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Prenatal Omega-3 Supplementation: Benefits Questioned
Abstract & Commentary
By Erica Lovett, MD, Faculty, Integrative Medicine, Central Maine Medical Center Family Medicine Residency Program, Lewiston, Maine. Dr. Lovett reports no relationships with companies related to this field of study.
Synopsis: Results of the DOMInO (DHA to Optimize Mother and Infant Outcomes) randomized control trial did not support using fish oil (DHA predominant) to prevent maternal postpartum depression or to improve cognitive ability in children at 18 months of age.
Source: Makrides M, et al. Effect of DHA supplementation during pregnancy on maternal depression and neurodevelopment of young children. JAMA 2010;304:1675-1683.
Initial population-based studies demonstrated a beneficial relationship between higher intakes of fish and seafood during pregnancy and reduced risk of depressive symptoms postpartum and improved cognitive outcomes in the children. Thus, it was hypothesized that the cause of the improved benefit may be related to n-3 long chain polyunsaturated fatty acids (LCPUFA).1,2 Additionally, through animal studies it was postulated that the specific n-3 LCPUFA most responsible for these effects is docosahexaenoic acid (DHA).3
This current study evaluated the use of DHA-predominant omega-3 fatty acid supplementation for women with singleton pregnancies from 22 weeks gestational age to birth to prevent postpartum depressive symptoms and improve cognition of the infant.4 The study had three phases. The initial treatment phase lasted approximately 18 weeks. There were two follow-up periods: one for depressive symptoms of the mother at 6 weeks and 6 months postpartum, and the second for cognitive effects on the infant at 18 months. Analysis of results was by intention to treat.
This randomized, double-blind study was conducted at five Australian perinatal centers. A total of 2399 English-speaking women were enrolled in the initial study and 726 children in the second part of the study (including all 96 preterm infants). Baseline characteristics recorded were maternal age, medical diagnosis of previous or current depression, social support using the Maternal Social Support Index, weight, highest level of education, occupation, and smoking status. The characteristics were similar between groups, although no confidence intervals were reported. Of note, there were significantly more smokers in the control group. Patients were excluded from the study if they had documented drug or alcohol abuse, were unable to give written informed consent, the primary language spoken at home was not English, or had bleeding disorders.
The intervention was DHA fish oil supplementation (800 mg/d of DHA) and 100 mg/d eicosapentaenoic acid (EPA) vs vegetable oil (rapeseed, sunflower, and palm) 500 mg/day capsules without DHA. The 800 mg/d DHA dose was chosen because it is above the threshold estimated to be associated with lower risk for depressed maternal mood and higher scores on developmental outcomes. The control placebo pill was designed to match the normal fatty acid intake of the typical Australian diet. Monitoring of the control and intervention groups was the same. Phone calls were made at 22 weeks gestation, at 28 weeks, and at 36 weeks. Each call included monitoring and encouraging compliance and recording of side effects.
Assessing compliance with treatment and placebo was determined by measuring DHA in cord blood of all infants at birth using capillary gas chromatography; as expected, the intervention group levels where higher. The amount measured in the control group was similar to previous studies with documented insufficient levels of fatty acids. Events that occurred at or shortly after birth were extracted from the medical record and included antenatal hospitalizations, antenatal hemorrhage, and postpartum hemorrhage.
Women completed a self-administered Edinburgh postnatal depression scale (EPDS) at 6 weeks and 6 months postpartum. A score of > 12 on the EPDS was used to indicate high levels of depressive symptoms for this study. There was no statistically significant difference between the moms taking DHA and the control group at 6 weeks (9.61% vs 10.88 %, adjusted relative risk [RR] 0.87, 95% confidence interval [CI] 0.68–1.10, P = 0.24) or 6 months postpartum (9.74% vs 11.50%, adjusted RR 0.83, 95% CI 0.66–1.05, P = 0.11).
Neurodevelopment at 18 months was assessed by one of four study psychologists. It is not stated if there was good interrater reliability between the psychologists or if the psychologists were blinded to what study group women were from. The test used for assessment was the Bayley Scales of Infant and Toddler Development, 3rd edition. There was no difference in the mean cognitive composite scores of the 18-month-old children whose moms took the DHA vs the control (101.81 vs 101.75, adjusted effect 0.01, 95% CI -1.36 to 1.37, P = 0.99), mean language composite score (96.47 vs 97.94, adjusted effect -1.42, 95% CI -3.07 to 0.22, P = 0.09).
Analysis of various small subgroups of the children noted a few statistically significant benefits and risks associated with taking DHA. Fewer children in the DHA group had delayed cognitive development than controls (11 vs 24, adjusted effect 0.41, 95% CI 0.007). Girls whose moms had used DHA had delayed language (20 vs 14, adjusted effect 1.81, 95% CI 1.06–3.08, P = 0.03) and lower mean language scores than controls (98.73 vs 103.24, adjusted effect -4.43, 95% CI -6.65 to -2.20, P = < 0.001). Girls also had poorer mean adaptive scores (101.27 vs 104.88, adjusted effect -3.55, 95% CI -3.55 to -1.20, P = 0.003). There was no difference in the number of 18-month-old children who excelled in language or cognition by total or gender.
Of note there were some secondary outcomes that were different between the groups. Women supplementing with DHA had fewer preterm babies born before 34 weeks gestational age (13 vs 27, adjusted relative risk [RR] 0.49, 95% CI 0.25–0.94, P = 0.03). Additionally, women using DHA had fewer post-term births requiring obstetric intervention (211 vs. 165, adjusted RR 1.28, 95% CI 1.06–1.54 P = 0.01). This is interesting because the duration of gestation was only 1 day less for the intervention group (282 vs 281, P = 0.05) The number of cesareans did not differ between the groups. The mean birth weight of infants from mothers in the intervention group was 68 g higher than control (95% CI 23–114 g, P = 0.03). There also were fewer infants of low birth weight born to moms in the intervention group (41 vs 63, adjusted RR 0.65, 95 % CI 0.44–0.96, P = 0.3) However, mean birth weight z scores (z scores are birth weights corrected for gestational age and sex) did not differ between groups indicating that the birth weight difference was more a function of gestational age at birth.
This study did support that DHA supplementation was safe. Frequency of hemorrhage and antenatal hospitalizations did not differ between groups. There was no difference between groups in the incidence of nose bleeds, vaginal blood loss, constipation, nausea, or vomiting at 28 and 36 weeks gestational age. The only statistically significant difference between the groups regarding side effects was that more women in the DHA group reported eructations compared to control (43.6 vs 25.6, adjusted RR 1.68, 95% CI 1.5–1.89, P < 0.001 at 28 weeks and 41.5 vs 29.2 at 36 weeks). Fewer women in the DHA group reported diarrhea; no maternal deaths occurred. Only two women from each group required an ICU stay.
This study also demonstrated safety for the infant of the mom taking DHA; 36 infants from the DHA group compared with 54 infants from the control group experienced one serious adverse event. (RR 0.67, 95% CI 0.44–1.01, P = 0.6). It is noteworthy that there were fewer infants with any admission to the Neonatal Intensive Care Unit from the moms using DHA compared to controls (1.86% vs 3.08%, 95% CI 0.34–0.97, P = 0.04).
Prenatal nutrition is certainly an important part of optimal fetal development. Initial research demonstrated that fish intake is inversely correlated with maternal postpartum depressive symptoms and positively correlated with cognitive development of the infant.1 LCPUFAs, specifically DHA, was thought to be the source of this health benefit.3 Based on these initial studies, prenatal vitamins that include these LCPUFAs are widely available. Even in this study population, more than 60% of women were excluded because they were already using fatty acid supplements.
This study's findings do not support the use of DHA to prevent postpartum depressive symptoms in the mom nor to improve cognitive development in their infant by 18 months of age. In fact, some concern of risk to female infants was demonstrated regarding speech and language development.
The study is not without shortcomings, the most significant of which being that supplementation occurred only from the second trimester on and ended at birth. The first trimester is a known period of rapid neuronal growth in the fetus.
It would have been interesting to include a sample of patients already taking fatty acid supplements to see if a difference existed with earlier supplementation. There is also no mention as to whether the results were adjusted for breastfeeding (which confers a protective effect against postpartum depression and is beneficial for cognitive development as well)5 or individual fatty acid supplementation by choice after delivery of the infant. Previous studies found differences in cognition for 9-month-olds only if compared to infants who did not breastfeed.6,7 These issues could be confounders and negate any differences found in this study if the critical period for DHA exposure is during the first trimester or infancy. Although there were significantly greater numbers of smokers in the control group, if anything this would likely magnify a positive association with the intervention group.
This study also used a cutoff of 12 for the Edinburgh Postnatal Depression Scale (EPDS). This level ensures fewer false positives and equates more to a significant risk of depression; however, previous positive studies using omega-3 fatty acids to prevent postpartum depression used a cutoff of 10 on the EPDS. It would have been better to use a similar cutoff level. The authors' response to this concern was the data do not support a different result using lower cut offs for the EPDS.8
Although there was enough power to use a smaller sample of children for the second part of the study, it would have been nice to use larger numbers and perhaps shrink the confidence intervals or clarify some of the concerns that emerged. The original study contained 2399 women, yet only 726 children were included in the cognition part of the study. Regarding small benefits for specific groups or risks (such as the girls with possible speech delay), a larger population would have been better.
In conclusion, results of this study call into question the benefit of large doses of DHA supplementation for pregnant mothers in their second trimester to birth to prevent postpartum depression or improve cognition in infants. There are still many unanswered questions, including whether the timing of the supplementation was suboptimal. The results regarding depression are not surprising, as other studies addressing incident depression in non-pregnant women do not support there being a preventive effect of omega-3 fatty acids, only that they may help children and adults respond to traditional antidepressants.9 The issue regarding the effect of DHA supplementation to improve children's cognition is still not clear and further studies must be completed to determine effectiveness.
1. Golding J, et al. High levels of depressive symptoms in pregnancy with low omega-3 fatty acid intake from fish. Epidemiology 2009;20: 598-603.
2. Hibbeln JR, et al. Maternal seafood consumption in pregnancy and neurodevelopmental outcomes in childhood (ALSPAC study): An observational cohort study. Lancet 2007;369: 578-585.
3. Brenna JT, Lapillonne A. Background paper on fat and fatty acid requirements during pregnancy and lactation. Ann Nutr Metab 2009;55: 97-122.
4. Makrides M, et al. Effect of DHA supplementation during pregnancy on maternal depression and neurodevelopment of young children: A randomized controlled trial. JAMA 2010;304:1675-1683.
5. Gaskin IM, Hunt P. Nursing mothers are less prone to depression than those who bottlefeed. Birth Gaz 1996;12: 46-48.
6. Birch EE, et al. A randomized controlled trial of long-chain polyunsaturated fatty acid supplementation of formula in term infants after weaning at 6 wk of age. Am J Clin Nutr 2002;75: 570-580.
7. Hoffman DR, et al. Visual function in breast-fed term infants weaned to formula with or without long-chain polyunsaturates at 4 to 6 months: A randomized clinical trial. J Pediatr 2003;142:669-677.
9. Lovett E, Ganta N. Advising patients about herbs and nutraceuticals: Tips for primary care providers. Prim Care 2010;37:13-30.
8. Suzuki T. Maternal depression and child development after prenatal DHA supplementation. JAMA 2011;305:359-360; author reply 360-361.