Preterm children are more likely to have lower IQ scores and cognitive impairments compared with term-born children.
Dr. Jacqueline Gould, who led the study now published in the New England Journal of Medicine, says infants born at the earliest gestations are deprived of the natural supply of DHA that normally builds up in the brain during the last trimester of pregnancy.
“These babies have low concentrations of DHA in their brain tissue, which may contribute to poorer cognitive outcomes,” Dr. Gould said.
“The goal of our research was to test if supplementing these children with DHA after they’re born, can make up for some of what they lacked due to preterm birth and boost brain development.”
They were compared with 333 children in the control group, who received an emulsion with no DHA. At five years old, children in both groups underwent the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) IQ test.
“On average, those in the DHA group scored 3.5 points higher on the IQ scale than those in the control group,” Dr. Gould said.
“These very promising results suggest DHA has the potential to improve cognitive performance when administered via emulsion for infants born before 29 weeks’ gestation.”
Although medical advances over the past 30 years have increased the survival rates of infants born before 29 weeks’ gestation, there has been no improvement in their cognitive development.
Supplying DHA to these infants while they are in hospital may be one simple intervention that can help boost brain function.
Why Are docosahexaenoic acid (DHA) and arachidonic acid (AA) Important in the Developing Brain?
LCPUFA and Neurodevelopment
DHA and AA together comprise a quarter of all brain fatty acids, particularly contributing to myelination and being enriched in neuronal synapses and cellular membranes [12], where their structure lends fluidity that aids neuronal functions such as neurotransmission [13,14].
Placental transfer and accretion of fatty acids into infant tissues is highest during the final trimester of pregnancy, with an essential reserve of AA and DHA stored in adipose in preparation for the post-natal demands of neurological development. Premature birth severs materno-fetal transfer, resulting in less LCPUFA availability relative to infants born at term, which may compromise neurodevelopment.
DHA is neuroprotective in animal models of neonatal asphyxia [15] and appears to encourage brain growth, myelination, and overall survival in prematurely born pigs [16]. In rats, improving LCPUFA availability to the offspring by supplementing the maternal diet can reduce the neurological damage associated with neonatal hypoxic-ischaemic brain injury [17]. Autopsy studies of human infants fed LCPUFA-deficient formula demonstrate the substitution of alternative N6 and N9 fatty acids in neural tissues [18,19].
DHA is also richly incorporated into photoreceptors, and deficiency is associated with reduced visual acuity and impaired visual transduction [20]. Randomized trials have shown reduced risk of severe retinopathy of prematurity (ROP) in preterm infants receiving enteral supplementation with DHA as well as a combination of DHA and AA [21,22].
ROP is a disease additionally associated with lower brain volumes and neurodevelopmental scores at two years of age [23]. Furthermore, greater erythrocyte levels of DHA correlate with positive MRI findings of brain microstructure development and with improved neurodevelopmental scores in infants born prematurely [24].
AA has multiple essential and wide-ranging roles in general infant development as well; dietary AA deficiency has been associated with growth impairment, which improves on return of dietary supply [25]. Feeding infants DHA unopposed by AA has also been associated with reduced preterm infant growth [25,26].
Overall, infants born prematurely and/or at a low-birth weight, thus with reduced adipose stores of LCPUFA, are more likely to experience neurosensory impairment, achieve lower levels of educational attainment, and have lower IQ scores [27].
LCPUFA Influence Inflammatory Signaling
AA exerts effects via its metabolism into bioactive molecules termed eicosanoids by the enzymes cyclooxygenase (COX) and lipoxygenase (LOX) [28]. Increased metabolism of AA into eicosanoids, such as prostaglandins, thromboxanes, and leukotrienes, occurs in response to infection or injury with consequent changes to vessel flow and permeability to aid delivery of immune cells [28].
For this reason, AA is often considered a pro-inflammatory agent. Conversely, DHA competes with AA for placement in cellular membranes and for metabolism by COX and LOX, and in doing so, it inhibits the production of eicosanoids and thus can be thought of as grossly having anti-inflammatory actions [28].
However, the roles of AA and DHA within inflammation are not binary; some AA-derived metabolites regulate the process of inflammation resolution. The prostaglandin PGE2 promotes the initial inflammatory response but subsequently acts to inhibit LOX to reduce further production of pro-inflammatory prostaglandins [29].
Some eicosanoids may protect and repair vessel membranes after injury [12]. Furthermore, PGE2 contributes to a ‘class switching’ event that stimulates COX and LOX to metabolize AA and DHA into lipid mediators such as lipoxins, resolvins, maresins, and neuroprotectins [29]. These metabolites, termed specialized pro-resolving mediators (SPM), inhibit inflammation and promote resolution to return tissues to pre-injury homeostasis [30,31]. While AA contributes to the production of lipoxins, the majority of SPMs are derived from DHA, including neuroprotectin D1 (NPD1), which has been shown to protect against oxidative stress and influence cell survival [32].
Although excessive inflammation is associated with negative outcomes [33], controlled inflammation is a necessary response to infection or injury. Imbalances in the N3:N6 ratio may therefore lead to domination of one fatty acid series over the other during competition for metabolism by COX and LOX, with consequent effects upon the availability of pro- or anti-inflammatory mediators and of pro-resolution agents.
While the balance of N3:N6 fatty acids have the potential to disrupt the inflammatory process, there is not yet a broad base of evidence to understand how the amounts and timing of LCPUFA administration may influence outcomes after premature birth. Within the available evidence, an observational study of LCPUFA blood levels of prematurely born infants associated low levels of DHA with an increased risk of chronic lung disease, while low levels of AA in the blood were associated with an increased risk of sepsis [34].
On the other hand, two large, randomized trials have failed to demonstrate a positive effect of postnatal DHA supplementation on preterm lung development [35,36]. The complexity of the AA and DHA balance is further demonstrated in an analysis of the effect of LCPUFA levels on ROP-risk in Sweden, concluding that higher levels of DHA were only associated with a reduced risk of ROP if the levels of AA were sufficiently high [37].
Premature birth itself may also be linked to inflammatory signaling, as illustrated by the actions of prostaglandins to precipitate preterm birth in sheep [38]. In humans, mothers whose blood content of AA + DHA was <1.6% of total blood fatty acids had 10-fold higher risk of premature birth in comparison to mothers with LCPUFA levels >1.8% [39]. A recent study showed that the DHA and AA status of cord blood correlates with levels of the inflammatory markers CRP and IL-6 of prematurely born infants [40], while inflammation in the fetal and early post-natal periods are linked with increased morbidity in later life [41,42].
LCPUFA Accretion into Fetal Tissues
In Utero LCPUFA Accretion
The final trimester is associated with rapid growth of tissues, including adipose tissue, skeletal muscle, and brain tissue [43]. Between 31 weeks of gestation and term, the brain increases in size from ~150 mL to ~400 mL [44], while brain weight increases by four- to five-fold [45].
This tissue growth is matched by an increased transfer of fatty acids from mother to fetus via the placenta to provide both energy and structural substrate for building new tissue. Furthermore, the placenta serves to selectively control the transfer of both AA and DHA from mother to infant. In a process termed biomagnification, the placenta transfers LCPUFA to the fetus even during circumstances of maternal LCPUFA depletion, resulting in higher LCPUFA contents of fetal blood and tissues than those of the mother [43].
AA transfer is high throughout pregnancy, with the biomagnification phenomenon maintaining fetal blood AA at levels twice those of the mother; at the beginning of the third trimester, the AA:DHA ratio is ~5.1 [46]. The rate of LCPUFA transfer across the placenta increases significantly in the final trimester, increasing from an average of 6.1 mg of AA and 2.3 mg of DHA per day in the 25th week of gestation to 95 mg AA and 42 mg of DHA per day in the final trimester [47].
The accelerated transfer of DHA in the third trimester results in fetal cord plasma DHA levels exceeding those of the mother at around 33 weeks [46]. At term, the AA:DHA ratio as measured in fetal cord blood is ~2.5:1 [46]. Changes in brain LCPUFA composition correspond with these blood LCPUFA changes, and between the gestational ages of 8 to 40 weeks, the relative brain content of AA decreases (~11% to 8.6%) and DHA content increases (3.2% to 8.4%) in infants born to women eating a traditional diet rich in DHA and without excessive LA [48].
Post-Natal LCPUFA Accretion
Accretion of LCPUFA continues in the postnatal period and throughout childhood up until the age of 18, but at a decreasing rate [49]. Maternal breastmilk is a rich source of LCPUFA in the postnatal period and contains ~0.6% AA and ~0.3% DHA; however, these concentrations show considerable variation with maternal diet [50] and genetic polymorphisms [1]. Over the first six months of life, breast fed infants accumulate DHA at ~10 mg/day [51].
LCPUFA Accretion into Adipose
While much of the LCPUFA transferred to the fetus in the final trimester contributes to brain growth and neurological development, by term, 90% of all maternally derived energy, including LCPUFA, is deposited into adipose tissue to result in seven-fold more DHA stored in adipose than in brain tissue [52], with the clinical sequela of this being that this DHA enrichment of adipose tissue is not afforded to prematurely born infants.
It is estimated that the deposition of N3 and N6 fatty acids into adipose tissue outweighs that of brain and other neural tissues by ~46-fold, consuming 78% and 70% of all N6 and N3 PUFA transferred from mother to infant [53]. While total N3 and N6 content in adipose increases, their percentage relative to other fatty acids decreases; AA and DHA similarly decrease from ~4% to ~0.4% between 19 to 38 weeks of gestation [48]. Indeed, the storage of both energy and LCPUFA is essential for ongoing tissue, brain, and neurological development in the post-natal period, in which a steady supply of nutrition from maternal breastmilk is not guaranteed [54].
The importance of LCPUFA stored in adipose tissue is demonstrated by Cunnane et al., who compared the LCPUFA tissue content of infants fed either breastmilk or LCPUFA-deficient formula in the postnatal period [51]. Formula-fed infants increased the LCPUFA content of their brains, but at the expense of their adipose tissue DHA stores, which were depleted to unmeasurable levels.
On the other hand, the breastfed infants increased both brain and adipose contents of DHA [51]. These findings demonstrate that, while adipose stores of LCPUFA can be mobilized to supply the brain, they are likely to be inadequate to fully support neurodevelopment and must be augmented by ongoing nutritional LCPUFA support postnatally.
In the absence of normal intrauterine LCPUFA supply, the deficits incurred by premature birth can be severe; an infant born at 35 weeks, despite being born at an appropriate weight for gestational age (AGA), will have half the LCPUFA content stored in their tissues of an AGA infant born at term [55]. This ‘gap’ increases exponentially with the increase of prematurity [46]; an infant born at 25 weeks may weigh 1300 g and have adipose stores 10% of those of a term infant [53].
In summary, the final weeks of gestation are a key period for accretion of these fatty acids, with LCPUFA stores and adipose tissue mass effectively doubling. Premature birth disadvantages infants two-fold, by limiting DHA accretion directly into neural tissues as would happen in utero and by hindering the accumulation of adipose stores that the infant must rely on to continue optimal post-natal brain development.
reference link :https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8775484/
Original Research: Closed access.
“Neonatal Docosahexaenoic Acid in Preterm Infants and Intelligence at 5 Years” by Jacqueline F. Gould et al. NEJM
