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•WHO study dismisses link with reduced blood pressure, obesity risk

A systemic review of the long-term effects of breastfeeding by a team of researchers from the World Health Organisation (WHO) found that even though the true effects may be underestimated, analyses at seven years of age showed significant effects on Intelligence Quotient (IQ).

The present analyses, which relied on a considerably larger evidence base, including 60 additional studies published in the last five years found no association with blood pressure or overweight/obesity. However, no results were given for cholesterol, diabetes or glucose levels.

The study was published last week in the WHO Library Cataloguing-in-Publication Data.

The researchers include: Dr. Bernardo L. Horta, and Dr. Cesar G. Victora, of the Universidade Federal de Pelotas, Pelotas, Brazil.

The meta-analyses of overweight/obesity, blood pressure, diabetes and intelligence suggest that benefits are larger for children and adolescents, and smallest among adults, suggesting a gradual dilution of the effect with time.

Another study published in Proceedings of the National Academy of Sciences by researchers at the University of Pittsburgh School of Medicine and Children’s Hospital (UPMC) found that an ingredient, which naturally occurs in breast-milk might be used to prevent premature babies from developing a deadly intestinal condition that currently is largely incurable.

The study showed that unlike normal mice, those bred to lack toll-like receptor 4 (TLR4) in their blood vessels did not develop necrotizing enterocolitis (NEC) in a model designed to induce the condition.

TLR4 is an immune protein that is involved in recognizing microbes and which they recently discovered plays a role in gut development.

The WHO team concluded: “This meta-analysis suggests that breastfeeding is associated with increased performance in intelligence tests in childhood and adolescence, of 3.5 points on average. Maternal IQ is an important confounder, but it accounts for only part of this association – even among those studies that adjusted for maternal intelligence, breastfeeding was associated with an additional 2.19 IQ points. The two existing randomized trial on this issue also reported significant benefits of breastfeeding, suggesting that this association is causal.

“On the other hand, the practical implications of a small increase in the performance in intelligence tests may be open to debate. Nevertheless, one Brazilian study suggests that breastfeeding is associated with achieved schooling in adolescents, in a population where breastfeeding duration does not present marked variability by socioeconomic position.”

Senior author, Watson Family Professor of Surgery, Pitt School of Medicine, and co-director of the Fetal Diagnosis and Treatment Center at Children’s Hospital, Prof. David Hackam, said the story begins with a baby who is born too early, meaning before 36 weeks gestation.  Once stable, typically the baby is fed with formula because often breast milk is not readily available to premature infants.

Hackam explained: “Within about 10 days of birth, the baby starts to vomit and a few hours later, the belly becomes distended and discolored. It becomes clear that the child has developed a major problem in his or her tummy, and an X-Ray will usually confirm the diagnosis of necrotizing enterocolitis, or NEC, in which the intestinal tissue is dying. We have no choice but to remove the dead parts of the intestine, but despite surgery, half of these preemie babies still die from the condition.”

Hackam and his team noted NEC occurs when the intestines start getting colonized with bacteria, a process that occurs normally after birth. They focused on toll-like receptor TLR4, an immune protein that is involved in recognizing microbes and which they recently discovered plays a role in gut development. In the current work, Hackam and colleagues found that TLR4 is present in higher amounts in the blood vessel lining in preemies than in full-term babies.

The findings indicate that bacteria in the blood activate TLR4 leading to a reduction in nitric oxide, which in turn narrows blood vessels and decreases blood flow.

Previous studies have established that breastfeeding has well-established short-term benefits, particularly the reduction of morbidity and mortality due to infectious diseases in childhood.

A pooled analysis of studies carried out in middle/low income countries showed that breastfeeding substantially lowers the risk of death from infectious diseases in the first two years of life.

Based on data from the United Kingdom Millennium Cohort, Quigley et al estimated that optimal breastfeeding practices could prevent a substantial proportion of hospital admissions due to diarrhea and lower respiratory tract infection.

A systematic review by Kramer et al confirmed that exclusive breastfeeding in the first six months decreases morbidity from gastrointestinal and allergic diseases, without any negative effects on growth. Given such evidence, it has been recommended that in the first six months of life, every child should be exclusively breastfed, with partial breastfeeding continued until two years of age.

The researchers wrote: “Building upon the strong evidence on the short-term effects of breastfeeding, the present review addresses its long-term consequences. Current evidence, mostly from high-income countries, suggests that occurrence of non-communicable diseases may be programmed by exposures occurring during gestation or in the first years of life (five to seven).

“Early diets, including the type of milk received, is one of the key exposures that may influence the development of adult diseases.”

The WHO team, in 2007, carried out a systematic review and meta-analysis on the long-term consequences of breastfeeding. The Department of Maternal, Newborn, Child and Adolescent Health of the WHO has now commissioned an update of this review.

The following long-term out- comes were reviewed: blood pressure, type-2 diabetes, serum cholesterol, overweight and obesity, and intellectual performance. These outcomes are of great interest to researchers, as made evident by the number of publications identified: 60 new publications were identified since 2006.

On long-term effect of breastfeeding on total cholesterol, the researchers found there was no effect in the overall meta-analyses. “In the 2007 review, there was a significant effect among adults, which is no longer present in the updated analyses. The UK trial of preterm infants showed a small protective effect, while the Belarus trial did not report on this outcome. We conclude that breastfeeding does not seem to protect against total cholesterol levels.”

On blood pressure, the researchers said the pooled estimate from the high-quality studies indicates a small reduction of less than 1 mmHg in systolic pressure among breastfed subjects, and no significant protection in terms of diastolic pressure. “Residual confounding may be an important problem. The Belarus and United Kingdom (UK) preterm trials found no effect of breastfeeding. We conclude that the protective effect of breast- feeding, if any, is too small to be of public health significance,” he said.

On diabetes, the researchers found substantial protection in the pooled analyses, with a 34 per cent reduction, but few studies are available and their results were considerably heterogeneous. “Only two high-quality studies were identified, with conflicting results (one showing an increase and another a reduction among breastfed subjects). The randomized trials did not present any results on these outcomes. Our conclusion is that further studies are needed on this outcome.”

On effect of breastfeeding on overweight-obesity, the researchers noted: “In the pooled analyses of all studies, breastfeeding was associated with a 24 per cent reduction in overweight and/or obesity, but the reduction was only 12 per cent in the high-quality studies.

“Residual confounding may be still affecting these results, because protection is not evident in studies from low and middle-income countries where the social patterning of breastfeeding is not clear cut. The Belarus trial did not find an association. We conclude that breastfeeding may provide some protection against overweight or obesity, but residual confounding cannot be ruled out.”

Hackam said: “This pathway can be dangerous when the preemie’s immature gut becomes inflamed from exposure to the bacteria normally present in the intestine. Abundant TLR4 triggers a shutdown of the blood supply to the intestine, leading to tissue death or necrosis.”

Premature babies who are nursed rather than formula-fed are more likely to survive NEC, so co-author and nitric oxide expert Dr. Mark Gladwin, chief, Division of Pulmonary Allergy and Critical Care Medicine, Pitt School of Medicine, and director of Pitt’s Vascular Medicine Institute, and the team took a closer look at the components of breast milk.

They found that breast milk contains high levels of sodium nitrate, which is converted to nitrite by gut bacteria. Nitrite can be directly converted to the vasodilator nitric oxide, which can both protect the intestinal lining and improve blood flow.

“The additional nitrite appears to overcome the effects of TLR4 activation and corrects the blood flow problem,” Gladwin said. “When we gave formula supplemented with a sodium nitrate and nitrite analog to the premature mice, we saw improved blood flow in the intestine, and NEC did not develop.”

Hackam and Gladwin are testing the compound, which is FDA approved for other uses, in other models of NEC with the hope that it could be routinely added to formula fed to premature infants to prevent NEC.

“This condition is frightening for parents and frustrating for doctors because currently there is little we can do to treat it,” said Hackam, a pediatric surgeon. “I look forward to one day putting myself out of business and having a therapy that truly saves these children.”