Multiple Micronutrient Supplementation During Pregnancy and Birth Outcomes in Low-Income Countries

I thank John Ovretveit (Karolinksa Institutet, Sweden) for bringing this important Lancet article to my attention.[1]

The study is a meta-analysis of individual patient data from 17 RCTs in low- and middle-income countries. The use of individual patient data enables multiple sub-group analyses to be carried out.

This paper confirms some things we already know. For example, iron reduces pre-term delivery and low birth weight. The effect is much greater in anaemic woman in both low- and high-income countries. Iron and folic acid combined have a more powerful effect on reducing these outcomes than either iron or folic acid alone.

This paper shows that including at least one further micronutrient has additional benefit. It also shows that multiple micronutrients reduce neonatal mortality, but only among girls. There is no solid biological explanation for this observation. Consistent with the underlying hypothesis, starting micronutrients early in pregnancy, and high adherence were associated with larger effect sizes. Importantly, no harms were demonstrated for micronutrients.

I recently summarised evidence regarding micronutrients for adults in high-income countries.[2] Here there was no evidence of benefit and evidence of harm with high doses of mineral supplementation. I would still be cautious about liberal use of mineral supplements in pregnancy, with the exception of iron.

— Richard Lilford, CLAHRC WM Director

References:

1. Smith ER, Shankar AH, Wu LS, et al. Modifiers of the effect of maternal multiple micronutrient supplementation on stillbirth, birth outcomes, and infant mortality: a meta-analysis of individual patient data from 17 randomised trials in low-income and middle-income countries. Lancet Glob Health. 2017; 5(11):e1090-100.
2. Lilford RJ. Stop Taking Those Supplements: Just Stop. NIHR CLAHRC West Midlands News Blog. 7 June 2019.

Stop Taking Those Supplements: Just Stop

There is a strong natural human instinct to take precautions to delay the death the lies ahead for us all. So strong is this instinct that we are predisposed to believe in all sorts of measures with a superficial, but fundamentally facile, theoretical basis. Food supplements are such a measure.

So yet another study shows that they do no good, and in some cases they likely increase the very risks that they are designed to prevent.[1] A recent article by Chen and colleagues follows up a cohort of over 30,000 adults who completed a nutrition questionnaire yearly for six years. A healthy diet was associated with lowered cancer mortality risk, but supplements were not, and could even raise risks. With respect to minerals, NEVER take supplements, because it is the balance between metal couples (sodium/potassium; magnesium/calcium; copper/zinc) that is important. So it is not surprising that calcium supplements were harmful in the above study.

Studies of this type are subject to personal and recall bias but, in my opinion, these work against the findings. People who take care of their health usually have better outcomes than people at large, and recall bias is augmented if the bad endpoint materialises, whereas the overall results in this study were null.

— Richard Lilford, CLAHRC WM Director

Reference:

1. Chen F, Du M, Blumberg JB, et al. Association Among Dietary Supplement Use, Nutrient Intake, and Mortality Among U.S. Adults. Ann Intern Med. 2019; 170: 604-13.

Letter To My Friends: Stop Taking That Testosterone!

About one man in 20 takes testosterone supplements at some point. It seems use of anabolic steroids has spilled over from athletes to men at large. However, it has long been suspected that testosterone increases atheroma, and hence cardiovascular risk; one of the reasons that men have higher risk of heart disease at an earlier age than women?

Some men are genetically predisposed to have higher testosterone levels than others. A good way to assess testosterone levels over the post-pubertal life course is through Mendelian randomisation. A recent study, based on the UK BioBank and two other data sources, confirms the association between genes that are associated with high testosterone levels and cardiovascular risk.[1] Of course, my friends might say that there is a trade-off and ask how big this risk really is. In fact, the risk is rather small and applies mostly to heart failure and thromboembolism, with a very small affect on myocardial infarction.

— Richard Lilford, CLAHRC WM Director

Reference:

1. Luo S, Lun Au Yeung S, Zhao JV, Burgess S, Schooling CM. Association of genetically predicted testosterone with thromboembolism, heart failure, and myocardial infarction: mendelian randomisation study in UK Biobank. BMJ 2019; 364: l476.

Fish oil supplementation in pregnancy and the size and body composition of the progeny

Almost 25 years ago I carried out a randomised trial of fish oil in pregnancy, finding no improvement in pre-eclampsia or fatal condition at birth.[1] This finding was subsequently corroborated by meta-analyses of subsequent trials, as well as my own.[2]

Well, birth outcome is one thing, but what about the growth of the children resulting from pregnancies with or without supplementation?

Vinding and colleagues report a randomised trial that specifically aimed to determine the effects of fish oil supplementation in pregnancy on the body composition and growth of children over the first six years of life.[3]

They randomised 523 pregnant women and provided either fish oil or olive oil supplements from 24 weeks of pregnancy to the child was six years old. They found significantly higher body lean mass and bone mineral content, but not fat mass in the fish oil supplemented children.

I guess the real question, however, is the effect of these apparently beneficial changes on long-term health. Sadly, this trial will be woefully underpowered to detect an effect on these long-term outcomes.

— Richard Lilford, CLAHRC WM Director

References:

1. Onwude JL, Lilford RJ, Hjartardottir H, Staines A, Tuffnell D. A randomised double blind placebo controlled trial of fish oil in high risk pregnancy. Br J Obstet Gynaecol. 1995; 102(2): 95-100.
2. Middleton P, Gomersall JC, Gould JF, Shepherd E, Olsen SF, Makrides M. Omega-3 fatty acid addition during pregnancy. Cochrane Database Syst Rev. 2018; 11: CD003402.
3. Vinding RK, Stokholm J, Sevelsted A, et al. Effect of fish oil supplementation in pregnancy on bone, lean, and fat mass at six years: randomised clinical trial. BMJ. 2018; 362:k3312.

 

Antioxidants and Age-Related Macular Degeneration

It is estimated that around 5% of the general population suffer from age-related macular degeneration (AMD),[1] where extracellular material known as drusen accumulate under the retina at the back of the eye and which can eventually lead to blurred or a loss of vision. It has been suggested that antioxidants may help prevent or delay development of AMD in people who do not suffer the condition by protecting the retina against oxidative stress, but it is unclear as to whether this is the case.

A systematic review in the Cochrane Database by Evans and Lawrenson looked at the effectiveness of antioxidant supplements as treatment in people who already had AMD,[2] and found that taking a multivitamin antioxidant vitamin may delay the progression of AMD when compared to a placebo or no treatment (odds ratio 0.72, 95% CI 0.58-0.90). The authors also conducted a systematic review looking at whether there was an association between taking antioxidant vitamins (carotenoids, vitamin C, vitamin E) or minerals (selenium, zinc) and the development of AMD in people without AMD.[3] Five RCTs were included, with a total of 76,756 individuals without AMD. These studies all looked at the use of various supplements against placebo. Generally, the various studies found that there was no effect of supplements on development of AMD, while in some cases there was evidence of an increased risk (see table below).

Comparison	No. of studies	Disease	Risk Ratio (95% Confidence Interval)
Vitamin E vs. placebo	4	AMD	0.97 (0.90-1.06)
		Late-stage AMD	1.22 (0.89-1.67)
Beta-carotene vs. placebo	2	AMD	1.00 (0.88-1.14)
		Late-stage AMD	0.90 (0.65-1.24)
Vitamin C vs. placebo	1	AMD	0.96 (0.79-1.18)
		Late-stage AMD	0.94 (0.61-1.46)
Multivitamin vs. placebo	1	AMD	1.21 (1.02-1.43)
		Late-stage AMD	1.22 (0.88-1.69)

— Peter Chilton, Research Fellow

References:

1. Owen CG, Jarrar Z, Wormald R, Cook DG, Fletcher AE, Rudnicka AR. The estimated prevalence and incidence of late stage age related macular degeneration in the UK. Br J Ophthalmol. 2012; 96(5): 752-6.
2. Evans JR, Lawrenson JG. Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration. Cochrane Database Sys Rev. 2017; 7: CD000254.
3. Evans JR, Lawrenson JG. Antioxidant vitamin and mineral supplements for preventing age-related macular degeneration. Cochrane Database Sys Rev. 2017; 7: CD000253.