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

Abstract

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).

Keywords: Clinical trial adherence; DHA; Pregnancy; Preterm birth; Red blood cell phospholipid DHA.

Figure 1.

Histogram of postpartum red blood cell phospholipid DHA (RBC-PL-DHA) (% of total fatty acids) by assigned dose.

Figure 2.

Time-to-event analysis of birth before 37 weeks by adherence with 1000 mg assigned dose using planned definition of adherence (red blood cell phospholipid or RBC-PL-DHA ≥5.5%). The number of births at each gestational age is cumulative. At 34, 35, 36 and 37 weeks, Bayesian posterior probabilities (pp) that the adherent group (1000+ mg) was superior to the 200 mg group were pp=0.93, 0.95, 0.98 and 0.99, respectively. The adherent group was also superior to the nonadherent group (1000- mg), respectively, 0.85, 0.92, 0.99 and 0.99, for these weeks. The non-adherent group (1000- mg) had a higher rate of PTB than the 200 mg group at 37 weeks gestation (pp=0.97) but was similar at 34-, 35- and 36-weeks’ gestation.

Figure 3.

Time-to-event analysis of birth before 37 weeks by adherence with 1000 mg assigned dose using observed ≥8% (cut point in bimodal distribution of red blood cell phospholipid or RBC-PL-DHA) to define high adherence. The number of births at each gestational age is cumulative. At 34, 35, 36 and 37 weeks, Bayesian posterior probabilities (pp) that the adherent group (1000+ mg) was superior to the 200 mg group were 0.92, 0.95, 0.99 and 0.99. The adherent group was also superior to the nonadherent group (1000- mg) are 0.75, 0.89, 0.99 and 0.99, respectively, at these gestational weeks. The non-adherent group (1000- mg) had a higher rate of PTB than the 200 mg group at 37 weeks gestation (pp=0.97) but was similar at 34-, 35- and 36-weeks’ gestation.