Mar 02

DHA on maternal depression and neurodevelopment

Journal reference: Makrides M, Gibson R, McPhee A, et al.  Effect of DHA supplementation during pregnancy on maternal depression and neurodevelopment of young children: a randomized controlled trial. JAMA. 2010; 304(15): 1675-1683 [1]

Link: http://dx.doi.org/10.1001/jama.2010.1507

Published: 20 October 2010

Evidence cookie says...

Docosahexanoic acid (DHA) supplements in the later half of pregnancy are not associated with improvements in maternal depression or infant neurodevelopment.

DHA supplements were associated with fewer pre-term deliveries less than 34 weeks but more post-term deliveries by induction and caesarian section. These findings are of unclear clinical significance.

There remains no compelling evidence for routine use of DHA supplements in pregnancy.

More details:


Article details


Study design:

multicentre, double blind randomised controlled trial


Study aim:

to determine whether increasing docosahexanoic acid (DHA) during the last half of pregnancy will result in fewer women with high levels of deperessive symptoms and enhance the neurodevelopmental outcome of their children


Methods summary:

  • the DOMInO trial
  • double blind, multicentre randomised controlled trial in 5 Australian perinatal centres
  • inclusions:
    • women with singleton pregnancies at less than 21 weeks gestation
    • approached by study research assistants during routine antental appointments to request trial participation
    • between Oct 31 2005 to Jan 11 2008
  • exclusions:
    • women already taking a prenatal supplement with DHA
    • if foetus had a known major abnormality
    • bleeding disorder where tuna oil was contraindicated
    • on anticoagulant therapy
    • documented drug or alcohol abuse
    • participating in another fatty acid trial
    • unable to give written informed consent
    • non English speaking background
  • treatment (from study entry until birth of child):
    • intervention:
      • 3 x 500 mg/day fish oil concentrate capsules
      • provides 800 mg of DHA and 100 mg of eicosapentanoic acid (EPA)
    • control:
      • 3 x 500 mg/d  capsules of vegetable oil devoid of DHA
    • phone calls to document gastrointestinal or bleeding events and monitor and encourage adherence at:
      • 2 weeks after enrolment (approximately 22 weeks gestation)
      • 28 weeks gestation
      • 36 weeks gestation
    • concentration of DHA in cord blood measured for independent biomarker of adherence
    • antenatal hospitalisations, antenatal and postnatal haemorrhage, pregnancy and birth outcomes recorded from review of medical records
    • self administered Edinburgh post-natal depression scale (EPDS) at 6 weeks and 6 months postpartum
  • outcome measures:
    • Primary outcome:
      • for maternal depression:
        • high level of maternal depressive symptoms; score of more than 12 on the EPDS at 6 weeks or 6 months post partum
      • for childhood outcome of neurodevelopment at 18 months
        • assessment by 1 of 4 study psychologists using the Cognitive and Language Composite Scales of the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III)
        • not all children assessed, selected all 96 preterm children and 630 randomly selected term children from Adelaide, Australia
        • families and staff blinded to selection until infants were 12 months of age
    • Secondary outcomes:
      • percentage of women medically diagnosed with depression or receiving treatment for depression (self reported) during pregnancy and at 6 months postpartum
    • All analyses according to intention to treat
  • power calculation made a priori
    • maternal depression:
      • powered to detect an absolute reduction of 4.2% in depressive symptoms with 80% power
      • sample size of 1121 women per group
      • planned to enrol 2280 women in total allowing for 2% loss to follow up
    • infant neurodevelopment:
      • powered to detect a difference of 5 points between groups (with standardised mean = 100, SD = 15) with 80% power
      • boys and girls separately
      • required a total sample of 572 children
      • planned to sample 630 term children allowing for 10% loss to follow up

Results summary:

  • 7821 women screened for trial eligibility
    • 3658 did not meet inclusion criteria
      • 2337 (64%) were alreadyon DHA supplementation
      • 1764 declined participation
  • 2399 women enrolled
    • good retention rates once enrolled in trial
    • only 79 women lost to follow up or withdrew consent
    • at 28 weeks gestation, two-third of women reported full or good compliance with medication
    • < 2% reported not taking capsules
  • 726 infants
    • 630 randomly selected term infants + all 96 pre-term infants
    • 694 of 726 infants (95.6%) were assessed at 18 months

Analyses:

Maternal primary outcome:

  • EPDS depressive score > 12 after 6 months post partum:
    • DHA group: 9.67%
    • Control group: 11.19%
    • adjusted RR = 0.85 (95% CI 0.70-1.02), P = 0.09
      • results does not reach statistical significance

Infant primary outcomes:

  • Bayley Scales of Infant and Toddler Development:
    • cognitive standardised score, weighted mean (SD):
      • DHA group:  101.81 (11.06)
      • Control group: 101.75 (12.56)
      • adjusted effect size: 0.01 (95% CI -1.36 to 1.37), P = 0.99
        • no statistical difference between the two groups
    • similarly no statistical difference found between DHA and control groups for language, motor, social-emotional and adaptive behaviour scores
    • small effects of statistical significance in female infants for language score (control group superior to DHA supplement) and adaptive behaviour (control group superior to DHA supplement)
      • these findings are of unclear/limited clinical significance
    • infants with cognitive standardized score < 85 (delayed performance):
      • DHA group: 2.71% (95% CI 1.59-4.62)
      • Control group: 6.64 % (95% CI 4.82-9.13)
      • adjusted RR = 0.41 (95% CI 0.22 to 0.78), P = 0.007

Infant secondary outcomes:

  • fewer preterm births < 34 weeks gestation in the DHA group:
    • DHA group: 1.09%
    • Control:  2.25%
    • adjusted RR =  0.49 (95% CI 0.25 – 0.94), P = 0.03
  • more post-term induction or post-term pre-labour caesarian delivery in DHA group:
    • DHA group: 17.59%
    • Control: 13.72%
    • adjusted RR = 1.28 (95% CI 1.06-1.55), P = 0.01

Study conclusion:

The use of DHA-rich fish oil capsules compared with vegetable oil capsules during pregnancy did not result in lower levels of postpartum depression in mothers or improved cognitive and language development in their offspring during early childhood.


Participants:

  • 2399 women with singleton pregnancies
  • 726 infants of the above women (all 96 preterm infants, and 630 randomly selected infants)
  • exclusions:
    • women already taking a prenatal supplement with DHA
    • if foetus had a known major abnormality
    • bleeding disorder where tuna oil was contraindicated
    • on anticoagulant therapy
    • documented drug or alcohol abuse
    • participating in another fatty acid trial
    • unable to give written informed consent
    • non English speaking background5 perinatal centres in Australia between Oct 31 2005 to Jan 11 2008
  • No significant difference in demographic between control and treatment arms
  • Average age of women 29 years
  • Median gestation at trial entry 19 weeks
  • 40% women were primiparous
  • 68% women had completed tertiary education
  • 24% with previous or current diagnosis of depression with 5% receiving current treatment
  • no significant differences between the DHA and control supplement groups

Methodological weaknesses

  • primary outcome for maternal depression was high EPDS score rather than clinical diagnosis
    • although a high EPDS score is correlated with major depression, it is not a diagnostic tool
    • sensitivity and specificity estimates vary considerably [2]
    • this potential limitation and threat to internal validity was commented on by the authors
  • primary measure for infants is the Bayley Score of Infant and Toddler Development
    • this is a helpful screening tool for determining infants for early intervention but has limited predictive value in determining which children will become developmentally delayed
  • possible Hawthorne effect may have reduced depressive symptoms in both study arms → reducing the power of the study to detect a statistically significant difference between groups
  • treatment allocation was not blinded at the infant review of 18 months
  • possible recruitment bias: 30% of the women screened for trial eligibility were already on DHA containing supplements (and thus excluded)
    • although this may not have affected the results given that an exaggerated effect from the DHA group would be expected, there could be an unknown confounding factor

Methodological strengths

  • multi-centre Australian study
  • good randomised design
  • intention to treat analyses
  • good participant compliance with the study medication
  • appropriate number of participants recruited according to a priori power calculations

Biases and conflicts of interests

  • Two authors  (Dr Makrides and Dr Gibson) report serving on scientific advisory boards for Nestle and Fonterra.  Dr Makrides also serves on the scientific advisory board for Nutricia.  They both also are paid associated honoraria to their institutions to support conference travel and continuing education for postgraduate students and early career researchers.
  • Treatment and placebo capsules were provided by Efamol, England, a company that produces Essential Fatty Acid Health Supplements.

Clinical relevance to primary health care

Docosahexanoic acid (DHA) supplements are widely used in pregnant women. Indeed, of the women screened for trial eligibility 30% were already taking supplements with DHA (and thus excluded).  This trial demonstrates that:

  • DHA supplements were not associated with benefits to maternal depression (as measured on the Edinburgh post-natal depression scale (EPDS)
  • DHA supplements were not associated with benefits to infant neurodevelopment (up to 18 months)

The study did reveal a number of interesting results.  Firstly, there is a non-significant trend towards less depression on the EPDS.  It is possible that DHA supplements have a smaller effect on depression that could be detected by the power of this study. This possibility should be considered speculative and hypothesis generating only. Secondly DHA supplements were associated with marginally worse language and adaptive behaviour scores in female infants. This is of unclear though likely limited clinical significance. Thirdly, DHA supplements in this study were associated with:

  • ↓ 51% risk of delivery before 34 weeks gestation (with a matching lower rate of cognitive scores suggesting delayed development)
  • ↑ 28% risk of post-term induction or post-term pre-labour caesarian delivery

The clinical significance of this pair of secondary outcome findings is of unclear clinical significance.

For the Australian general practitioner in primary health care, a sensible interpretation is that there does not appear to be convincing evidence for routine DHA-rich fish oil supplements during the later half of pregnancy. Specifically, there was no association with benefits to maternal depression or infant neurodevelopment up to 18 months post-partum.

References

  1. Makrides M, Gibson R, McPhee A, et al.  Effect of DHA supplementation during pregnancy on maternal depression and neurodevelopment of young children: a randomized controlled trial. JAMA. 2010; 304(15): 1675-1683
  2. Eberhard-Gran M, Eskild A, Tambs K, et al. Review of validation studies of the Edinburgh Postnatal Depression Scale. Acta Psychiatr Scand. 2001 Oct;104(4):243-9

Co-editor: Michael Tam

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