Micronutrient supplementation for women of all ages TONY

Micronutrient supplementation for women of all ages TONY MANDER FRCOG NUFFI ELD MANO R HO SPITA L O XFO RD PAST PRE SIDE NT FO RU M O F F OO D AND HEALTH RS M LONDON

ROLE OF IMPORTANT NUTRIENTS IN PREGNANCY Ingredient Benefit Calcium is an essential nutrient during pregnancy and lactation that supports the growth and development of the foetus, especially because of its maternal-fetal transfer. Pregnancy places a significant demand on calcium, in that the dynamic balance of calcium storage is upset, and calcium is drawn from the maternal skeleton. Because most pregnant women do not consume the recommended quantity of calcium at any time in their lives, including the critical pregnancy and lactation periods, supplementation should be recommended to restore the balance. Iron stores in newborns are related to maternal iron status and the materno-fetal unit is dependent on exogenous iron, which is necessary to prevent iron deficiency in both mothers and infants. Studies show that women with fertility problems got pregnant with iron supplementation Vitamin D 3 Produced in the body when skin is exposed to sunlight, but vitamin D is also found in foods Essential for reduction of Preeclampsia, Gestational diabetes Folic acid fortification is associated with significant decreases in the prevalence of spina bifida Preconception folic acid is especially relevant for those who have previously taken the contraceptive pill Vitamin B 6 & B 12 Essential for reduction of Hyperhomocysteinaemia Research has shown that women who had previously had difficulty in conceiving saw a marked increase in their fertility after being given B 6; periods were regulated and incidence of pregnancy rose Study showed a 60% increase in sperm count in men after 2 -13 months of B 12 supplementation

ROLE OF IMPORTANT NUTRIENTS IN PREGNANCY Ingredient Benefit Thiamine Vitamin B 1 is needed for ovulation and implantation Riboflavin Deficiency linked with sterility, miscarriage and low birth weight West Z. , Fertility & Conception (2014) Niacin Vitamin B 3 is used in the carbohydrate metabolism to release energy; also important for the functioning of the CNS, digestive system, skin health, but it is also good for couples trying to conceive Pantothenic acid Vitamin B 5 is important for foetal development, so is essential before and at conception Vitamin E Research shows that taking vitamin E can increase fertility in both men and women Taking anti-oxidants can reduce age-related ovulation decline Copper Essential for development of brain; deficiency results in teratogenicity.

Multiple-micronutrient supplementation for women during pregnancy Cochrane 17 April 2017 Cochrane Pregnancy and Childbirth's Trials Register (11 March 2015). This systematic review included 19 trials involving 138, 538 women, but only 17 trials involving 137, 791 women contributed data. pregnant women who supplemented their diets with multiple micronutrients with iron and folic acid with pregnant women who received a placebo or supplementation with iron, with or without folic acid. Overall, pregnant women who received multiple-micronutrient supplementation had fewer low birthweight babies and small-for-gestational-age babies than pregnant women who received only iron, with or without folic acid. provide a strong basis to guide the replacement of iron and folic acid with multiplemicronutrient supplements for pregnant women in low- and middle-income countries where multiple-micronutrient deficiencies are prevalent among women. The evidence for the main outcomes was found to be of high quality.

Importance Calcium is the most abundant mineral in the human body, with over 99% of the amount present being found in the bones and teeth For the growth and maintenance of healthy bones it is essential that there is sufficient calcium intake, otherwise there is risk of developing osteoporosis

Age-related changes in bone mass Attainment of peak bone mass Consolidation Bone mass Age-related bone loss Menopause Men Fracture threshold Women 0 20 Age (years) Compston JE. Clin Endocrinol 1990; 33: 653– 682. 50

Risk factors for osteoporosis The School run Perception of risk

Clinical Evidence Effect of calcium supplementation on bone resorption in pregnancy and the early postpartum: a randomized controlled trial in Mexican women Conclusion: Calcium administered during pregnancy and the early postpartum period, to women with intakes around adequacy, was associated with reduced bone resorption and, thus, may constitute a practical intervention to prevent transient skeletal loss associated with childbearing - Nutr J. 2014 Dec 16; 13(1): 116.

PIH, Pre eclampsia & Eclampsia Pregnancy Induced hypertension: It is hypertension in pregnancy Diastolic BP >90 mm Hg and systolic BP >140 mm Hg Preeclampsia: Development of hypertension with proteinuria (protein in the urine) or edema between the 20 th week of pregnancy and the end of the 1 st week postpartum Eclampsia: Eclampsia occurs when preeclampsia is complicated by seizures or coma

Calcium & PIH (Pregnancy Induced Hypertension) complication According to WHO, Hypertension complicates approximately 10% of all pregnancies worldwide, and pre-eclampsia and eclampsia are major causes of maternal and perinatal morbidity and mortality Pre-eclampsia and eclampsia complicate 2– 8% of pregnancies and, overall, 10– 15% of direct maternal deaths are associated with these conditions

Meta-analysis of randomized trials from developing countries 0. 00 -12. 00 -20. 00 -45. 00 -60. 00 -59. 00 -80. 00 Gestational Hypertension Preeclampsia Pre-term birth Calcium supplementation during pregnancy is associated with a reduction in risk hypertension, pre-eclampsia neonatal mortality and pre-term birth in developing countries. BMC Public Health. 2011; 11(S 3): 518

Vitamin D 3 Important for the intestinal absorption of both Calcium & Magnesium Vitamin D deficiency in pregnancy has been associated with: • Increased risk of pre-eclampsia • Preterm birth • Impaired fetal skeletal formation causing infant rickets (softening of bones commonly leading to deformities and/or fractures) and • Reduced bone mass

Vitamin D 3 and pre eclampsia Maternal vitamin D deficiency is an independent risk factor for preeclampsia. Low maternal serum 25(OH)D concentrations increase pre-eclampsia risk and that vitamin D supplementation lowers this risk. Ann Nutr Metab. 2013; 63(4): 331 -40

Vitamin D pregnancy Cochrane Jan 2016 Vitamin D is produced by the human body from exposure to sunlight and can also be consumed from foods such as fish-liver oils, fatty fish, mushrooms, egg yolks, and liver. During pregnancy, vitamin D deficiency may develop Vitamin D supplementation during pregnancy has been suggested to safely improve pregnancy and infant outcomes. This review included 15 randomised controlled trials involving 2833 women. Nine trials compared the effects of vitamin D alone with no supplementation or a placebo and six trials compared the effects of vitamin D and calcium with no supplementation further rigorous randomised trials are required to confirm these effects.

Vitamin D supplementation for women during pregnancy New studies have provided more evidence on the effects of supplementing pregnant women with vitamin D alone or with calcium on pregnancy outcomes. Supplementing pregnant women with vitamin D in a single or continued dose increases serum 25 -hydroxyvitamin D at term and may reduce the risk of pre-eclampsia, low birthweight and preterm birth. However, when vitamin D and calcium are combined, the risk of preterm birth is increased. The clinical significance of the increased serum 25 -hydroxyvitamin D concentrations is still unclear. In light of this, these results need to be interpreted with caution. Data on adverse effects were lacking in all studies. Cochrane Jan 2016

Role of Calcium in women’s health

Menopause The average that women go through the menopause is 52, but a woman could start to experience menopausal symptoms between the ages of 45 and 55. About 8 in every 10 women will have additional symptoms for some time before and after their periods stop. Common symptoms include: • Hot flushes (75% of women experience this) • Night sweats • Difficulty sleeping • Reduced sex drive • Problems with memory and concentration • Vaginal dryness NICE Guidelines Nov 2015 NG 23 • • Headaches Low mood Anxiety Palpitations Joint stiffness Reduced muscle mass Urinary tract infections

Turkey and the menopause The menopausal transition takes around four years for most women The highest incidence of hot flashes and sweating occurred in 2010 in Turkey, reaching 97% of the women surveyed. Similarly as in the case of hot flashes, the highest frequency of occurrence of discomfort associated with muscle and joint pain occurred in Turkey, reaching 95% of the surveyed women NICE Guidelines Nov 2015 NG 23

How much calcium do you need? During pregnancy the body increases the amount of calcium it absorbs, so the baby is still able to get enough calcium without the intake being increased. The RNI for calcium is 700 mg. NRV(RDA)= 800 mg. The RNI for calcium while breastfeeding increases to 1250 mg per day Without a good dietary dairy intake, achieving these amounts may be difficult.

How much calcium do you get? A pregnant woman would have to consume on a daily basis: OR

How much calcium do you get? Women who are breastfeeding would have to consider over 5 glasses a day! On a single day this might be achievable, however to keep this up daily would be difficult. Calcium supplementation can help achieve the required amounts of calcium intake without the extra consumption of food. Most calcium supplements will also contain vitamin D – vital for the absorption of calcium.

Healthy bone of a 30 year old woman Osteoporotic bone of a 70 year old woman © Tim Arnett. University College London

Osteoporosis Current Guidelines?

Vitamin D and post menopause • Vitamin D is known to play a role in calcium homeostasis and skeletal mineralization, and serum 25(OH)D levels <50 nmol/L are associated with increased bone turnover, bone loss, and poorer outcomes for frailty and hip fracture. • There is growing evidence that vitamin D regulates many other cell functions, and the potential effect of vitamin D on skeletal muscle mass and strength is receiving recent attention. • Vitamin D promotes protein synthesis and calcium and phosphate transport in muscle, thus influencing muscle strength. Vitamin D deficiency is associated with a loss of muscle mass and strength in older people, and a decline in physical performance. • Muscle strength and physical performance are linked to risk of falls in older individuals. Low 25(OH)D levels <25 nmol/L are associated with an increased risk of falls and recur- rent falls. • There is evidence that vitamin D supplementation (700– 1000 IU/d) reduces the risk of falls by 14– 19%, • Although the benefit may be limited to those with low vitamin D status.

Synergistic combination of Ca + Mg + Zn + Vit. D 3 Calcium: For bone mineralization and preservation of bone mass & bone mineral density Clinical Evidence: Six months of breast feeding is associated with 5. 1% bone mineral density (BMD) loss.

Magnesium needs active vitamin D 3 for absorption Magnesium deficiency Low active Vitamin D 3 NORMOCALCEMIA cannot be maintained until the deficit of MAGNESIUM is corrected

Clinical evidence- Cochrane (Feb 2015) The evidence for a 14% relative reduction in preterm birth for zinc compared with placebo was primarily represented by trials involving women of low income and this has some relevance in areas of high perinatal mortality. UNICEF is already promoting antenatal use of multiple-micronutrient supplementation, including zinc, to all pregnant women in developing countries. Finding ways to improve women's overall nutritional status, particularly in low-income areas, will do more to improve the health of mothers and babies than supplementing pregnant women with zinc alone. In low- to middle- income countries, addressing anaemia and infections, such as malaria and hookworm, is also necessary.

Moderate regular intake only. . Vitamin D The daily recommended dose of vitamin D varies from 400 IU to 2, 000 IU. Different experts from all around the world have recommendations based on life stage and race. One off mega doses are not ideal (unless severely deficient), but small daily doses are recommended to keep vitamin D levels constant throughout the year. Very high levels of vitamin D (50, 000 IU daily) can cause: hypercalcemia poor appetite, nausea and vomiting, weakness, frequent urination and kidney problems also may occur. Calcium Very high levels of calcium can cause: kidney stone formation, kidney damage and failure, abnormal heart rhythms, calcification in areas of the body other than bone tissue, dementia and coma. Too much calcium can also interfere with iron absorption.

Moderate regular intake only. . Magnesium Very high levels of magnesium can cause: Diarrhoea, as magnesium acts as a laxative. Stomach upset, nausea, vomiting and abdominal cramping. Severe drops in blood pressure, arrythmias , have been reported after taking excessive doses of magnesium. Zinc Very high levels of zinc can cause: Upset stomach, vomiting and diarrhoea. High doses of zinc have also been associated with decreased urine output, which is the number one reason for hospitalisation associated with zinc toxicity. Excess amounts of zinc lead can lead to heavy metal poisoning.

Importance of Micronutrient Supplementation. . Micronutrient supplementation is a vital part of: • Prenatal care programmes • Avoidance of pregnancy complications • Health and lifestyle • The avoidance of disability in older age after the menopause • The Future -The Human Microbiome

Useful websites NICE Guidelines Ng 23, Diagnosis and Management of Menopause https: //www. nice. org. uk/guidance/ng 23 National Osteoporosis Society www. nos. org. uk British Menopause Society www. thebms. org. uk Women’s Health Concern www. womens-health-concern. org FRAX TOOL – Osteoporosis www. shef. ac. uk/FRAX

ROLE OF IMPORTANT NUTRIENTS IN PREGNANCY Ingredient Benefit Magnesium Essential for avoiding pregnancy complications like Preeclampsia Lower Mg levels can be a cause of infertility and miscarriage because of oxidation of cell membranes Manganese Deficiencies in this trace element can lead to defective ovulation – lack of Mn may inhibit the synthesis of cholesterol, limiting the synthesis of sex hormones and thus leading to infertility Selenium Prevents chromosome breakage, known to cause miscarriage and birth defects Also useful for healthy formation of sperm; deficiency reduces the density and motility of sperm Zinc 82% of the pregnant women worldwide have inadequate zinc intakes. Poor maternal zinc status has been associated with foetal loss, congenital malformations, IUGR, reduced birth weight, prolonged labour and preterm or post-term deliveries (Paediatr Perinat Epidemiol. 2012 July ; 26(0 1): 118– 137)

Zinc is an essential mineral known to be important for many biological functions including – • Protein synthesis • Cellular division • Nucleic acid metabolism

Magnesium deficiency leads to: Synthesis & release of PTH Active vitamin D 3 Bone resorption Urinary Ca 2+ excretion

Multiple-micronutrient supplementation for women during pregnancy Cochrane 17 April 2017 Cochrane Pregnancy and Childbirth's Trials Register (11 March 2015). This systematic review included 19 trials involving 138, 538 women, but only 17 trials involving 137, 791 women contributed data. pregnant women who supplemented their diets with multiple micronutrients with iron and folic acid with pregnant women who received a placebo or supplementation with iron, with or without folic acid. Overall, pregnant women who received multiple-micronutrient supplementation had fewer low birthweight babies and small-for-gestational-age babies than pregnant women who received only iron, with or without folic acid. provide a strong basis to guide the replacement of iron and folic acid with multiplemicronutrient supplements for pregnant women in low- and middle-income countries where multiple-micronutrient deficiencies are prevalent among women. The evidence for the main outcomes was found to be of high quality.

Osteoporosis • 1 in 2 women over the age of 50 are expected to break a bone during their lifetime, the incidence is higher in women due to the depletion of oestrogen during the menopause. • Women can lose up to 20% of their bone density in the five to seven years after the menopause. • Osteoporosis is estimated to affect 200 million women worldwide - approximately one-tenth of women aged 60, one-fifth of women aged 70, two-fifths of women aged 80 and two-thirds of women aged 90 • In women over 45 years of age, osteoporosis accounts for more days spent in hospital than many other diseases, including diabetes, myocardial infarction and breast cancer • In 2009, there were approximately 24, 000 hip fractures estimated in Turkey, 73% of which were found in women. NICE Guidelines Nov 2015 NG 23

Importance of Micronutrient Supplementation. . • After multimicronutrients supplementation (MMS) to undernourished anemic pregnant women: -25% and 38% reduction in early infant mortality was observed respectively -MMS reduced early infant mortality than observed with iron and folic acid supplement • Thus, micronutrient supplementation has a vital part of overall strengthening of prenatal-care programs

Clinical Evidence: Effect of multiple micronutrient supplementation on maternal nutrient status, infant birth weight and gestational age at birth in a low income, multiethnic population. Michael Crawford et al. Institute of Brain Chemistry and Human Nutrition

Clinical evidence • Observational studies have found an inverse association between maternal calcium intake and hypertension disorders of pregnancy • Hofmeyr et al conducted a study which assessed the effects of supplementation with 1 g or more of calcium per day on hypertensive disorders and other maternal and child outcomes in non-hypertensive pregnant women at less than 34 weeks of gestation. • The study concludes that calcium supplementation reduces the risk of hypertension and pre-eclampsia during pregnancy