Key messages
• Lutein and zeaxanthin supplementation probably reduces severe eye disease in preterm infants.
• We found no evidence of any other clear beneficial or harmful effects of the interventions in reducing gut (stomach/digestive system) or brain problems in preterm babies. However, all five studies were conducted in Italy and the USA.
• Future studies should be conducted in a variety of countries and settings. These studies should evaluate major outcomes such as death, gut or brain problems, sepsis (blood infection), and neurodevelopmental outcomes.
The population (participants)
Preterm babies are born early, before the full nine months of pregnancy. They may suffer from illnesses because their organs are not fully developed. Problems may occur in their eyes, brains, and gut (stomach and digestive systems). An eye problem may be retinopathy of prematurity (extra blood vessels in the eyes, which may lead to blindness); a gut problem may be necrotising enterocolitis (inflammation in the intestines); a brain problem may be intraventricular haemorrhage (bleeding in the brain). There are a number of factors contributing to these problems, but one is too much oxygen. Supplements with antioxidant properties may help reduce the negative impact of these problems.
What are lutein and zeaxanthin?
Lutein and zeaxanthin are substances produced by plants, algae, bacteria, and fungi and ingested by humans by eating these foods. Lutein and zeaxanthin have antioxidant properties and are present in many types of food. Before and after birth, babies receive lutein and zeaxanthin naturally: before birth through the umbilical cord (a tube connecting the baby to its mother) and after birth through breast milk. The antioxidant properties of lutein and zeaxanthin may contribute to improved health, by helping the body combat the impact of too much oxygen. However, the amount of lutein and zeaxanthin babies receive through feeding may not be enough. Therefore, this review looks at providing babies with extra (supplemental) lutein and zeaxanthin and whether this improves the outcomes of preterm babies.
What did we want to find out?
We wanted to find out if giving preterm babies extra lutein and zeaxanthin (more than they receive in milk) helps to reduce the occurrence of eye, lung, stomach, and brain problems.
We also wanted to find out if giving preterm babies extra lutein and zeaxanthin causes any harmful effects, such as skin discolouration/skin colour changes, and eye and kidney toxicity.
What did we do?
We searched for studies that compared lutein and zeaxanthin supplementation compared to no treatment.
We compared and combined the results of the studies and rated our confidence in the evidence based on factors such as whether the studies were well-conducted and reported.
What did we find?
The included studies involved 666 preterm babies. There was one main comparison: supplementation with lutein and zeaxanthin compared with a substance of no therapeutic value (a placebo). There were no studies using lutein or zeaxanthin supplementation alone. The incidence of overall retinopathy of prematurity did not differ between groups. However, lutein and zeaxanthin supplementation probably reduces the incidence of severe retinopathy of prematurity in preterm babies. There were no studies that looked at eye vision loss. There may be little or no difference in all other outcomes, including death, intraventricular haemorrhage, and necrotising enterocolitis. We found no harmful effects from lutein and zeaxanthin supplementation.
What are the limitations of the evidence?
All studies were conducted in Italy and the USA. Our confidence in the evidence is only moderate because there are not enough studies to prove that lutein and zeaxanthin supplementation has an effect on other outcomes. Future studies should be conducted in a variety of countries and settings with the aim of evaluating major outcomes such as death, long-term visual problems, gut or brain problems, and sepsis.
How up-to-date is this evidence?
The evidence is up-to-date until December 2024.
While supplementation with lutein and zeaxanthin from day one of life in preterm infants until discharge probably reduces the incidence of ROP stage 3 and above, it may have little or no effect on the incidence of ROP at any stage, IVH or NEC, or mortality assessed throughout the NICU stay. However, the pooled estimates for these outcomes may change with further rigorously conducted trials. There were no adverse effects reported.
Lutein and zeaxanthin are nutrients with antioxidant properties found in the macula of the eye and brain tissue. They have been reported to play a role in reducing oxidative damage, especially in the eyes and possibly in other organ systems. Oxygen free radicals are one of the agents postulated to cause tissue damage in preterm infants, which leads to morbidities such as retinopathy of prematurity (ROP), intraventricular haemorrhage (IVH), and necrotising enterocolitis (NEC). Supplementation with lutein and zeaxanthin may reduce oxidative damage, hence reducing morbidity and mortality in preterm infants.
To assess the effectiveness of lutein and zeaxanthin supplementation in reducing morbidity and mortality in preterm infants.
We conducted searches up to 17 December 2024 in CENTRAL, MEDLINE, Embase, and two trial registries. We also searched the reference lists of included studies, and related reviews and studies.
We included randomised controlled trials (RCTs), cluster-RCT, cross-over trials, and quasi-RCTs that compared lutein and zeaxanthin supplementation against placebo or no supplementation for preterm infants less than 37 completed weeks' postmenstrual age.
We used standard Cochrane methods. Our primary outcomes were the incidence of any stage of ROP, incidence of ROP stage 3 and above, incidence of visual impairment, and mortality assessed throughout the neonatal intensive care unit (NICU) stay. Secondary outcomes included the incidence of IVH, incidence of NEC, and any reported adverse effects. We used GRADE to assess the certainty of the evidence.
We included five studies (666 preterm infants) that compared lutein and zeaxanthin supplementation versus control (placebo or no supplementation). All five studies were conducted in high-income countries (Italy and the USA). We did not find any studies comparing lutein or zeaxanthin separately versus placebo or no supplementation. Most of the studies had a low risk of bias in most key domains, such as allocation concealment and blinding.
The evidence suggests that lutein and zeaxanthin supplementation probably has little or no effect on ROP (any stage) when comparing infants who received lutein and zeaxanthin supplementation with those who did not (risk ratio (RR) 0.90, 95% confidence interval (CI) 0.66 to 1.24; P = 0.53; I2 = 0%; 4 studies, 532 infants; moderate-certainty evidence). Lutein and zeaxanthin supplementation probably reduces the incidence of ROP stage 3 and above (RR 0.49, 95% CI 0.29 to 0.81; P = 0.005; I2 = 0%; 4 studies, 532 infants; moderate-certainty evidence). No studies assessed the incidence of visual impairment. Lutein and zeaxanthin supplementation may have little or no effect on mortality assessed throughout the NICU stay (RR 0.95, 95% CI 0.42 to 2.17; P = 0.91; I2 = 0%; 4 studies, 470 infants; low-certainty evidence), incidence of IVH (all grades) (RR 0.87, 95% CI 0.44 to 1.75; P = 0.70; I2 = 0%; 4 studies, 483 infants; low-certainty evidence), and incidence of NEC: Bell's stage II or greater (RR 0.87, 95% CI 0.43 to 1.76; P = 0.71; I2 = 0%; 5 studies, 666 infants; low-certainty evidence). No adverse effects were reported in either group.