Omega-3 fatty acid deficiency in infants before birth identified using a randomized trial of maternal DHA supplementation in pregnancy

Abstract

Background: DHA is accumulated in the central nervous system (CNS) before birth and is involved in early developmental processes, such as neurite outgrowth and gene expression.

Objective: To determine whether fetal DHA insufficiency occurs and constrains CNS development in term gestation infants.

Design: A risk reduction model using a randomized prospective study of term gestation single birth healthy infants born to women (n = 270) given a placebo or 400 mg/day DHA from 16 wk gestation to delivery. Fetal DHA deficiency sufficient to constrain CNS development was assessed based on increased risk that infants in the placebo group would not achieve neurodevelopment scores in the top quartile of all infants in the study.

Results: Infants in the placebo group were at increased risk of lower language development assessed as words understood (OR 3.22, CL 1.49-6.94, P = 0.002) and produced (OR 2.61, CL 1.22-5.58, P = 0.01) at 14 mo, and words understood (OR 2.77, CL 1.23-6.28, P = 0.03) and sentences produced (OR 2.60, CL 1.15-5.89, P = 0.02) at 18 mo using the McArthur Communicative Developmental Inventory; receptive (OR 2.23, CL 1.08-4.60, P = 0.02) and expressive language (OR 1.89, CL 0.94-3.83, P = 0.05) at 18 mo using the Bayley Scales of Infant Development III; and visual acuity (OR 2.69, CL 1.10-6.54, P = 0.03) at 2 mo.

Trial registration: ClinicalTrials.gov NCT00620672.

Figure 1. Schematic to illustrate the concept that individuals with high neurodevelopment test scores are unlikely to be nutrient deficient.

We assessed whether fetal DHA insufficiency sufficient to constrain CNS development occurs based on failure to achieve a neurodevelopmental test score in the upper 25% of infant scores, representing the range of achievement where deficiency is less likely.

Figure 2. Flow diagram of study participants and their infants from enrolment to completion.

Subject withdrawal from 16 to 36n = 9, 16; protocol non-compliance, n = 7, 6; preterm delivery, miscarriage, elective pregnancy termination or other pregnancy complications, n = 5, 5; and one woman in the placebo group delivered twins, lost 36 wk blood sample n = 1, 0. One subject in the placebo group withdrew between 36 wk gestation and infant delivery, with self-withdrawal and loss to follow-up of infants between 2 and 9 mo of age of n = 5,4; between 9 and 12 mo of age of n = 0,1; between 12 and 14 mo of age n = 1,2; between 14 and 16 mo of age n = 1,1; and between 16 and 18 mo of age n = 0, 0 for the pacebo and DHA groups, respectively. Three infants born at term gestation did not meet the protocol requirements for follow up, explained by congenital disorders, n = 1,1 and intrauterine growth retardation, n = 1,0 in the two groups, respectively, and one infant in the placebo group died from sudden infant death syndrome before 2 mo of age. After birth, the number of infants at each milestone, with the number of infants attending assessments, and number of tests incomplete or not analyzed is given. For the placebo and DHA groups, respectively, infant tests done but not analyzed were: at 2 mo, n = 0,1 technical error, n = 2,1 uncooperative infant; at 9 mo non-native contrast test, n = 15,11 technical error, n = 4,0 uncooperative infant, n = 1,0 did not habituate, n = 0,1 exposed to Hindi at home; at 12 mo visual acuity, n = 0,2 uncooperative infant; at 14 mo, n = 1,0 unresolved parent reporting error; at 16 mo, n = 15,14 technical error, n = 18,16 uncooperative infant, n = 6,0 did not habituate; and at 18 mo, BSID-III, n = 3,2 technical error and n = 5,2 uncooperative infant. Technical errors included video-recording and test protocol errors, or external disruption, such as noise causing infant distraction; infant errors include fussy or uncooperative behaviour, and parent interference.

Figure 3. Boxplots to show maternal red blood cell (RBC) phosphatidylethanolamine (PE) g/100 g fatty acids for women assigned to a placebo (open bars) or supplement of 400 mg/d DHA (closed bars) from 16 wk gestation until infant delivery.

Panels A, B and C are the RBC PE DHA, 22:4n-6+ 22:5n-6, and ratio of DHA/22:4n-6+ 22:5n-6, respectively; n = 111 and 111for the placebo group, and n = 102 and 104 for the DHA group at 16 and 36 wk gestation. # Value at 36 wk gestation different from 16 wk gestation within a group, *value for placebo group different from DHA group at the same stage of gestation, P<0.01, by two way ANOVA.

Figure 4. Representative weighted Kernal density plots to show examples of the distributions of test scores for the DHA and placebo groups for all infants, boys and girls for outcomes in which maternal DHA decreased risk of not achieving high development: CDI, communicative developmental inventories and BSID, Bayley Scales of Infant development receptive and expressive language in panels A-L, or had no effect, BSID-III cognitive in panels M-O.