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Maternal-Fetal Medicine

Micronutrients and Pregnancy Outcomes: Implications and Challenges

Prakesh S. Shah, MBBS, DCH, MRCP, MRCPCH

New evidence shows that pregnant women who supplement their diet with multiple micronutrients, as opposed to just iron and folic acid, have lower risks for low-birth-weight infants. What are the implications and challenges associated with improving fetal growth rates through the use of this supplementation?

Dietary insufficiency of major and minor nutrients is widely prevalent among women of child-bearing age.1 The rates vary globally; however, no areas of the world are immune.2 Periconceptional nutritional status has major and direct influence on maternal and child health. Iron deficiency anemia is the most prevalent nutritional deficiency among pregnant women. Based on existing knowledge at the time, the World Health Organization (WHO) in 2003 recommended and promoted supplementation of iron and folic acid to pregnant women rather than multiple micronutrients (MMN). With the joint efforts of UNICEF, WHO, and other regional partners, pregnant women receive iron–folic acid combination (IFA) free of charge during pregnancy in many parts of the world.3

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WHAT IS THE EVIDENCE OF EFFECTIVENESS OF MMN?

With the increasing awareness of coexisting major and minor nutrient deficiencies, several randomized controlled trials have recently evaluated the effectiveness of MMN during pregnancy. In a systematic review and meta-analyses of 13 randomized controlled trials of more than 30,000 women, Shah and Ohlsson compared traditional IFA with MMN (containing IFA).4 A clinically and statistically significant reduction in the risk for low-birth-weight (LBW) births was identified among women who received MMN compared to IFA (relative risk [RR], 0.82; 95% CI, 0.73-0.92). Birth weight was higher among infants whose mothers received MMN compared to IFA, by an average of 62 g (95% CI, 49-75 g). There was no difference in the risk for preterm and small-for-gestational-age births between the two groups. This translates to an 18% (95% CI, 8%-27%) reduction in LBW births with MMN supplementation.

The number of women required to receive supplementation to prevent one LBW infant was 50 (95% CI, 33-100). Comparison of MMN with placebo also revealed similar results. Globally, a staggering 1.5 million LBW births could be avoided annually if all pregnant women received MMN during pregnancy.4 Given the long-term consequences of LBW births throughout the entire life span of the survivors, this intervention has a major health-promoting impact.5 Interestingly, it was noticed from trials that time of initiation of MMN during pregnancy had little effect; ie, women who started MMN before 20 weeks’ gestational age had similar benefit to those who started MMN after 20 weeks of gestation.

The components of MMN present in the majority of studies that showed effectiveness included vitamin A ≥2,640 IU, vitamin D ≥200 IU, vitamin E ≥10 mg, vitamin B1 ≥1.4 mg, folic acid ≥400 μg, vitamin C ≥70 mg, zinc ≥15 mg, and iron ≥30 mg; however, authors were unable to distinguish a clear composition of MMN that was essential. It is important to note that the MMN composition includes IFA.4

Mechanisms of beneficial action of MMN during pregnancy are most likely multifactorial. A generalized improvement in the immune function, reduction of risk of infection, improvement in energy metabolism, improvement in anabolic processes, appropriate reactions to stressors (as compared to heightened stress exhibited by malnourished mothers), higher fluid retention, increased plasma volume expansion, and improved hemoglobin are proposed mechanisms.6,7

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WHAT ARE THE IMPLICATIONS OF NEW EVIDENCE?

These findings have clear implications for maternal-child health initiatives in North America and around the world. All of these trials were conducted in areas of the world where nutritional deficiencies are highly prevalent and where the majority of births occur. Current practice of IFA supplementation needs to be challenged in light of this new evidence.

Women require additional supplementation during pregnancy, and selective supplementation to target only anemia may not be adequate.2 Based on common practice, the majority of women in the Western world receive MMN as a supplement in addition to IFA. Approximately 75% to 80% of women in Canada receive MMN during pregnancy. However, the numbers may not be similar in all developed nations, particularly in women who are socially disadvantaged, who do not have adequate medical insurance coverage, or who are malnourished at the beginning of their pregnancy.2 Such women should be targeted to receive MMN supplementation as soon as pregnancy is detected. There is even an argument for prenatal supplementation for these women similar to that of folic acid. Improvement of the nutritional milieu of these mothers during the preconceptional period may prepare them to sustain pregnancy and reduce adverse consequences.2

The interaction of various components of MMN should be considered when combining multiple nutrients and preparing formulations. For example, absorption of iron is affected by the presence of vitamin C; high intake of iron can affect zinc and copper absorption; selenium and vitamin E interact with each other; and plasma folate can affect zinc absorption.2

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CHALLENGES

Individual Level Challenges
Awareness, access, and tolerability are issues at an individual level. Knowledge of the importance of MMN during or even before pregnancy is lacking among women of childbearing age. It has taken 10 years for increased awareness of the importance of folic acid in the preconceptional period. Programs to highlight the importance of MMN would include educational campaigns in high school, public events, advertisements at local pharmacies, use of media, and promotion in prenatal clinics.

The majority of malnourished women live in socially disadvantaged community sectors where medical or health insurance coverage may not be adequate to cover the cost of MMN. In addition, lack of prenatal care, unplanned pregnancy, shorter interpregnancy interval, young maternal age, and preexisting malnutrition are common issues among women in low-income neighborhoods. Tolerance of MMN could be an issue for women with coexisting nausea and vomiting during pregnancy. This may preclude certain women from taking any additional tablets. They should be encouraged to take MMN when their symptoms subside, as benefits of MMN are shown when it is initiated at any time during pregnancy.

Regional/National Level Challenges
Improvement in maternal and child health has been the least attractive portfolio for many national health care sectors.2 Additional costs of making MMN free to all pregnant women in the entire nation can be a very challenging prospect for some of the populous countries, and the total cost may exceed the entire health care budget.2 However, in the US, Canada, and other developed countries, practitioners should be made aware of the benefits and encouraged to identify at-risk mothers. Public health initiatives to support, promote, and improve availability of MMN for pregnant women who cannot afford to purchase them will be needed. It is important that these issues be identified and openly debated with the public to determine strategic directions in the improvement of maternal-child health.

Global Challenges
It is also important that WHO or UNICEF undertake positive steps. Change may be required in the content of their programs without affecting the infrastructure of these programs. Recent successes of large-scale beneficial experimentations at community levels have shown that this is achievable.8,9 At the same time, care must be taken not to affect existing infant and child nutrition programs, as maternal and childhood malnutrition accompany each other.

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WHAT ARE THE NEXT STEPS?

The most important step in knowledge translation is the action on a synthesized knowledge. Notwithstanding the challenges mentioned above regarding implementation of routine MMN supplementation to all pregnant women, the most important issue will be cost.2 However, in the long run, the cost of managing one LBW child during the neonatal and postneonatal periods is much higher to society than the cost of supplementing MMN to 50 pregnant women. Partnership with industries in reducing the cost of preparation, formulation, packaging, and supplying MMN may make this an affordable and highly rewarding program. Local governments, nonprofit agencies, national academic societies, pharmaceutical industry, and public partnership are crucial building stones in moving forward this agenda.

The take-home message for individual health care professionals involved in maternal-child health in any part of the world is that MMN supplementation initiated at any time during pregnancy could be beneficial in reducing LBW rates and improving fetal growth.

The author reports no actual or potential conflict of interest in relationship to this article.

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Prakesh S. Shah, MBBS, DCH, MRCP, MRCPCH, is Staff Neonatologist and Clinical Epidemiologist, Department of Pediatrics, Mount Sinai Hospital, Toronto, Ontario; and Associate Professor, Division of Neonatology, Department of Pediatrics, and Department of Health Policy, Management, and Evaluation, University of Toronto, Ontario.

References

1. Bhutta ZA, Haider BA. Prenatal micronutrient supplementation: are we there yet? CMAJ. 2009;180(12):1188-1189.
2. Ladipo OA. Nutrition in pregnancy: mineral and vitamin supplements. Am J Clin Nutr. 2000;72(1 Suppl):280S-290S.
3. Lumbiganon P. Multiple-micronutrient supplementation for women during pregnancy: RHL commentary (last revised: 23 August 2007). WHO Reproductive Health Library; Geneva: World Health Organization. Available at: http://apps.who .int/rhl/pregnancy_childbirth/antenatal_care/nutrition/plc om2/en/index.html. Accessed on May 10, 2010.
4. Shah PS, Ohlsson A; Knowledge Synthesis Group on Determinants of Low Birth Weight and Preterm Births. Effects of prenatal multimicronutrient supplementation on pregnancy outcomes: a meta-analysis. CMAJ. 2009;180(12):E99-E108.
5. Barker DJ. The origins of the developmental origins theory. J Intern Med. 2007;261(5):412-417.
6. Keen CL, Clegg MS, Hanna LA, et al. The plausibility of micronutrient deficiencies being a significant contributing factor to the occurrence of pregnancy complications. J Nutr. 200;133(5 Suppl 2):1597S-1605S.
7. Susser M. Maternal weight gain, infant birth weight, and diet: causal sequences. Am J Clin Nutr. 1991;53(6):1384-1396.
8. Shankar AH, Jahari AB, Sebayang SK, et al. Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia: a double-blind cluster-randomised trial. Lancet. 2008;371(9608):215-227.
9. Zeng L, Dibley MJ, Cheng Y, et al. Impact of micronutrient supplementation during pregnancy on birth weight, duration of gestation, and perinatal mortality in rural western China: double blind cluster randomised controlled trial. BMJ. 2008;337:a2001.

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