.51 μIU/mL; p<0.01) compared with placebo, supporting healthy blood glucose control in pregnancy.[116]
Further to this, antioxidants vitamin C[117] and selenium[118] have been demonstrated to reduce oxidative stress, insulin excess and elevated plasma glucose levels in GDM.
In 105 pregnant women with GDM, 1 g/d of vitamin C was shown to lower insulin levels compared to placebo (25.6 ± 20.3 versus 40.5 ± 23.7; p<0.05) and also reduced neonatal intensive care unit (NICU) admissions by improving stabilisation in infant blood sugars (p<0.05).[119]
Additionally, statistically significant reductions in fasting plasma glucose, serum insulin and insulin resistance (p<0.05) were observed in a trial of 70 GDM patients receiving either 200 µg/d of selenium or placebo over six weeks.[120]
Further to this, chromium has long been associated with healthy blood glucose control, with studies confirming pregnant women with GDM have lower levels of serum chromium compared to women without GDM.[121] Additionally, serum chromium levels have been shown to be proportional to the degree of insulin resistance during pregnancy.[122]
Preeclampsia
Preeclampsia (PE): Affects between 2% and 8% of pregnancies and begins with the failure of normal placentation, resulting in a hypoxic placenta, followed by endothelial dysfunction and clinical hypertension.[123]
Antioxidant nutrients may be used to protect against PE, for instance, maternal lutein levels have been shown to share a statistically significant inverse relationship with PE, as demonstrated in a study of 5,000 pregnant women at less than 24 weeks of gestation.[124]
Similarly, in 26 healthy pregnant women, 12 weeks of choline supplementation at either 480 mg/d or 930 mg/d from 26 to 29 weeks gestation was shown to significantly downregulate an antiangiogenic factor associated with PE, soluble fms-like tyrosine kinase-1 (sFLT1), in the placental tissues by 30% (Figure 5).[125]
Selenium also offers protection from PE. In a clinical trial, 166 pregnant women were randomised to receive 100 µg/d of selenium or placebo from first trimester until delivery. The incidence of PE was lower in the selenium group (n=0) than in the control group (n=3).[127]
Further to this, pregnant women taking >100 µg/d were shown to have a reduced incidence of PE, with a statistically significant effect in women at high risk of PE (p<0.05);[128] supporting the role of selenium in reducing PE risk.
Bone Mass
45 mg/d of vitamin K2 was associated with reduced back pain and markers of bone metabolism, suggesting that vitamin K2 may preserve bone mass and support bone repair in pregnancy-associated osteoporosis.
Pregnancy-associated osteoporosis: Is a condition that causes vertebral compression fractures.[129] A preliminary case series published in 2012 indicated that 45 mg/d of vitamin K2 was associated with reduced back pain and markers of bone metabolism, suggesting that vitamin K2 may preserve bone mass and support bone repair in pregnancy-associated osteoporosis.[130]
PROMOTES HEALTHY NEONATAL OUTCOMES
Key nutrients have been associated with a lowered risk of birth defects, which are defined as functional or structural abnormalities in a developing foetus.[131]
For example, choline, vitamin B6 and B12 have been demonstrated to lower the risk of NTD-affected pregnancy in conjunction with 400 µg/d of folic acid.[132]
Furthermore, a 2015 Cochrane review concluded that folic acid supplementation >360 µg/d before conception and during the first trimester prevents the occurrence and recurrence of NTDs.[133] Further analysis of the prevalence of birth defects in a Chinese population has found that folic acid supplementation offers a protective effect against cardiovascular system and nervous system defects.[134]
In addition to folic acid,[135] essential trace elements including zinc[136] and selenium[137] have been associated with a lower risk of cleft lip and cleft palate malformations, indicating that nutrient supplementation is an effective strategy for lowering the risk of birth defects.
Another adverse neonatal outcome, low infant birth weight (LBW) is associated with several risk factors, including poor nutritional status. Defined as infants born weighing <2,500 g, LBW has been linked to maternal undernutrition, lack of nutritional counselling, inadequate iron supplementation and low vitamin D status.[138]
Research in a large Chinese cohort (n=11,311) revealed iron supplementation throughout pregnancy, alongside folic acid in early pregnancy, reduces low birth weight incidence.[139]
This is consistent with findings from additional studies; [140] thus, preventing iron deficiency is an important factor in reducing the risk of LBW.
Evidence also supports nutritional supplementation in enhancing neonatal cognitive development. Research indicates that choline supplementation in the third trimester of pregnancy, at a dose of either 480 mg/d or 930 mg/d, enhances infant information processing speed and visuospatial memory at 4, 7, 10 and 13 months of age.[143].
Mean reaction time across the four age groups was significantly faster for infants born to mothers consuming 930 mg/d of choline (p=0.03), indicating that maternal consumption of choline during the last trimester of pregnancy supports neonatal cognitive development.
SUPPORTS MATERNAL ENERGY PRODUCTION
One of the most common complaints in pregnancy is fatigue, which in part is likely to be associated with nutritional deficiency in pregnancy. Iron plays an important role in energy production as it transports oxygen via hemoglobin between mother and baby.[98]
The requirements for iron intake increase from 1.0 mg/d in the first trimester to 7.4 mg/d in the third trimester, and can be difficult to achieve through dietary intake alone.[99]
Recent Australian research has revealed that 68% to 82% of women do not meet the RDI for iron both periconceptionally and throughout pregnancy.[100] Further, data suggests that the majority of women in Western countries cannot fulfil iron requirements in the second and third trimesters.[101] As such, supporting adequate iron intake helps promote energy and reduce fatigue associated with iron-deficiency anemia.
Furthermore, activated B vitamins such as riboflavin sodium phosphate (vitamin B2), P5P (vitamin B6) and mecobalamin (vitamin B12) support energy production via cellular mitochondria.[102] Specifically, B vitamins serve as cofactors within the citric acid cycle, supporting energy production during pregnancy and lactation.[103]
Nutrients that offer superior bioavailability such as the bisglycinate forms of minerals, including magnesium (MetaMag®),[26] iron (Meta Fe®),[27] and zinc (Meta Zn®), are taken into the enterocyte more efficiently. This enhanced bioavailability is due to mechanisms such as a reduction in complex formation with anti-nutrients (e.g. phytates, oxalic acid)[28],[29] and improved absorption due to the pH-buffering action of glycine enhancing passive transport.[30]
Active B vitamins also provide superior bioavailability compared to non-active forms; pyridoxal 5’ phosphate (P5P) and methylcobalamin are two examples. These forms of Vitamin B6 and B12, respectively, are directly utilised in the body’s biochemical pathways, which is an important consideration when optimising nutritional status.
For example, the activated form of folic acid, 5-methyltetrohydrofolate (5-MTHF), can directly enter the folic acid cycle,[31] and may therefore be better utilised by individuals with an impaired ability to convert folic acid associated with methylenetetrahydrofolate reductase (MTHFR) mutations.
However, despite being a non-active form, folic acid has well-validated benefits beyond 5-MTHF. A large body of evidence supports the use of folic acid to lower the risk of neural tube defects (NTD), while the effectiveness of 5-MTHF for this indication has not been evaluated.[32] It should be noted that other non-active forms of folic acid, such as folinic acid (calcium folinate), do not have advantages over 5-MTHF or folic acid.
Calcium folinate, also known as folinic acid, is made up of a combination of L- and D-isomers, however the D-isomer only delivers 20% bioavailability,[33] making this a poor supplemental form. Further, it has not been specifically evaluated in NTD prevention. Combining both folic acid and 5-MTHF therefore provides superior bioavailability while also providing the form of folic acid proven to reduce the incidence of NTD. As such, comprehensive combinations of vitamins and minerals can support varying nutritional needs in pregnancy, supporting the health outcomes of both mother and baby.
SUPPORTS HEALTHY SKELETAL GROWTH
Skeletal health in neonates is dependent on the availability of key nutrients during foetal development and the neonatal period. Adequate maternal levels of vitamin D are vital for offspring bone development.[34]
Vitamin D receptors and 1 alpha-hydroxylase enzymes, which convert inactive ergocalciferol (vitamin D2) into its active form, 1,25dihydroxycholecalciferol (vitamin D3), are found in high concentration within pregnancy-specific tissues (i.e. the placenta and decidua).[35]
Their increased presence during pregnancy maximises vitamin D availability, enhancing calcium deposition within the foetal skeleton.[36] Vitamin D deficiency during pregnancy has been documented in many populations, with maternal vitamin D levels below 25 nmol/L correlating with vitamin D inadequacy in neonates, and impaired skeletal development.[37]
Vitamin K is also a key factor required for the formation of the neonatal skeleton. It supports bone homeostasis via three independent mechanisms, which promote bone growth, prevent tissue calcification and limit calcium resorption from bone.[38]
In the context of foetal development, supporting osteoblast function is the core mechanism whereby vitamin K influences skeletal growth. Specifically, vitamin K2 (menaquinone) targets the steroid and xenobiotic receptor (SXR) that operates as a transcriptional regulator of osteoblastic genes and extracellular matrix-related genes.[39]
Moreover, vitamin K2 upregulates various bone growth markers, including tenascin C, bone morphogenetic protein-2 (BMP-2), growth differentiation factor 15 and stanniocalcin, supporting multiple pathways involved in healthy skeletal development.[40]
Lastly, manganese is an essential cofactor in bone formation[41] due to its role as a cofactor in the synthesis of chondroitin sulfate,[42] which is involved in bioscaffold design in the development of bone and cartilage.[43] As such, manganese aids skeletal development by supporting the structural growth of bone tissue.
SUPPORTS FOETAL NEURODEVELOPMENT
Gestational neurodevelopment is highly sensitive to nutritional status. Recent research has revealed that dietary carotenoid lutein shares a direct relationship with activin A, a trophic and neuroprotective biomarker in the brain, demonstrating it has a role in in neurodevelopment.[44]
Human data indicates lutein accounts for 59% of total brain carotenoids, and is found in high concentration within the infant nervous system, particularly in the occipital cortex and hippocampus; involved in learning and memory.[45]
Furthermore, lutein supports intracellular communication within neurons, exerts neuroprotective properties, and enhances brain metabolism and growth in neonates.[46]
Iron is important for infant neurodevelopment, with iron deficiency during pregnancy shown to impair mental and psychomotor development.[47]
Further, prenatal iron intake has been shown to improve neurological outcomes in children, highlighting the importance of maternal iron adequacy.[48]
Similarly, zinc plays an essential role in early neonatal brain development. At a molecular level, zinc regulates gene expression and supports the activity of several neuronal enzymes that enhance synaptic activity and neuronal plasticity throughout development.[49]
Further, zinc supplementation has been shown to help correct neurological dysfunction in neonates, underscoring the importance of zinc in neurological development.[50]
Choline is essential for the developing brain as it is a precursor of acetylcholine,[51] a key neurotransmitter that regulates neuronal proliferation, differentiation, migration, maturation and plasticity, as well as synapse formation.[52]
Choline is also a necessary substrate in the formation of choline phospholipids, phosphatidylcholine and sphingomyelin, which are key components of neuronal and cellular membranes required for brain development.[53] Further, choline carries three methyl groups that support DNA methylation involved in neural growth.
Data extracted from a national survey conducted in the United States of America indicates that approximately 6% of females consumed adequate choline, highlighting the importance of ensuring sufficient choline intake in pregnant women.[54]
Iodine supports maternal thyroid function during pregnancy and lactation due to its role in the production of thyroid hormones, free thyroxine (T4) and triiodothyronine (T3).[56]
Demand for iodine is increased during pregnancy as the foetus is reliant on maternal T4 for cellular metabolism, neuronal migration and myelination during development.[57],[58],[59],[60]
Further, T4 availability also influences dendritic cell branching, synaptogenesis, glial cell differentiation and migration, in addition to neuronal proliferation within the cerebral cortex, hippocampus and medial ganglionic eminence.[61] These developmental events occur in the first and second trimester of pregnancy, with neuronal maturation continuing throughout foetal development (Figure 3).[62]
Vitamin B12 is essential for healthy neonatal neurodevelopment also. B12 deficiency has been shown to produce a cluster of neurological symptoms associated with delayed myelination, impaired methylation and imbalances within neurotrophic and neurotoxic cytokines,[64] indicating the importance of maternal B12 adequacy.
SUPPORTS HEALTHY METHYLATION
Pregnancy is a critical time during which DNA methylation can shape neonatal health outcomes by helping regulate healthy gestational development and genetic expression.[65]
Inadequate methylation is associated with a number of disease states; however, nutrients that act as methyl donors can promote healthy methylation.[66]
Adequate consumption of choline provides 60% of the body’s methyl groups[67] by serving as a precursor for betaine involved in S-adenosylmethionine (SAMe) production; the universal methyl donor in the body (Figure 4).[68] SAMe availability facilitates the regeneration of methionine from homocysteine (Hcy), reducing the accumulation of Hcy[69] associated with pregnancy complications.[70],[71]
Further to this, data indicates many women do not meet adequate intake levels of choline (440mg/d) during pregnancy,[72] suggesting that many pregnancies may be at risk of preeclampsia (PE),[73]early term miscarriage,[74] NTDs, and poor brain development[75] due to impaired methylation and elevated Hcy.
Genetic polymorphisms associated with impaired methylation have been linked to the accumulation of Hcy, [77] which is associated with adverse outcomes in pregnancy, including PE[78] and miscarriage.[79] Nutritional status has been shown to promote the recycling of Hcy by enhancing methylation in these populations. For example, vitamin B6,[80] B12[81] and folic acid[82] reduce Hcy levels in patients with MTHFR mutations. Furthermore, 5-MTHF significantly reduces total Hcy levels in patients with mild to moderate elevations, contributing to healthy methylation.[83] As such, methylating nutrients support genetic expression and development during gestation.
PROMOTES NEURAL TUBE CLOSURE
NTDs are congenital malformations of the central nervous system (CNS) due to failed neural tube closure during embryogenesis.[84]
As a result, anencephaly and spina bifida can develop in neonates.[85] Folic acid supplementation reduces the incidence of NTD by 50% to 75%.[86] However, several other risk factors can increase foetal NTD incidence, including low levels of methylation cofactors such as vitamin B12 and choline.[87]
Moreover, nutrient availability, high levels of oxidative stress and poor glycaemic control may also elevate the risk of NTD.[88]
5-MTHF has been shown to effectively increase both serum and red blood cell folic acid concentrations[89]; however, the vast majority of research on NTD prevention has been conducted using folic acid. Folic acid at a dose of 0.36 mg (360 µg/d) was originally shown to reduce the rate of NTDs from 5.9% to 0.5%, a finding that has been replicated in many studies since the early 1980s.[90] Supported by the results of a 2017 Cochrane review, the vast majority of research shows a reduction in NTDs with periconceptional folic acid supplementation.[91]
Recent Australian research has revealed that 68% to 82% of women did not meet the RDI for iron both periconceptionally and throughout pregnancy.
Furthermore, research has revealed that dietary lutein intake is inversely related to the incidence of NTD in women.[92]
A 2010 study also found dietary lutein to reduce NTD incidence via its antioxidant mechanisms, countering oxidative stress.[93] Moreover, the development of the CNS is particularly sensitive to choline availability; high choline intake has been shown to lower the risk of NTD, including anencephaly and spinal bifida.[94],[95]
Therefore, high serum levels of choline in folic acid-replete pregnant women have been associated with a lowered risk of NTD.[96] Research also shows high maternal intake of choline, vitamin B6, B12, and methionine, in addition to a moderate intake of betaine, halves the risk of an NTD-affected pregnancy.[97] Such findings support the protective effects of methylation cofactors against NTD.
PROVIDES NUTRITIONAL SUPPORT FOR LACTATION
Lutein is required for healthy infant development, including brain and retinal growth,[144] and varies in concentration in breast milk depending on maternal intake.[145]
A study in 89 lactating mothers receiving either 6 mg/d or 12 mg/d of lutein demonstrated an increase in plasma lutein breastfed infants by 180% and 330% respectively (p<0.05).[146]
Moreover, vitamin D is an essential nutrient provided by breast milk that increases in response to supplementation. High dose oral supplementation (600,000 IU/ for 10 days) has been shown to raise maternal vitamin D to 101 ± 54 nmol/L at six months which translated to 73 ± 36.5 nmol/L in breastfed infants.[147]
This level of serum vitamin D protected infants in the treatment group from rickets, which developed in 16.94% of non-supplemented infants with vitamin D levels <40 ± 44 nmol/L .
Similarly, demand for choline is also high during lactation.[148] Research in 28 lactating mothers supplementing either 480 mg/d or 930 mg/d of choline resulted in enriched choline levels in breast milk.[149]
Further, iodine supplementation in lactating mothers has been shown to increase infant urinary iodine, a measure of iodine status, by three months of age, compared to direct infant supplementation (Figure 6).[150]
In another study, 241 mother-infant pairs with mild iodine deficiency were randomised to receive either 400 µg/d of iodine for maternal intake, or 100 µg/d to administer directly to the infant. By three months, median infant urinary iodine was sufficient in the maternal treatment group, whereas infant urinary iodine concentration was sufficient only at six months in the direct supplementation group.
Such findings support iodine supplementation in lactating mothers to protect infants from cretinism, cognitive impairment, and other health risks associated with inadequate iodine intake.
Maternal concentrations of, vitamin B1, B2, B6 and B12 also influence the nutritional composition of breast milk.[152] Maternal supplementation during lactation rapidly increases the concentrations of B1, B2, and B6, whilst supplementing vitamin B12 results in smaller increases.[153]
Interestingly, in 80 exclusively breastfed infants with suboptimal birth weight, lower neurodevelopment scores were associated with inadequate B vitamin intake,[154] supporting the therapeutic benefits of maternal supplementation.
Similarly, maternal vitamin K2 supplementation at a dose of 15 mg/d has been shown to maintain infant vitamin K status throughout the late neonatal period. Thirty-one infants whose mothers had received vitamin K2 supplementation from delivery demonstrated low levels of Protein Induced by Vitamin K Absence II (PIVKA-II), a blood clotting biomarker that is low in the presence of adequate vitamin K. In contrast, the control group was modestly higher in PIVKA-II, indicating lower infant vitamin K status.[155]
A large body of evidence strongly supports the benefits of a wide range of nutrients to support the mother-infant dyad, promoting better health outcomes in preconception, pregnancy and breastfeeding.
INGREDIENTS
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DIRECTIONS
Adults:
Take 1 tablet twice daily with food for at least one month before conception.
Continue with 1 tablet twice daily, during pregnancy and lactation.
EVIDENCE
References
[1] Gernand AD, Schulze KJ, Stewart CP, West Jr KP, Christian P. Micronutrient deficiencies in pregnancy worldwide: health effects and prevention. Nat Rev Endocrinol. 2016 May;12(5):274.
[2] Cuervo M, Sayon-Orea C, Santiago S, Martínez JA. Dietary and health profiles of Spanish women in preconception, pregnancy and lactation. Nutrients. 2014 Oct 20;6(10):4434-51 DOI: 10.3390/nu6104434.
[3] Bookari K, Yeatman H, Williamson M. Exploring Australian women's level of nutrition knowledge during pregnancy: a cross-sectional study. Int J Womens Health. 2016 Aug 16;8:405-19 DOI: 10.2147/IJWH.S110072.
[4] Grains Research and Development Corporation. Crop Nutrition Fact Sheet: Micronutrients. Canberra (AU): Grains Research and Development Corporation Australian Government; Nov 2013. p.4.
[5] Freeland-Graves JH, Sanjeevi N, Lee JJ. Global perspectives on trace element requirements. J Trace Elem Med Biol. 2015;31:135-41 DOI: 10.1016/j.jtemb.2014.04.006.
[6] Tara F, Maamouri G, Rayman MP, Ghayour-Mobarhan M, Sahebkar A, Yazarlu O, et al. Selenium supplementation and the incidence of preeclampsia in pregnant Iranian women: a randomized, double-blind, placebo-controlled pilot trial. Taiwan J Obstet Gynecol. 2010 Jun;49(2):181-7 DOI: 10.1016/S1028-4559(10)60038-1.
[7] Maged AM, Torky H, Fouad MA, GadAllah SH, Waked NM, Gayed AS, et al. Role of antioxidants in gestational diabetes mellitus and relation to fetal outcome: a randomized controlled trial. J Matern Fetal Neonatal Med. 2016 Dec;29(24):4049-54 DOI: 10.3109/14767058.2016.1154526.
[8] Asemi Z, Jamilian M, Mesdaghinia E, Esmaillzadeh A. Effects of selenium supplementation on glucose homeostasis, inflammation, and oxidative stress in gestational diabetes: randomized, double-blind, placebo-controlled trial. Nutrition. 2015 Oct;31(10):1235-42 DOI: 10.1016/j.nut.2015.04.014.
[9] Morrison JL, Regnault TR. Nutrition in pregnancy: optimising maternal diet and fetal adaptations to altered nutrient supply. Nutrients. 2016 Jun 4;8(6) DOI: 10.3390/nu8060342.
[10] Young MF, Nguyen PH, Addo OY, Hao W, Nguyen H, Pham H, et al. The relative influence of maternal nutritional status before and during pregnancy on birth outcomes in Vietnam. Eur J Obstet Gynecol Reprod Biol. 2015 Nov;194:223-7 DOI: 10.1016/j.ejogrb.2015.09.018.
[11] Nnam NM. Improving maternal nutrition for better pregnancy outcomes. Proc Nut Soc. 2015 Nov;74(4):454-9.
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[255] Roti E, Uberti ED. Iodine excess and hyperthyroidism. Thyroid 2001;11(5):493-500.
[256] Australian Government – National Health and Medical Research Council [Internet]. Canberra (AU): Commonwealth of Australia; c2006. Iodine; 2018 [updated 2014 Apr 9; cited 2018 Jan 10]. Available from: https://www.nrv.gov.au/nutrients/iodine.
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[263] Oregon State University - Linus Pauling Institute [Internet]. Corvallis (OR): Linus Pauling Institute; c2002-2018. Micronutrient information centre - iodine; 2001 [updated 2015 Aug; cited 2018 Jan 10]. Available from: http://lpi.oregonstate.edu/mic/minerals/iodine.
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[265] Stargrove MB, Treasure J, McKee DL. Herb, nutrient, and drug interactions. St Louis (MO): Mosby Elsevier; 2010. p. 312-313.
[266] Skidmore-Roth L. Mosby’s Handbook of Herbs and Natural Supplements. Missouri (USA): Mosby Elsevier; 2010. p. 63.
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[285] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 3rd ed. Sydney (AU): Elsevier/Churchill Livingstone; 2010. p. 942-943.
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[287] Gaby AR, Batz F, Chester R, Constantine G. A-Z guide to drug-herb-vitamin interactions. 2nd ed. New York (NY): Three Rivers Press; 2006. p. 131.
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[289] Braun L, Cohen M. Vitamin B3 – Niacin. In: Herbs and natural supplements: an evidence-based guide. 3rd ed. Sydney (AU): Elsevier/Churchill Livingstone. 2010; p. 936-945.
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[291] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 2. Sydney (AU): Elsevier/Churchill Livingstone; 2015. p. 180-90.
[292] Vitamin B6. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2008 [cited 2017 Dec 19]. Available from: http://www.naturaldatabase.com. subscription required to view.
[293] Harkness R, Bratman S. Mosby’s handbook of drug-herb and drug-supplement interactions. St Louis (MO): Mosby Inc.; 2003. p. 270-1.
[294] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 2. Sydney (AU): Elsevier/Churchill Livingstone; 2015. p. 1218.
[295] Stargrove MB, Treasure J, McKee DL. Herb, nutrient, and drug interactions. St Louis (MO): Mosby Elsevier; 2010. p. 618-652.
[296] Chromium. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2018 [updated 2018 Jun 19; cited 2018 Jul 12]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=932. subscription required to view.
[297] Stargrove MB, Treasure J, McKee DL. Herb, nutrient, and drug interactions. St Louis (MO): Mosby Elsevier; 2010. p. 508.
[298] Vitamin D. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2008 [cited 2018 September 28]. Available from: http://www.naturaldatabase.com. subscription required to view.
[299]Natural Medicines. Choline. [Online]. 2015. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs supplements/professional.aspx?productid=1017. [Cited 04/05/2017].
[300] Nutrient Reference Values for Australia and New Zealand. Australian Government Department of Health and Ageing. [Online]. 2017. Available from: https://www.nhmrc.gov.au/_files_nhmrc/file/publications/17122_nhmrc_nrv_update-dietary_intakes-web.pdf. [Cited 04/05/2017].
[301] Selenium. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2018 [cited 2018 Jan 10]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=1003. subscription required to view.
[302] Vitamin K. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2018 [updated 2018 March 7; cited 2018 Apr 27]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=983#adverseEvents. subscription required to view.
[303] Higdon J. An evidence-based approach to phytochemicals and other dietary factors. New York (NY): Thieme; 2003. p. 90 - 96.
[304] Vitamin D. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2008 [cited 2018 September 28]. Available from: http://www.naturaldatabase.com. subscription required to view.
[305] Choline. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2008 [cited 2017 May 04]. Available from: http://www.naturaldatabase.com. subscription required to view.
[306] Nutrient Reference Values for Australia and New Zealand. Australian Government Department of Health and Ageing. [Online]. 2017. Available from: https://www.nhmrc.gov.au/_files_nhmrc/file/publications/17122_nhmrc_nrv_update-dietary_intakes-web.pdf. [Cited 04/05/2017].
[307] Selenium. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2018 [cited 2018 Jan 10]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=1003. subscription required to view.
[308] Vitamin K. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2018 [updated 2018 March 7; cited 2018 Apr 27]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=983#adverseEvents. subscription required to view.
[309] Higdon J. An evidence-based approach to phytochemicals and other dietary factors. New York (NY): Thieme; 2003. p. 90 - 96.
[310] Vitamin D. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2008 [cited 2018 September 28]. Available from: http://www.naturaldatabase.com. subscription required to view.
[311] Baghurst K. Vitamin D. In: Nutrient References Values for Australia and New Zealand. Australian Government: Department of Health and Ageing, National Health and Medical Research Council, Canberra. 2005. p. 127-38.
[312] Stargrove MB, Treasure J, McKee DL. Herb, nutrient, and drug interactions. St Louis (MO): Mosby Elsevier; 2010. p. 399-421.
[313] National Health and Medical Research Council. Nutrient Reference Values for Australia and New Zealand. Iodine [Internet]. Canberra (ACT): Australian Government. 2018. [cited 2018 Oct 29]. Available from: https://nhmrc.gov.au/about-us/publications/nutrient-reference-values-australia-and-new-zealand-including-recommended-dietary-intakes.
[314] Gropper SS, Smith JL. Advanced nutrition and human metabolism. 6th ed. Belmont (CA): Wadsworth; 2013. p 448.
[315] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 2. Sydney (AU): Elsevier/Churchill Livingstone; 2015. p. 688-9.
WARNINGS
Contraindications
Allergies and sensitivities: Avoid in individuals with known allergy or hypersensitivity to cobalamin and/or cobalt,[168] iodine,[169] betacarotene,[170],[171] or lutein.[172]
Calcipotriene: Calcipotriene is a vitamin D analogue used topically for psoriasis. It can be absorbed in sufficient amounts to cause systemic effects, including hypercalcemia. Theoretically, combining calcipotriene with vitamin D supplements might increase the risk of hypercalcemia. Avoid concurrent use.[173]
Calcitriol: Calcitriol is a vitamin D analogue and when used in conjunction with vitamin D supplements may have an additive effect and increase risk of vitamin D toxicity and hypercalcemia. Avoid concurrent use.[174]
Warfarin and indandione anticoagulants – These medications work by inhibiting conversion of the vitamin K epoxide back to vitamin K. Excessive vitamin K intake will interfere with the anticoagulant effect of these drugs unless closely monitored, and adverse effects can be rapid and serious. Avoid using.[175],[176],[177]
Moderate Level Cautions
Aluminium / aluminium-containing phosphate binders: The protein that transports calcium across the intestinal wall can also bind and transport aluminium. This protein is stimulated by vitamin D, which may therefore increase aluminium absorption. This mechanism may contribute to increased aluminium levels and toxicity in people with renal failure, when they take vitamin D and aluminium-containing phosphate binders long term.[178] In patients with renal failure it is recommended to exercise caution when taking this combination and to only do so under medical supervision.
Aluminium-containing antacids: Vitamin C may increase aluminium’s absorption, therefore separate antacids that contain aluminium from vitamin C by at least 2 hours.[179],[180],[181]
Antithyroid drugs: These drugs are used to treat hyperthyroidism, and include propylthiouracil and carbimazole. The concomitant use of antithyroid drugs with iodine may alter a patient’s thyroid activity; therefore, monitor patient’s thyroid function if taking antithyroid medication.[182],[183]
Calcium channel blockers: Use with caution in patients on calcium channel blockers. Hypercalcaemia due to high doses of vitamin D can reduce the effectiveness of such medications in atrial fibrillation. Avoid vitamin D doses above 2,000 IU/d (50 µg) and monitor.[184],[185],[186]
Chemotherapy/Radiotherapy: It has generally been thought that antioxidants may interfere with chemotherapy and/or radiotherapy by decreasing the efficacy of the treatment, although recent studies have found that antioxidants are safe to use in conjunction with these treatments.[187],[188],[189] In particular, selenium has been shown to provide potentially beneficial effects alongside certain chemotherapy drugs.[190],[191],[192],[193],[194] However, it is still advisable to check with a patient’s oncologist before recommending a formula containing antioxidants.[195]
Digoxin: Hypercalcaemia induced by high doses of vitamin D (i.e. doses > 2,000 IU/d or 50 µg/d) can increase the risk of fatal cardiac arrhythmias with cardiac glycosides. Avoid vitamin D doses above 2,000 IU/d (50 µg/d) and use under medical supervision only.[196],[197],[198],[199]
Haemochromatosis and other diseases of iron accumulation: Use with caution in cases of uncontrolled haemochromatosis, thalassaemia, sideroblastic anaemia or erythrocyte G6PD deficiency. Iron overload is a risk in people with haemoglobinopathies, such as haemochromotosis, or other refractory anaemias erroneously diagnosed as iron deficiency anaemia. Consider using iron studies to monitor iron levels in these patients.[200],[201]Vitamin B2 is involved in mobilising iron from its storage form (ferritin), for heme and globin synthesis, thereby increasing haemoglobin levels. However, B2 does not seem to significantly influence iron absorption.[202] The effect of B2 on iron utilisation is probably only significant in people with B2 deficiency and has only been examined in a few small studies, including a study on 123 women who were given 2 to 4 mg riboflavin/d.[203],[204]
Vitamin C increases iron absorption.[205],[206]
Hypercalcaemia: Vitamin D doses above 2,000 IU/d (50 µg/d) may cause hypercalcemia and should be avoided due to the risk of increased calcium accumulation.[207] Use with caution and only under medical supervision.[208],[209]
Hyperparathyroidism: Vitamin D doses above 2,000 IU/d (50 µg/d) may cause hypercalcemia and should be avoided due to the risk of increased calcium accumulation. Use with caution and only under medical supervision.[210],[211]
Levodopa/Carbidopa/Methyldopa: There is some evidence in healthy people that iron forms chelates with levodopa, reducing the amount of levodopa absorbed by around 50%, and therefore interfering with the absorption of levodopa, carbidopa and methyldopa. Advise patients to separate doses of levodopa and iron by at least 2 hours.[212],[213],[214]
Levothyroxine: Iron can decrease the absorption and efficacy of levothyroxine by forming insoluble complexes in the gastrointestinal tract and reduce its absorption. Advise patients to separate levothyroxine and iron doses by at least two hours.[215],[216]
Methotrexate: Methotrexate exerts its cytotoxic effects by preventing conversion of folic acid to the active form needed by cells.
Cancer:
5-MTHF: There is some evidence that folic acid supplements reduce the efficacy of methotrexate in the treatment of acute lymphoblastic leukaemia, and theoretically they could reduce its efficacy in the treatment of other cancers.[217],[218] Theoretically, L-5-methyl-THF may be associated with a reduced interaction with drugs that inhibit dihydrofolate reductase.[219] Seek approval from patient’s oncologist before recommending the use of folic acid.
Penicillamine: Zinc forms an insoluble complex with penicillamine, therefore interfering with absorption and activity, reducing the bioavailability of each other.[220],[221] Therefore, it is recommended to separate doses by 2 hours.
Phenobarbitone (phenobarbital): Use cautiously in patients on this medication and monitor for symptom changes, including increased seizure activity.At doses above 200 mg/d, vitamin B6 can reduce plasma levels of this anticonvulsant.[222],[223]
Folic acid can have direct convulsant activity in some people, reversing the effects of phenobarbital and worsening seizure control. Note that phenobarbital also reduces serum folic acid levels.[224],[225],[226]
Phenytoin: Use cautiously in patients on this medication and monitor for symptom changes.Vitamin B6 at doses above 200 mg/d can reduce plasma levels of this anticonvulsant.[227],[228]
Folic acid may be a cofactor in phenytoin metabolism, and may reduce serum levels of in some patients. Increases in seizure frequency have been reported. If folic acid supplements are added to established phenytoin therapy, monitor serum phenytoin levels closely. Note that the administration of folic acid with phenytoin can reduce toxicity caused by the drug.[229],[230],[231]
Quinolone antibiotics: These antibiotics may form complexes when taken with zinc and reduce the efficacy of one another, therefore it is recommended to separate doses by taking the medication 2 hours before, [232],[233],[234] or 4 to 6 hours after zinc.[235] Some quinolone antibiotics include ciprofloxacin (Cipro), levofloxacin (Levaquin), ofloxacin (Floxin), moxifloxacin (Avelox), gatifloxacin (Tequin), and others.
Renal failure and/or chronic kidney disease: Use with caution under medical supervision and do not exceed recommended dosage.Vitamin D doses above 2,000 IU/d (50 µg/d) may cause hypercalcemia and should be avoided due to the risk of increased calcium accumulation.[236]
Theoretically, chromium might exacerbate renal disease, however this was only seen in case reports using very high doses of chromium picolinate (600 to 2400 mcg/d [237],[238]) and in a case report where other ingredients in the formulation were more likely causes of renal failure.[239]
Sarcoidosis or other granulomatous disease: The synthesis of vitamin D is altered by granulomatous inflammation, resulting in increased production of 1, 25-dihydroxyvitamin D.[240] Vitamin D doses above 2,000 IU/d (50 µg/d) should be avoided due to the risk of increased calcium accumulation. Use with caution and only under medical supervision.[241],[242]
Smokers and individuals exposed to asbestos: Heavy smokers should avoid long term consumption of high doses (i.e. >20 mg/d) of supplemental betacarotene as this may increase the risk of lung and prostate cancer, intracerebral hemorrhage, and cardiovascular and total mortality in people who smoke cigarettes or have a high-level exposure to asbestos. A recent review suggests that consuming small amounts of supplemental betacarotene (i.e. less than 20 mg / day) in supplements and/or food is safe.[243],[244]
Tetracycline antibiotics: These antibiotics may form complexes when taken with zinc and reduce the efficacy of one another, therefore it is recommended to separate doses by taking the medication 2 hours before,[245],[246],[247] or 4 to 6 hours after zinc.[248],[249]
Thiazide diuretics: Thiazide diuretics decrease urinary calcium excretion, which could lead to hypercalcemia if vitamin D supplements are taken concurrently. This has been reported in people being treated with vitamin D for hypoparathyroidism, and also in elderly people with normal parathyroid function who were taking a thiazide, vitamin D, and calcium-containing antacids daily. Use combinations of thiazides and vitamin D with caution and monitor serum calcium levels.[250],[251]
Thyroid dysfunction/disease: Prolonged use or excessive amounts of iodides (above the RDI) may cause or exacerbate thyroid gland disorders.[252],[253] In particular, prolonged high doses of iodine may cause or exacerbate thyroid gland hyperplasia, thyroid adenoma, goitre, and severe hypothyroidism.[254] Iodine-induced hyperthyroidism has been reported in euthyroid patients with previous thyroid diseases.[255] The current Australian recommended daily intake (RDI) for iodine is 150 mg/d, with the upper level of intake for adult men and women recommended to be 1100 mg/d.[256] Evaluate total combined daily intake of iodine from all sources in patients with thyroid disease/dysfunction, and monitor thyroid hormone levels if altered thyroid function is suspected. Doses in excess of RDI should only be used under professional supervision.[257]
Verapamil: Hypercalcaemia induced by high doses of vitamin D (i.e. doses >2,000 IU/d or 50 µg/d) can reduce the effectiveness of verapamil in atrial fibrillation. Avoid vitamin D doses above 2,000 IU/d (50 µg/d) and monitor serum calcium levels in people taking vitamin D and verapamil concurrently.[258],[259]
Low Level Cautions
Amiloride: This thiazide and potassium-sparing diuretic has conflicting information regarding a potential interaction with zinc. Amiloride has been reported to lead to zinc deficiency, and also reduce zinc excretion, leading to zinc accumulation. Monitor zinc status.[260],[261]
Amiodarone: Use cautiously in patients on this medication and monitor for symptom changes.
This class III anti-arrhythmic drug contains iodine and concomitant use with iodine may increase the risk of high iodine levels and altered thyroid function.[262],[263]
Conflicting information exists regarding potential interactions between amiodarone and vitamin B6. Preliminary research suggests that vitamin B6 can exacerbate amiodarone-induced photosensitivity. Other research suggests a protective effect.[264],[265]Angioplasty: There is some concern that when antioxidant vitamins, including betacarotene, are used together they might have harmful effects in patients after angioplasty. They may prevent beneficial vascular remodeling in patients after angioplasty by promoting fibrosis at the site of angioplastic intervention. Patients should avoid taking supplements of these vitamins immediately before and following angioplasty without the supervision of a healthcare professional.[266],[267]
Antibiotics: Separate doses by at least 4 hours.Iron may form insoluble complexes with certain antibiotic medications, and can result in reduced antibiotic efficiency.[268],[269],[270]
Manganese may form insoluble complexes with some antibiotics.[271],[272]
Anticonvulsant medication (including carbamazepine and valproate/valproic acid): Nicotinamide has been reported to cause an increase in plasma levels of anticonvulsant medication, due to the inhibition of cytochrome P450 pathways.[273],[274] This is based on animal studies and case reports using large doses (60-80 mg/kg/d), and the clinical significance of this interaction is unknown. The interaction is likely to be insignificant when using smaller doses; however, it is advised to monitor patients taking vitamin B3 alongside anticonvulsant medication.
Copper deficiency: Molybdenum has a copper-chelating effect and may theoretically lower serum copper levels. Use cautiously in patients with copper deficiency or metabolic disorders that decrease copper.[275],[276]
Gout: Large doses of niacin or nicotinamide may impair uric acid excretion and worsen hyperuricaemia in patients with gout.[277],[278],[279] Monitor symptoms and uric acid levels in patients with a history of gout if using large doses of vitamin B3.
HMG-CoA reductase inhibitors: The use of vitamin B3 alongside cholesterol-lowering medication is conflicting. For example, vitamin B3 alongside drugs such as lovastatin and simvastatin has been found to reduce requirements for statin medication as B3 may improve patient’s lipid profile.[280],[281],[282] However, some reports also suggest vitamin B3 can increase adverse effects of cholesterol-lowering drugs.[283],[284] Whilst the majority of the evidence supports the use of vitamin B3 alongside statin medication and adverse effects are solely based on case reports,[285],[286] caution is warranted. Beneficial interaction is likely, however patients should be monitored and if adverse symptoms occur vitamin B3 should cease.
Insulin and other hypoglycaemic medications: Monitor blood glucose and symptoms.Niacin and nicotinamide can interfere with blood glucose control requiring dosing adjustment of antidiabetic agents,[287] which may cause hyperglycaemia, abnormal glucose tolerance, and glycosuria in diabetic patients. About 10% to 35% of diabetic patients may need adjustments in hypoglycaemic therapy when niacin/nicotinamide is added to their regime.[288],[289]
Chromium may have insulin sensitizing effects and may reduce the requirement for hypoglycaemic medications, consequently increasing the risk of hypoglycaemia as well.[290],[291]
Levodopa: Vitamin B6 at doses of 5 to 25 mg and above, may enhance the metabolism of levodopa, reducing its anti-parkinsonism effects. Monitor patients when combining.[292],[293]
Nonsteroidal anti-inflammatory drugs (NSAIDs): Separate doses by at least 2 hours.
Zinc may form insoluble complexes with certain NSAIDs.[294],[295]
There is some evidence that NSAIDs might increase chromium levels by increasing chromium absorption and retention,[296] however this was only seen in an animal model with no case reports or trials demonstrating this.[297]
Pregnancy, Breastfeeding and Children
Pregnancy
Doses of choline of up to 3 g/d for pregnant and lactating women up to 18 years of age, and 3.5 g/d for women 19 years and older are not expected to cause adverse effects.[299],[300]
The upper tolerable limit of selenium per day during pregnancy is 400 µg/d.
No risks associated with vitamin K were found in humans although research is limited or unavailable (a tolerable upper intake level for vitamin K in pregnancy has not been set).[302],[303]
Breastfeeding
Appropriate for use.Vitamin D is safe when used in doses below the tolerable upper intake level (UL) of 4,000 IU/d.[304]
Choline is likely safe when used orally and appropriately. Doses of choline up to 3 g/d for pregnant and lactating women up to 18 years of age, and 3.5 g/d for women 19 years and older are not likely to cause adverse effects.[305],[306]
The upper tolerable limit of selenium per day during lactation is 400 µg.
No risks associated with vitamin K were found in humans although research is limited or unavailable (a tolerable upper intake level for vitamin K during lactation has not been set).[308],[309]
Children
Appropriate for use.
Please note the following recommended intake of vitamin D for children: Infants from 0-6 months should not exceed the UL of 1,000 IU/d. Infants aged 6-12 months should not exceed the UL of 1,500 IU/d. Children aged 1-3 years should not exceed the UL of 2,500 IU/d. Children aged 4-8 years should not exceed the UL of 3,000 IU/d. Children aged nine years and older should not exceed the UL of 4,000 IU/d; however, much higher doses are often needed for the short-term treatment of vitamin D deficiency. Some research shows that giving vitamin D 14,000 IU/week for a year in children aged 10-17 is safe[310],[311]; though intakes of 2,000 – 3,000 IU/d may cause toxicity symptoms in some children as may doses of 1,000 IU/d in hypersensitive infants.[312]
Do not exceed the stipulated Upper Limits (UL) of iodine – 200 mcg/d for children 1 to 3 years, 300 mcg/d for children 4 to 8 years, 600 mcg/d for children 9 to 13 years and 900 mcg/d for adolescents.[313]
No information was available for zinc, vitamin C, vitamin B1, vitamin B2, vitamin B3, vitamin B5 and vitamin B6.
Toxicity
Toxicity is rare as excessive magnesium intake can be excreted via the kidneys.[314] Hypermagnesaemia, although rare, is seen mostly in the elderly, people with renal insufficiency, dialysis or with serious bowel disorders.[315]
MGXPCA
