Micronutrients in Pregnancy

Introduction

Adequate maternal micronutrient status is especially critical during pregnancy and lactation. This is because pregnancy is a period of increased metabolic demands, involving changes in the woman’s physiology and the requirements of a growing fetus. During this time, inadequate stores or intake of vitamins or minerals, referred to collectively as micronutrients, can have adverse effects on both the mother and the fetus. The maternal effects are anemia, hypertension, complications of labor and even death, while the fetal effects include stillbirth, pre-term delivery, intrauterine growth retardation, congenital malformations, reduced immunocompetence and abnormal organ development.¹

Causes of micronutrient deficiency

Poor quality diet The main cause of multiple micronutrient deficiencies is a poor quality diet, often due to an inadequate intake of animal source foods (meat and/or milk), especially in developing countries.

Increased demand In pregnancy and/or lactation, the requirements of most nutrients are higher, increasing the risk of inadequate intake.

Gene polymorphism This contributes to micro-nutrient deficiencies by impairing the absorption or altering the metabolism, resulting in suboptimal maternal status of single nutrients. For example, folate deficiency may cause maternal polymorphisms, which may increase the risk of neural tube defects.

Phytates and polyphenols The presence of these substances in the diet limit the absorption of foods that are high in unrefined grains and legumes, even though the amount of nutrients consumed may be adequate.

Diseases Diseases like malaria and infection with intestinal parasites also impair status and alter the metabolism of multiple micronutrients.²

Micronutrient intakes and pregnancy outcome

It is well known that deficiencies of certain micronutrients can contribute to abnormal prenatal development and/or pregnancy outcome. These include folate, iron, and iodine deficiencies. Less well recognized for their importance are deficiencies of B-vitamins (and subsequently elevated plasma homocysteine concentrations), vitamin D, zinc, copper and iodine. There is growing evidence that maternal antioxidant status is important to prevent abnormal pregnancy outcomes. In lactation, maternal status of the above micronutrients (except zinc) affects their concentrations in breast milk.²   Adequate studies are not available to provide evidence to confirm the safety of boron in pregnancy and nursing. It is best to avoid boron supplementation in pregnancy due to potential effects on estrogen metabolism.³

A review by Ramakrishnan et al⁴   concluded that

• Supplementation with zinc, calcium and magnesium improved pregnancy outcomes
• Vitamin A supplementation may be associated with reduced maternal mortality and increased birthweight
• Folate supplementation prevents neural tube defects
• Iron supplementation increases hemoglobin levels
• Vitamin C deficiency may result in preterm delivery
• Severe maternal iodine deficiency leads to mental retardation and cretinism
• The B-complex vitamins, copper and selenium may also affect pregnancy outcomes

Importance of various micronutrients during pregnancy

Calcium

The fetal skeleton undergoes rapid mineralization, which increases the demand for calcium (Ca²⁺). This additional demand is met by significant transplacental Ca²⁺transfer from the mother, especially during the last trimester. This, coupled with the obligate loss ofCa²⁺in the breast milk during lactation, jeopardizes the maternal bone mineral homeostasis. During pregnancy, increased intestinal absorption ofCa²⁺from the gut, mainly due to higher generation of calcitriol (1,25 dihydroxy vitamin D), helps in maintaining maternalCa²⁺levels. The considerable changes in bone mineral metabolism during pregnancy are associated with future risk of osteoporosis, particularly in India, as a significant proportion of pregnancies occur in the early twenties when peak bone mass is not yet achieved. Further, malnutrition, anemia and vitamin D deficiency are commonly encountered in this age group. This may have an impact on future bone health of the mother.⁶

In addition, a number of observational studies have led to the hypothesis that an increase in Ca²⁺ intake during pregnancy might reduce the incidence of hypertension and pre-eclampsia among women with low Ca²⁺ intake. The decrease in the risk of pre-eclampsia was more pronounced when the women were either at risk of pre-eclampsia or when they had lower baseline Ca²⁺ intakes. Although there was no effect of Ca²⁺ supplementation on stillbirth or death before discharge from the hospital, the incidence of low birthweight was low.⁷

Calcium supplements during pregnancy seem also to have a more sustained effect in the neonatal period and infancy. In a follow-up study of 591 children, the systolic blood pressure was lower in children of Ca²⁺-supplemented mothers as compared to children of mothers given placebo.⁷

These findings were confirmed in a recent meta-analysis, which concluded that additional intake of Ca²⁺during pregnancyis an effective measure to reduce the incidence of pre-eclampsia, especially in women at high risk of pre-eclampsia due to ethnicity, gender, age, high BMI and in those with low baselineCa²⁺intake.⁸

Vitamin D

Recent data suggest that vitamin D, through its effects on immune function and surveillance, plays a role beyond Ca²⁺ and bone metabolism on the health status of both the mother and her fetus. Following birth, this process persists; the lactating mother continues to be the main source of vitamin D for her infant. Thus, during both pregnancy and lactation, maternal deficiency predicts fetal and infant deficiency.⁹

Vitamin D itself is devoid of biological activity, but enzymatic conversion to 1,25-dihydroxyvitamin D [1,25(OH)₂D] generates the hormonal form with diverse biological activities. The actions of 1,25(OH)₂D are mediated through specific, high affinity binding to the vitamin D receptor (VDR), which is present in multiple tissues. It has been recently discovered that the VDR and VDR signaling pathways play important roles in the placenta. Human placental trophoblasts express the VDR, and the P450 cytochromes encoded by the CYP27B1 and CYP24A1 genes. Trophoblasts produce as well as respond to 1,25(OH)₂D. 1,25(OH)₂D regulates synthesis of hormones involved in pregnancy and influences the trophoblast anti-inflammatory and anti-microbial responses. In early pregnancy, 1,25(OH)₂D induces decidualization, which is essential for implantation. Moreover, CYP27B1 modulates immune function during early gestation and vitamin D deficiency is associated with bacterial vaginosis, impaired calcium metabolism and fetal growth, pre-eclampsia, insulin resistance, gestational diabetes mellitus and primary cesarean section.¹⁰

An association between vitamin D intake during pregnancy and birthweight has also been found. It has been reported that with every additional 40 IU (1 ug) of maternal vitamin D intake, there was an associated increase of 11 gm in birthweight.¹¹

Currently, the American College of Obstetrics and Gynecology and the Institute of Medicine recommend 600 IU of daily vitamin D supplementation during pregnancy to support maternal and fetal bone metabolism.¹²     The recommended ratio of calcium and vitamin D is 2:1; in pregnancy, the daily requirement is 1000-1200 mg of calcium and 600 IU of vitamin D.

There is a strong relationship between maternal and fetal (cord blood) circulating 25-hydroxyvitamin D levels such that maternal vitamin D deficiency is mirrored by neonatal vitamin D deficiency. Vitamin D status during pregnancy appears to play a role in fetal skeletal development, tooth enamel formation, general fetal growth and development.¹¹

A Cochrane review¹³   of the efficacy of vitamin D supplementation during pregnancy found that women who received vitamin D supplements during pregnancy had higher concentrations of vitamin D in serum at term than women who received no intervention or a placebo. It was also observed that women who receive vitamin D supplements during pregnancy less frequently had a baby with a birthweight below 2500 grams.

Zinc

Zinc (Zn) is a trace element and an essential constituent of over 200 metalloenzymes participating in carbohydrate and protein metabolism, nucleic acid synthesis, and antioxidant functions. Its role in vital functions like cellular division and differentiation makes it essential for successful embryogenesis. During pregnancy, Zn is important for fetal brain development and also assists in labor.¹  

The requirement of Zn during the third trimester is approximately twice as high as that in nonpregnant women. But the average diet in pregnant women has been found to contain not more than 50% of the daily requirement of Zn.⁵

Zinc deficiency has been associated with complications of pregnancy and delivery, such as pre-eclampsia, premature rupture of membranes and pre-term delivery, and with fetal growth retardation and congenital abnormalities.¹

Zinc supplementation is especially beneficial in developing countries where Zn deficiency is more prevalent.⁵   Some trials of Zn supplementation in developing countries have found significant benefits on pregnancy complications or birth outcomes.¹   In cases of fetal growth restriction, Zn is used to improve fetal growth. Other benefits of supplementation include reduced incidence of pregnancy-induced hypertension or low birthweights. In a randomized double-blind placebo-controlled trial by Goldenberg et al ,⁵   zinc supplementation led to a significantly greater birthweight and head circumference compared to the placebo group.   One trial in a developing country found that zinc-supplemented pregnant women had fetuses with enhanced neurobehavioral development, compared with those of non-supplemented women,   highlighting the importance of adequate zinc supply during pregnancy.¹

Zinc deficiency in utero adversely affects the development of the fetal immune system also. Trials in developing countries have found that babies whose mothers were given Zn supplements in pregnancy had improved immune function and a reduction in diarrhea and respiratory illnesses in infancy, suggesting effects on immune competence that persist beyond birth.¹

In 17 out of 41 observation studies, maternal Zn status was associated with birthweight. Some other trials showed benefits like reduction in premature delivery, higher birthweight, and reduction in hypertension. In Peruvian women, Zn supplementation did not affect fetal dimensions, birthweight, or the incidence of preterm delivery, but it did reduce fetal heart rate, and increase heart rate accelerations and variability, and fetal movements, which was interpreted to indicate better fetal development. In Bangladesh, maternal supplementation in pregnancy reduced morbidity of low birthweight infants in the first 6 months of life. ²  

Manganese

Manganese (Mn) is an essential nutrient for humans and animals, and plays a role in bone formation, protein and energy metabolism, metabolic regulation, and functions as a cofactor in a number of enzymatic reactions.¹⁴

Diet is the main source of Mn under normal circumstances; current requirements for the mineral are shown in Table 1.⁵

Manganese activates enzymes of fatty acid synthesis, hepatic gluconeogenesis, and is a critical component of Mn superoxide dismutase (SOD) involved in mitochondrial oxidant defense system. ¹⁵   Manganese SOD is also thought to protect the placenta from oxidative stress by detoxifying superoxide anions. ⁵  

Overt Mn deficiency (characterized by bone abnormalities, connective tissue defects and alterations in carbohydrate and lipid metabolism) is rare. Subclinical effects of Mn deficiency have not been well studied, but recent evidence suggests that this syndrome may include osteoporosis.¹⁴

In humans, Mn blood levels increase through pregnancy, and Mn crosses the placenta via active transport mechanisms. Postnatally, neonates and young infants exhibit increased gastrointestinal absorption of ingested Mn and decreased elimination mechanisms, possibly increasing their susceptibility to high Mn exposure.¹⁴  

In an experimental study by Ganeshan et al ,¹⁵   maternal Mn restriction increased the susceptibility of the offspring to high-fat-induced adiposity, dyslipidemia, and a proinflammatory state but did not affect their glycemic or insulin status.

In one study,   Mn concentration in the umbilical cord blood of neonates born to mothers with pre-eclampsia was less than that in controls.¹⁶

Iodine

Iodine requirements are increased ≥50% during pregnancy . Iodine deficiency during pregnancy can cause maternal and fetal hypothyroidism and impair neurological development of the fetus. The consequences depend upon the timing and severity of the hypothyroidism; the most severe manifestation is cretinism.

Endemic cretinism is characterized by multiple neurological defects, including deaf-mutism, diplegia, squint and mental deficiency. In moderate-to-severely iodine -deficient areas, iodine   supplementation before or during early pregnancy has been shown to prevent new cases of cretinism, increase birthweight, reduce rates of perinatal and infant mortality and generally increase developmental scores in young children by 10-20%. Two meta-analyses have estimated that iodine -deficient populations experience a mean reduction in IQ of 12-13.5 points.¹⁸

Control of this widespread problem in developing countries has focused on administration of iodized oil before or during pregnancy and on making iodized salt available in iodine-deficient settings.¹

Studies have shown that iodized oil provides a very satisfactory correction of severe iodine deficiency. A controlled trial¹⁹   carried out in the Western Highlands of New Guinea showed that intramuscular administration of iodized oil prior to conception can prevent endemic cretinism.

In order to study long-term outcomes of maternal iodine supplementation, two trials were started in 2008 in areas of low iodine status — Bangalore and Bangkok. The trials recruited pregnant women <14 weeks gestational age and randomized them to receive either a daily dose of 200 ug I (as KI) or an identical placebo throughout pregnancy . Both trials are ongoing, and women are followed up during pregnancy and at delivery. Child development is assessed at 6 weeks, 12 months and 24 months of age. The outcomes of these trials will make a major contribution to the evidence base for iodine supplementation of pregnant women living in areas of mild iodine deficiency.²⁰

Copper

Copper(Cu) and iron are both essential micronutrients. Because they can both accept and donate electrons, they are essential for many energy-dependent chemical reactions. During pregnancy , when cell proliferation and differentiation are going on, deficiency of these nutrients can lead to serious problems, which can persist into adulthood, with an increased risk of mental disorders, such as schizophrenia and, in animal models at least, hypertension and obesity. ²¹  

Copper is an essential cofactor for a number of enzymes involved in metabolic reactions, angiogenesis, oxygen transport and antioxidant protection, including catalase, SOD and cytochrome oxidase. During pregnancy, plasma copper concentrations significantly increase, returning to normal nonpregnant values after delivery.

Copper is essential for embryonic development. Table 1 summarises the current recommendations on intakes. The dietary intake of Cu in women aged between 19 and 24 years is generally below the recommended levels. Maternal dietary deficiency can result in both short-term consequences, including early embryonic death and gross structural abnormalities, and long-term consequences, such as increased risk of cardiovascular disease and reduced fertilization rates. Severe Cu deficiency can lead to reproductive failure and early embryonic death, whereas mild or moderate deficiency has little effect on either the number of live births or neonatal weight. ⁵  

Cu/Zn SOD is an important antioxidant known to be expressed in both maternal and fetal tissues. A recent observational Turkish study on 61 placentae from healthy pregnancies between 37- and 40-week gestation found that Cu concentrations positively correlated with neonatal weight. ⁵  

Magnesium

Magnesium (Mg) is an essential mineral required in relatively large amounts by humans. In a number of retrospective studies Mg levels during pregnancy were found to be associated with the risk of seizures in pre-eclampsia, prematurity and low birthweight. ⁷  

Magnesium plays important roles in physiology and pharmacology during pregnancy. It interferes with calcium uptake in the cells, resulting in decreased muscle contractility. This property forms the basis of its use in preterm labor. ²²

Some trials conducted in developed countries found fewer pre-term births and less intrauterine growth retardation with magnesium supplementation during pregnancy. ¹  

A study by Yamasaki ²³   found that

• Blood levels of total Mg, ionized Mg and intracellular ionized Mg of platelets become low in the 2nd trimester of pregnancy and thereafter.
• Urinary excretion of Mg does not change during the whole period of pregnancy .
• Intestinal absorption of Mg does not increase during pregnancy compared with the non-pregnant state.

These data suggest that pregnant women tend to become magnesium deficient. Moreover, Mg metabolic parameters of pregnant women with pre-eclampsia are relatively lower than those of healthy pregnant women. In obstetrical practice magnesium sulfate is frequently used as a drug of choice in the therapy of threatened premature delivery and eclampsia.

The effect of magnesium therapy on vascular endothelial growth factor (VEGF), placental growth factor (PlGF), nitric oxide (NO) metabolites, soluble fm-like tyrosine kinase-1 (sFlt-1) and endoglin levels and the effect of this treatment on the feto-maternal outcome was studied in pre-eclampsia (PE). Pre-eclampsia manifested as hypertension, proteinuria and decreased number and weight of live offspring relative to the control group.

Magnesium therapy ameliorated systolic hypertension and proteinuria and decreased sFlt-1, VEGF receptor-2 (VEGFR-2), VEGFR-3 and endoglin levels but increased NO metabolites. It also improved offspring weight. By its vasodilatory action and increased NO production, Mg is thought to increase placental blood flow and help fetal nutrition and development. Relief of placental ischemia decreases the production of antiangiogenic growth factors and restores the bioavailability of angiogenic factors (PlGF and VEGF). These changes resulted in better fetal outcome and an improved clinical picture of PE.

These findings are promising and encourage further study of the mechanism of action of Mg to support its widespread use in the prevention and management of the manifestations and complications of PE. ²⁴

Another beneficial effect of Mg is neuroprotection, as Mgadministration before preterm birth reduces the risk of cerebral palsy and major motor dysfunction. Since neonatal inflammatory cytokine levels correlate with neurological outcomes, Sugimoto et al ²⁵   evaluated the effect of Mgon cytokine production, and found that the mineralreduced cytokine production in intrapartum women, term and preterm neonates, demonstrating effectiveness in those at risk for inflammation-associated adverse perinatal outcomes. Further, the immunomodulatory effect mediated by Mgwas reversible. These findings establish a new paradigm for innate immunoregulation, whereby Mgplays a critical regulatory role in cytokine production and disease pathogenesis.

Conclusion

Vitamins and minerals, collectively referred to as micronutrients, have important influences on the health of pregnant women and the growing fetus. There is considerable evidence supporting the role of various micronutrients in determining pregnancy outcomes, such as low birthweight and prematurity. The problem of micronutrient deficiency is especially acute in developing countries like India, and all efforts should be made to prevent it by adequate supplementation with all the vital micronutrients in order to maintain maternal and fetal health. This is particularly important for women in high-risk categories, such as those who are complete vegetarian or have a poor quality diet, are heavy smokers or consume alcohol or are drug abusers, or have multifetal gestations.

References

1. Black RE. Micronutrients in pregnancy. British Journal of Nutrition 2001;85(S2):S193-S197.
2. Allen LH. Multiple micronutrients in pregnancy and lactation: an overview. Am J Clin NutrMay 2005;81(5):1206S-1212S.
3. Stargrove MB, Treasure J, McKee DL. Boron. Herb, Nutrient, and Drug Interactions: Clinical Implications and Therapeutic Strategies.pg 460.
4. Ramakrishnan U, Manjrekar R, Rivera J, Gonzles-Cosso T, Martorell R. Micronutrients and pregnancy outcome: A review of the literature. Nutrition Research 1999;19(1):103–159.
5. Mistry HD, Williams PJ. Theimportanceofantioxidantmicronutrientsinpregnancy. Oxid Med Cell Longev. 2011;2011:841749.
6. Mahadevan S,Kumaravel V,Bharath R. Calciumand bone disorders in pregnancy. Indian J Endocrinol Metab.2012 May;16(3):358-63.
7. Kolsteren PW, De Souza S. Micronutrients and Pregnancy Outcome. Available at http://www.jsieurope.org/safem/collect/safem/pdf/s2931e/s2931e.pdf. Accessed on August 16, 2012.
8. Patrelli TS,Dall’asta A,Gizzo S,et al. Calciumsupplementation and prevention of preeclampsia: a meta-analysis. J Matern Fetal Neonatal Med.2012 Aug 14.
9. Wagner CL,Taylor SN,Johnson DD,Hollis BW. The role of vitamin D in pregnancy and lactation: emerging concepts. Womens Health (Lond Engl).2012 May;8(3):323-40.
10. Shin JS, Choi MY, Longtine MS, Nelson DM. Vitamin D effects on pregnancy and the placenta. Placenta. 2010;31(12):1027-34.
11. Wagner CL, Taylor SN, Dawodu A, Johnson DD, Hollis BW. Vitamin D and its role during pregnancy in attaining optimal health of mother and fetus. Nutrients. 2012 Mar;4(3):208-30.
12. Urrutia RP,Thorp JM. Vitamin D in pregnancy: current concepts. Curr Opin Obstet Gynecol.2012 Mar;24(2):57-64.
13. De-Regil LM,Palacios C,Ansary A,Kulier R,Pena-Rosas JP. Vitamin D supplementation for women during pregnancy. Cochrane Database Syst Rev.2012 Feb 15;2:CD008873.
14. Zota AR, Ettinger AS, Bouchard M, Amarasiriwardena CJ, Schwartz J, Hu H, Wright RO. Maternal blood manganese levels and infant birthweight. Epidemiology. 2009 May;20(3):367-73.
15. Ganeshan M, Sainath PB, et al. Maternal Manganese Restriction Increases Susceptibility to High-Fat Diet-Induced Dyslipidemia and Altered Adipose Function in WNIN Male Rat Offspring. Exp Diabetes Res. 2011; 2011: 486316.
16. Jones EA, Wright JM, Rice G, Buckley BT, Magsumbol MS, Barr DB, Williams BL. Metal exposures in an inner-city neonatal population. Environ Int. 2010 Oct;36(7):649-54.
17. McClelland A. Micronutrients in Pregnancy. Available at http://www.stgeorgedgp.asn.au/education/uploadedFiles/ 1238369474641-5979.pdf. Accessed on August 16, 2012
18. Zimmermann MB. The effects of iodinedeficiency in pregnancyand infancy. Paediatr Perinat Epidemiol.2012;26 Suppl 1:108-17.
19. Pharoah P,Buttfield I,Hetzel B. Neurological damage to the fetus resulting from severe iodine deficiency during pregnancy. Int J Epidemiol.2012 Jun;41(3):589-92.
20. Melse-Boonstra A,Gowachirapant S,Jaiswal N,Winichagoon P,Srinivasan K,Zimmermann MB. Iodinesupplementation in pregnancyand its effect on child cognition. J Trace Elem Med Biol.2012 Jun;26(2-3):134-6.
21. Gambling L,Kennedy C,McArdle HJ. Iron and copperin fetal development. Semin Cell Dev Biol.2011 Aug;22(6):637-44.
22. Scheans P. The role of magnesiumsulfate in the prevention of cerebral palsy. Neonatal Netw.2012 Mar-Apr;31(2):121-4.
23. Yamasaki M. Recent Progress in MagnesiumResearch. Magnesiumand pregnancy. Clin Calcium.2012;22(8):1205-10.
24. Korish AA. Magnesiumsulfate therapy of preeclampsia: an old tool with new mechanism of action and prospect in management and prophylaxis. Hypertens Res.2012 Jul 5.
25. Sugimoto J,Romani AM,et al. Magnesiumdecreases inflam-matory cytokine production: a novel innate immunomodu-latory mechanism. J Immunol. 2012 Jun 15;188(12):6338-46.