Docosahexaenoic acid (DHA) intake estimated from a 7-question survey identifies pregnancies most likely to benefit from high-dose DHA supplementation.

BACKGROUND: Two randomized trials found women with low blood docosahexaenoic acid (DHA; an omega 3 fatty acid) had fewer early preterm births (<34 weeks gestation) if they were assigned to high dose DHA supplementation, however, there is currently no capacity for clinicians who care for pregnancies to obtain a blood assessment of DHA. Determining a way to identify women with low DHA intake whose risk could be lowered by high dose DHA supplementation is desired. OBJECTIVE: To determine if assessing DHA intake can identify pregnancies that benefit from high dose DHA supplementation. STUDY DESIGN: This secondary analysis used birth data from 1310 pregnant women who completed a 7-question food frequency questionnaire (DHA-FFQ) at 16.8 ± 2.5 weeks gestation that is validated to assess DHA status. They were then randomly assigned to a standard (200 mg/day) or high dose (800 or 1000 mg/day) DHA supplement for the remainder of pregnancy. Bayesian logistic regressions were fitted for early preterm birth and preterm birth as a function of DHA intake and assigned DHA dose. RESULTS: Participants who consumed less than 150 mg/day DHA prior to 20 weeks' gestation (n = 810/1310, 58.1%) had a lower Bayesian posterior probability (pp) of early preterm birth if they were assigned to high dose DHA supplementation (1.4% vs 3.9%, pp = 0.99). The effect on preterm birth (<37 weeks) was also significant (11.3% vs 14.8%, pp = 0.97). CONCLUSION: The DHA-FFQ can identify pregnancies that will benefit most from high dose DHA supplementation and reduce the risk of preterm birth. The DHA-FFQ is low burden to providers and patients and could be easily implemented in obstetrical practice.

Early and late preterm birth rates in participants adherent to randomly assigned high dose docosahexaenoic acid (DHA) supplementation in pregnancy.

BACKGROUND: Intention-to-treat analyses do not address adherence. Per protocol analyses treat nonadherence as a protocol deviation and assess if the intervention is effective if followed. OBJECTIVE: To determine the rate of early preterm birth (EPTB, <34 weeks gestation) and preterm birth (PTB, <37 weeks gestation) in participants who adhered to a randomly assigned docosahexaenoic acid (DHA) dose of 1000 mg/day. STUDY DESIGN: Eleven hundred women with a singleton pregnancy were enrolled before 20-weeks' gestation, provided a capsule with 200 mg/day DHA and randomly assigned to two additional capsules containing a placebo or 800 mg of DHA. In the Bayesian Adaptive Design, new randomization schedules were determined at prespecified intervals. In each randomization, the group with the most EPTB was assigned fewer participants than the other group. Adherence was defined a priori as a postpartum red blood cell phospholipid DHA (RBC-PL-DHA) ≥5.5%.and post hoc as ≥8.0% RBC-PL-DHA, the latter after examination of postpartum RBC-PL-DHA. Bayesian mixture models were fitted for gestational age and dichotomized for EPTB and PTB as a function of baseline RBC-PL-DHA and dose-adherence. Bayesian hierarchical models were also fitted for EPTB by dose adherence and quartiles of baseline RBC-PL-DHA. RESULTS: Adherence to the high dose using both RBC-PL-DHA cut points resulted in less EPTB compared to 200 mg [Bayesian posterior probability (pp) = 0.93 and 0.92, respectively]. For participants in the two lowest quartiles of baseline DHA status, adherence to the higher dose resulted in lower EPTB (≥5.5% RBC-PL-DHA, quartiles 1 and 2, pp = 0.95 and 0.96; ≥8% RBC-PL-DHA, quartiles 1 and 2, pp = 0.94 and 0.95). Using the Bayesian model, EPTB was reduced by 65%, from 3.45% to 1.2%, using both cut points. Adherence also reduced PTB before 35, 36 and 37 weeks using both cut points (pp ≥ 0.95). In general, performance of the nonadherent subgroup mirrored that of participants assigned to 200 mg. CONCLUSION: Adherence to high dose DHA reduced EPTB and PTB. The largest effect of adherence on reducing EPTB was observed in women with low baseline DHA levels. CLINICALTRIALS: gov (NCT02626299).

Validation of an abbreviated food frequency questionnaire for estimating DHA intake of pregnant women in the United States.

Docosahexaenoic acid (DHA) intake was estimated in pregnant women between 12- and 20-weeks' gestation using the National Cancer Institute's (NCI) Diet History Questionnaire-II (DHQ-II) and a 7-question screener designed to capture DHA intake (DHA Food Frequency Questionnaire, DHA-FFQ). Results from both methods were compared to red blood cell phospholipid DHA (RBC-DHA) weight percent of total fatty acids. DHA intake from the DHA-FFQ was more highly correlated with RBC-DHA (rs=0.528) than the DHQ-II (rs=0.352). Moreover, the DHA-FFQ allowed us to obtain reliable intake data from 1355 of 1400 participants. The DHQ-II provided reliable intake for only 847 of 1400, because many participants only partially completed it and it was not validated for Hispanic participants. Maternal age, parity, and socioeconomic status (SES) were also significant predictors of RBC-DHA. When included with estimated intake from the DHA-FFQ, the model accounted for 36% of the variation in RBC-DHA.

Utility of a 7- question online screener for DHA intake.

The secondary analyses of two large, recently completed randomized clinical trials of DHA supplementation in pregnancy found that women with a low baseline DHA status benefited from randomization to a higher dose (800 vs 0 and 1000 vs 200 mg/day DHA). To obtain DHA status, it is necessary to obtain a blood sample and conduct an analysis using gas chromatography (GC) or GC-mass spectrometry (GCMS), both barriers to clinics where pregnant women receive advice on nutrition. Participants consuming less than 150 mg/day of DHA at baseline in our recent trial had a lower risk of early preterm birth and preterm birth when assigned to 1000 vs 200 m/day DHA. DHA intake was determined using a 7-question food frequency questionnaire administered by a trained nutritionist. Because the need for trained personnel to administer the questionnaire would be a barrier to implementing this finding in clinical management of pregnancy, the goal of this study was to determine if an online version of the questionnaire could be validly completed without assistance.

Higher maternal weight is related to poorer fetal autonomic function.

Maternal obesity is an established risk factor for poor infant neurodevelopmental outcomes; however, the link between maternal weight and fetal development in utero is unknown. We investigated whether maternal obesity negatively influences fetal autonomic nervous system (ANS) development. Fetal heart rate variability (HRV) is an index of the ANS that is associated with neurodevelopmental outcomes in the infant. Maternal-fetal magnetocardiograms were recorded using a fetal biomagnetometer at 36 weeks (n = 46). Fetal HRV was represented by the standard deviation of sinus beat-to-beat intervals (SDNN). Maternal weight was measured at enrollment (12-20 weeks) and 36 weeks. The relationships between fetal HRV and maternal weight at both time points were modeled using adjusted ordinary least squares regression models. Higher maternal weight at enrollment and 36 weeks were associated with lower fetal HRV, an indicator of poorer ANS development. Further study is needed to better understand how maternal obesity influences fetal autonomic development and long-term neurodevelopmental outcomes.

Predicting the effect of maternal docosahexaenoic acid (DHA) supplementation to reduce early preterm birth in Australia and the United States using results of within country randomized controlled trials.

The DHA to Optimize Mother Infant Outcome (DOMInO) and Kansas DHA Outcomes Study (KUDOS) were randomized controlled trials that supplemented mothers with 800 and 600mg DHA/day, respectively, or a placebo during pregnancy. DOMInO was conducted in Australia and KUDOS in the United States. Both trials found an unanticipated and statistically significant reduction in early preterm birth (ePTB; i.e., birth before 34 weeks gestation). However, in each trial, the number of ePTBs were small. We used a novel Bayesian approach to estimate statistically derived low, moderate or high risk for ePTB, and to test for differences between the DHA and placebo groups. In both trials, the model predicted DHA would significantly reduce the expected proportion of deliveries in the high risk group under the trial conditions of the parent studies. Among the next 300,000 births in Australia we estimated that 1112 ePTB (95% credible interval 51-2189) could be avoided by providing DHA. And in the USA we estimated that 106,030 ePTB (95% credible interval 6400 to 175,700) could be avoided with DHA.

Docosahexaenoic acid supplementation (DHA) and the return on investment for pregnancy outcomes.

The Kansas University DHA Outcomes Study (KUDOS) found a significant reduction in early preterm births with a supplement of 600mg DHA per day compared to placebo. The objective of this analysis was to determine if hospital costs differed between groups. We applied a post-hoc cost analysis of the delivery hospitalization and all hospitalizations in the following year to 197 mother-infant dyads who delivered at Kansas University Hospital. Hospital cost saving of DHA supplementation amounted to $1678 per infant. Even after adjusting for the estimated cost of providing 600mg/d DHA for 26 weeks ($166.48) and a slightly higher maternal care cost ($26) in the DHA group, the net saving per dyad was $1484. Extrapolating this to the nearly 4 million US deliveries per year suggests universal supplementation with 600mg/d during the last 2 trimesters of pregnancy could save the US health care system up to USD 6 billion.

Long chain polyunsaturated fatty acid supplementation in infancy increases length- and weight-for-age but not BMI to 6 years when controlling for effects of maternal smoking.

Long chain polyunsaturated fatty acids (LCPUFA) are added to infant formula but their effect on long-term growth of children is under studied. We evaluated the effects of feeding LCPUFA-supplemented formula (n = 54) compared to control formula (n = 15) throughout infancy on growth from birth-6 years. Growth was described using separate models developed with the MIXED procedure of SAS(®) that included maternal smoking history and gender. Compared to children fed control formula, children who consumed LCPUFA supplemented formula had higher length-/stature-/and weight-for-age percentiles but not body mass index (BMI) percentile from birth to 6 years. Maternal smoking predicted lower stature (2-6 years), higher weight-for-length (birth-18 months) and BMI percentile (2-6 years) independent of LCPUFA effects. Gender interacted with the effect of LCPUFA on stature, and the relationship between smoking and BMI, with a larger effect for boys. Energy intake did not explain growth differences. A relatively small control sample is a limitation.

Docosahexaenoic acid (DHA) supplementation in pregnancy differentially modulates arachidonic acid and DHA status across FADS genotypes in pregnancy.

Some FADS alleles are associated with lower DHA and ARA status assessed by the relative amount of arachidonic acid (ARA) and docosahexaenoic acid (DHA) in plasma and red blood cell (RBC) phospholipids (PL). We determined two FADS single nucleotide polymorphisms (SNPs) in a cohort of pregnant women and examined the relationship of FADS1rs174533 and FADS2rs174575 to DHA and ARA status before and after supplementation with 600mg per day of DHA. The 205 pregnant women studied were randomly assigned to placebo (mixed soy and corn oil) (n=96) or 600mg algal DHA (n=109) in 3 capsules per day for the last two trimesters of pregnancy. Women homozygous for the minor allele of FADS1rs174533 (but not FADS2rs174575) had lower DHA and ARA status at baseline. At delivery, minor allele homozygotes of FADS1rs174533 in the placebo group had lower RBC-DHA compared to major-allele carriers (P=0.031), while in the DHA-supplemented group, all genotypes had higher DHA status compared to baseline (P=0.001) and status did not differ by genotype (P=0.941). Surprisingly, DHA but not the placebo decreased ARA status of minor allele homozygotes of both FADS SNPs but not major allele homozygotes at delivery. Any physiological effects of changing the DHA to ARA ratio by increasing DHA intake appears to be greater in minor allele homozygotes of some FADS SNPs.

Effects of docosahexaenoic acid supplementation during pregnancy on fetal heart rate and variability: a randomized clinical trial.

DHA (22:6n-3) supplementation during infancy has been associated with lower heart rate (HR) and improved neurobehavioral outcomes. We hypothesized that maternal DHA supplementation would improve fetal cardiac autonomic control and newborn neurobehavior. Pregnant women were randomized to 600 mg/day of DHA or placebo oil capsules at 14.4 (+/-4) weeks gestation. Fetal HR and HRV were calculated from magnetocardiograms (MCGs) at 24, 32 and 36 weeks gestational age (GA). Newborn neurobehavior was assessed using the Neonatal Behavioral Assessment Scale (NBAS). Post-partum maternal and infant red blood cell (RBC) DHA was significantly higher in the supplemented group as were metrics of fetal HRV and newborn neurobehavior in the autonomic and motor clusters. Higher HRV is associated with more responsive and flexible autonomic nervous system (ANS). Coupled with findings of improved autonomic and motor behavior, these data suggest that maternal DHA supplementation during pregnancy may impart an adaptive advantage to the fetus.

Polyunsaturated fatty acids and infant growth.

Because of the rapid rate of growth during infancy, and the potentially deleterious effect of differences in the availability of dietary essential nutrients, growth is an important outcome variable in any study assessing a diet designed for infants. Nearly 10 yr after the first demonstration of reduced growth in preterm infants fed a fish oil-enriched formula, there is very little additional information to confirm or refute the finding that long-chain n-3 polyunsaturated fatty acid (LC-PUFA) intake can modulate growth in infants. To evaluate the issue of a possible relationship between PUFA intake and growth of infants, we reviewed a total of 32 randomized studies, 13 in preterm infants and 19 in term infants. From the data published to date, it seems clear that long-chain n-3 fatty acids can reduce growth achievement in preterm and term infants under some experimental conditions. However, the effect of n-3 PUFA supplementation on the growth of preterm and term infants appears to be minimal and of questionable clinical and/or physiologic relevance. Nonetheless, n-3 fatty acids have an effect on gene transcription, at least in some species, and this finding may provide important clues to the mechanism by which n-3 and n-6 fatty acids regulate growth.

Long chain polyunsaturated fatty acids (LC-PUFA) and perinatal development.

UNLABELLED: This paper reports on the conclusions of a workshop on the role of long chain polyunsaturated fatty acids (LC-PUFA) in maternal and child health. The attending investigators involved in the majority of randomized trials examining LC-PUFA status and functional outcomes summarize the current knowledge in the field and make recommendations for dietary practice. Only studies published in full or in abstract form were used as our working knowledge base. CONCLUSIONS: For healthy infants we recommend and strongly support breastfeeding as the preferred method of feeding, which supplies preformed LC-PUFA. Infant formulas for term infants should contain at least 0.2% of total fatty acids as docosahexaenoic acid (DHA) and 0.35% as arachidonic acid (AA). Since preterm infants are born with much less total body DHA and AA, we suggest that preterm infant formulas should include at least 0.35% DHA and 0.4% AA. Higher levels might confer additional benefits and should be further investigated because optimal dietary intakes for term and preterm infants remain to be defined. For pregnant and lactating women we consider it premature to recommend specific LC-PUFA intakes. However, it seems prudent for pregnant and lactating women to include some food sources of DHA in their diet in view of their assumed increase in LC-PUFA demand and the relationship between maternal and foetal DHA status.

Long-chain polyunsaturated fatty acids in infant nutrition: effects on infant development.

In the past year, two groups of investigators reported the effects of feeding n-3 and n-6 long chain polyunsaturated fatty acids on term-infant development. In general, these small randomised studies, along with two recent large randomised clinical trials, one with preterm and one with term infants, confirm and extend data on efficacy from smaller clinical studies reported in the past ten years. In addition, two independent systematic reviews published this year evaluated all but the most recent studies. Both systematic reviews concluded that there were benefits of feeding long chain polyunsaturated fatty acids to preterm infants in the short-term and acknowledged the absence of studies to address their effects on long-term visual development in infants. The continuing controversy as to the need for long chain polyunsaturated fatty acids by term infants is highlighted by the different conclusions reached in the systematic reviews. A middle view can also be supported by the data; that is, that fewer term infants than preterm infants can benefit from these fatty acids because of greater long chain polyunsaturated fatty acid accumulation in utero. Differences in intrauterine accumulation of these fatty acids may also play a role in inconsistent results among term studies.

Docosahexaenoic acid and arachidonic acid in infant development.

Docosahaxaenoic acid and arachidonic acid are highly concentrated in the central nervous system. The amount of these fatty acids in the central nervous system increases dramatically during the last intrauterine trimester and the first year of life. A central question of research conducted during the past 20 years is if the essential fatty acid precursor of docosahexaenoic acid is sufficient to achieve optimal DHA accumulation in the central nervous system and, therefore, infant development. The important role of non-human primate studies in characterising the behavioral effects of n-3 essential fatty acid deficiency and subsequent low brain DHA accumulation, the difference between essential fatty acid deficiencies and conditional deficiencies of docosahexaenoic acid and arachidonic acid, and the evidence that human infants have a conditionally essential need for docosahexaenoic acid and, perhaps, for arachidonic acid are summarised. The current suggestive evidence for several possible mechanisms underlying behavioral effects are also provided.

Behavioral methods used in the study of long-chain polyunsaturated fatty acid nutrition in primate infants.

Domains of behavior may be broadly categorized as sensory, motor, motivational and arousal, cognitive, and social. Differences in these domains occur because of changes in brain structure and function. Docosahexaenoic acid (DHA; 22:6-23) and arachidonic acid (AA; 20:4-26) are major structural components of the brain that decrease when diets deficient in the essential fatty acids (EFA) alpha-linolenic acid and linoleic acid are consumed. Early electrophysiologic and behavioral studies in EFA-deficient rodents showed behavioral effects attributable to lower-than-normal accumulation of DHA and AA in the brain. More recently, electrophysiologic and behavioral studies in EFA-deficient primate infants and analogous studies in human infants have been conducted. The human infants were fed formulas that could result in lower-than-optimal accumulation of long-chain polyunsaturated fatty acids (LCPUFAs) in the brain during critical periods of development. This article describes the behavioral methods that have been used to study primate infants. These methods may be unfamiliar to many physicians and nutritionists who wish to read and interpret the human studies. The behavioral outcomes that have been evaluated in LCPUFA studies represent only a fraction of those available in the behavioral sciences. Specific developmental domains have been studied less often than global development, even though studies of nonhuman primates deficient in EFAs suggest that the former provide more information that could help target the underlying mechanisms of action of LCPUFAs in the brain.

Long-chain polyunsaturated fatty acids and development of human infants.

Human infants require n-6 and n-3 long-chain polyunsaturated fatty acids (LCPUFA), derivatives of the essential fatty acids, linoleate (n-6) and linolenate (n-3), for growth and neural development. Animals fed diets deficient in the essential fatty acids have low neural LCPUFA and behavioral changes that imply adverse effects on brain function. Studies of animals deficient in essential fatty acids have provided the rationale and outcomes for studies to determine whether human infants need dietary LCPUFA. After including n-3 LCPUFA in formula, preterm infants showed higher sensory function (retinal responses to light, visual acuity), visual attention characteristic of higher maturity during infancy, and higher scores on test of global development (6- and 12-mo Bayley Mental Developmental Index). In term infants, some but not all studies found higher visual acuity, 4-mo Brunet-Lezine psychomotor development, and 10-mo means-end problem solving with LCPUFA-containing formulae compared to formulae in general use. Because preterm infants have lower LCPUFA accumulation at birth than term infants, it may be easier to show benefits of dietary LCPUFA for neural development in the former group. In addition to low gestational age, other variables may influence LCPUFA accumulation at birth and determine whether a particular group of infants will respond to dietary LCPUFA. One current challenge is to identify and characterize the effects of those variables. Another is to learn the mechanisms by which LCPUFA status may influence behavior.