Fetal inflammation, as well as early postnatal inflammation, have been associated with increased mortality, and both short- and long term morbidity in preterm infants [1
]. Polyunsaturated fatty acids have several important structural and functional roles in the body and bioactive fatty acid metabolites are of importance in immune/inflammation system regulation [5
]. After preterm birth, placental transfer of LCPUFAs (long-chain polyunsaturated fatty acid) is abruptly interrupted. Preterm infants are able to synthesize DHA and AA from their C18 counterparts (α-linolenic and linoleic acid, respectively), albeit the endogenous synthesis rate is believed to be too low to meet infants’ requirements [7
], and preterm infants are at risk of dysregulated inflammation.
Supplementation with omega-3 LCPUFAs during pregnancy reduces the risk of preterm birth [9
], potentially by a reduced inflammatory response [10
]. Studies of postnatal supplementation with omega-3 have shown heterogeneous results [11
]. We performed a randomized trial comparing morbidity in extremely preterm infants receiving a parenteral olive oil-based lipid solution (without omega-3 LCPUFA) to a solution containing fish oil with omega-3 LCPUFAs. There were no differences in morbidity between the treatment groups [16
]. In a secondary analysis, lower postnatal levels of AA were associated with a higher risk of developing retinopathy of prematurity (ROP) [17
The present study aimed to investigate if serum levels of DHA and AA, in cord blood and during the first postnatal day, were associated with inflammatory conditions during the perinatal and early postnatal periods in extremely preterm infants.
In this study, we demonstrated that levels of the omega-3 LCPUFA DHA the first postnatal day were lower in extremely preterm infants with early systemic inflammation compared to infants without systemic inflammation. We also demonstrated that low levels of both DHA and the omega-6 LCPUFA AA were associated with high levels of the pro-inflammatory cytokine IL-6 in cord blood.
LC-PUFAs of the omega-6 and omega-3 series might influence immune system regulation through several mechanisms, such as alterations in cell signaling pathways, cell membrane composition, gene expression, metabolite production, and mediation of oxidative stress [5
]. The fatty acids in the omega-6 series mainly have functions in the pro-inflammatory response, whereas the fatty acids in the omega-3 series have functions important in inflammation resolution [23
]. The omega-6 fatty acid AA is the precursor for both pro-inflammatory and pro-resolving metabolites [24
]. IL-6 is produced in both infectious and noninfectious inflammatory conditions. It is highly expressed, easy to detect in the peripheral circulation, and widely used as an inflammatory biomarker [25
]. Experimental models have demonstrated that administration of DHA reduce the expression of IL-6 [26
Fetal levels of fatty acids are determined by maternal supply, placental metabolism, and transfer [28
]. In a large study of DHA supplementation during pregnancy, the authors concluded that factors that explain the variation of DHA in cord blood are mainly unknown [29
]. Chorioamnionitis and inflammation might influence placental fatty acid metabolism. Plasma levels of IL-6 in pregnant women had a negative correlation with placental lipoprotein activity, but in cell culture of human trophoblast cells, IL-6 stimulated fatty acid accumulation [30
]. Fatty acid metabolism might also be disturbed due to a catabolic state. In intrauterine growth restricted fetuses, the maternal fetal ratio of DHA and AA was lower compared to inappropriate for gestational age fetuses [31
Although inflammation might influence fetal levels of fatty acids, most studies argue that omega-3 fatty acids have the potential to attenuate the neonatal inflammatory response. Haghiac et al. showed that supplementation with the omega-3 LCPUFAs DHA and eicosapentaenoic acid (EPA) during pregnancy is associated with reduced expression of pro-inflammatory cytokines in the placenta [32
]. Another study showed lower maternal levels of IL-6 in women who consumed a diet enriched in EPA, but no differences in cord blood cytokines [33
]. Gold et al. demonstrated, in a cohort of mostly term infants, that higher levels of EPA and AA in cord plasma were associated with reduced proliferation and cytokine expression in antigen-stimulated lymphocytes. A comparison between Japanese preterm infants fed a soy-based lipid solution and Australian preterm infants fed a lipid solution containing omega-3 LCPUFAs, showed differences between the cohorts in the levels of some of the relevant non-esterified fatty acids and also in their downstream oxidized metabolites [34
The association between higher infant levels of DHA the first postnatal day and reduced risk of early systemic inflammation has, to our knowledge, not been previously demonstrated among preterm infants. Fares et al. showed that preterm infants with late-onset sepsis, defined as clinical symptoms and positive blood culture after 72 h, had lower DHA the first postnatal day [35
]. Higher linoleic acid to DHA ratio, during the period after the first postnatal week, was also associated with an increased risk of late-onset sepsis in another study [36
]. Studies of supplementation with omega-3 fatty acids during pregnancy have not shown differences in the rate of sepsis among the offspring [9
]. Most studies of prenatal supplementation have not evaluated preterm infants separately. Previous studies of parenteral lipid solutions containing omega-3 fatty acids have not demonstrated differences in the rate of sepsis [13
]. Most studies of pre- and postnatal supplementation of LCPUFAs have not included systemic inflammation as an outcome.
A heightened inflammatory response is thought to be an important part of the pathogenesis of several neonatal morbidities. Both fetal inflammation and early neonatal inflammatory conditions have been associated with increased risk of short term morbidities as well as long term impairments [2
One limitation of this study was the low number of cord blood samples. Histological diagnoses of chorioamnionitis or fetal inflammation were not significantly associated with levels of DHA or AA in our study. This could be due to differences in inflammation origin or mechanisms compared with early postnatal inflammation or an effect of small sample size. There was a discrepancy between infants with histological diagnoses of chorioamnionitis or fetal inflammation and early systemic inflammation that could indicate a difference between the conditions. The association between IL-6 and LCPUFAs in cord blood might reflect a different type of inflammation affecting infants in the first postnatal days or other mechanisms in relation to the transition to extrauterine life. In a study of lipid mediators in amniotic fluid, samples from patients with clinical chorioamnionitis had higher levels of IL-6 and lower levels of inflammation resolving mediators derived from omega-3 fatty acids compared to patients without clinical chorioamnionitis [41
]. Quantification of non-esterified fatty acid could have provided additional information to our analyses, but it is reasonable to believe that serum phospholipid levels can be used as a surrogate reflecting tissue levels of DHA and AA in preterm infants. Another limitation of this study is the lack of information regarding the maternal levels of fatty acids and cytokines during pregnancy. We do not know if maternal levels of DHA were lower during pregnancy in infants who developed early systemic inflammation, or if the levels were reduced in association with birth.
As we have previously reported, infants receiving SMOFlipid showed increased serum levels of DHA but lower AA compared to infants receiving Clinoleic [16
], and high levels of AA were associated with less ROP [17
]. The results in this study also support the hypothesis that increasing both DHA and AA might be beneficial to the infant. Fetal levels of DHA and AA are affected by maternal dietary intake, enzymatic activity regulating fatty acid metabolism, and placental transport [42
]. After birth, infant levels are affected by the composition of omega-6 and omega-3 fatty acids in parenteral and enteral supply [43
]. Recent recommendations state that AA should be provided to preterm infants along DHA [45
]. As the exposure during both the fetal and neonatal periods are significant for infant development, it is urgent to determine the optimal composition of fatty acid exposures during both these time periods.
This study adds to the evidence that DHA and AA are integrated parts of the inflammatory response during fetal and early postnatal life. It also highlights the importance of taking the entire prenatal to neonatal period into consideration while studying the complex interactions of fatty acids, inflammation, and neonatal outcomes.