Consistent with the prenatal programming hypothesis,1 there is now evidence from multiple studies using a variety of methodologies and across different species that the mother's level of psychosocial stress during pregnancy is significantly associated with suboptimal developmental outcomes in their offspring including disturbances in attention,2,3 impaired learning and disruption in neurogenesis,4,5 and increased anxiety-like behaviors.2 The strength of the causal claim is based on rigorous controlled experiments in which the prenatal effect is distinguished from postnatal effects by using methods such as cross-fostering or nursery rearing. The pattern of findings in humans closely mirrors those from controlled animal studies.6–9 The strongest candidate for the mechanism by which prenatal stress confers risk to the offspring is the maternal hypothalamic–pituitary–adrenal axis. Prenatal stress causes long-term alterations in the functioning of the offspring's hypothalamic–pituitary–adrenal axis,10,11 and each of the phenotypic outcomes identified can be linked with disruptions in the hypothalamic–pituitary–adrenal axis.
A few investigators have examined the effects of docosahexaenoic acid (DHA) supplementation during pregnancy on later developmental functioning. Neuroprotective effects of DHA supplementation during pregnancy on the offspring has been reported in controlled animal studies.12–14 In humans, fatty acid supplementation is also associated with reductions in stress reactivity in controlled studies.15–18 Given this strong evidence, it is important to initiate studies of the prevention of the negative effects of prenatal stress in humans. This is especially important for women living in poverty, who are at higher risk for adverse birth outcomes,19 and whose offspring are at higher risk for poor developmental outcomes.20,21 Notably, DHA intake and blood levels of DHA are approximately a quarter to a third of the recommended levels for pregnant women living in low-income environments.22 African American women living in dense, urban poverty appear to have the highest risk for adverse birth outcomes.23 These data converge to support the hypothesis that prenatal DHA supplementation among women living in stressful environments would lead to reductions in perceived stress and greater modulation of the activation of the hypothalamic–pituitary–adrenal axis in response to stress.
MATERIALS AND METHODS
Pregnant women were recruited from Obstetrics Clinics within the University of Pittsburgh Medical Center from 2010 to 2012. Sample size was determined based on power calculations using existing data on perceived stress and cortisol response to the Trier Social Stress Test among pregnant women. Given the goals of the study, only demographically eligible women were approached for screening. Demographic eligibility included Medicaid insurance or Medicaid eligible, African American race, age between 20 and 30 years, and 16–21 weeks of gestation.
In addition to African American women being disproportionately represented among families living in inner-city poverty in the United States and having higher rates of suboptimal birth outcomes,19 there are race differences in cortisol reactivity to stress and pregnancy.24–26 To control for these group differences, either adequate numbers of participants of different races would need to be included or the study would have to be limited to a single race. Given the scope of the study, we chose to study African Americans only. We limited the sample to ages 20–30 years, which comprises more than 60% of pregnancies among African Americans.27 This range excluded younger and older ages of mothers during which the risk for suboptimal pregnancy outcomes increases.
Power calculations were computed using published data; the standard deviation of perceived stress using the Perceived Stress Scale was estimated to be 7.4.28 Forty participants in the supplement group and 20 in the placebo group yielded 80% power to detect a difference in stress levels of approximately four between the two groups using a two-sided test at the .05 significance level. The standard deviation of the cortisol response to the Trier Social Stress Test at 20 minutes was estimated to be equal to 8 nmol/L.29 Forty participants in the supplement group and 20 in the placebo group yielded 80% power to detect a difference in peak response of approximately 6 nmol/L between the two groups using a two-sided test at the .05 significance level.
Women were recruited using two methods. First, research assistants attended obstetric clinics and provided flyers to patients that listed the demographic inclusion criteria (ie, African American race, Medicaid insurance, gestational age between 16 and 21 weeks, and maternal age between 20 and 30 years) asking those eligible to complete the screening. Second, demographically eligible patients identified through electronic medical records were contacted by mail and phone to assess interest in the study. Telephone screenings were then conducted to assess eligibility. Exclusion criteria included two or more servings of sea fish per week, known medical complications (gestational diabetes, preeclampsia, subchorionic hematoma), regular use of steroid medications, regular alcohol use, cigarettes or use of illegal substances (by maternal report), use of blood thinners or anticoagulants, use of psychotropic medications, body mass index (calculated as weight (kg)/[height (m)]2) higher than 40, and allergy to iodine or soy. One hundred forty-six participated in screening for eligibility. Of those screened, 26 were ineligible, 64 were eligible and enrolled, 48 were eligible at the time of screening but could not be enrolled before the enrollment window (ie, 16–21 weeks of gestation), and eight refused to participate (Fig. 1).
Participants were reimbursed on an accelerated schedule with $40 for their first visit and an increase in payments of $10 for each subsequent visit. The institutional review boards of the University of Chicago and University of Pittsburgh approved all study procedures. This study also was a registered clinical trial (NCT01158976).
Once enrolled, women were randomly assigned on a two-to-one ratio to receive the omega-3 nutritional supplement (n=43) or a corn and soybean oil placebo (n=21) beginning at enrollment and up through the end of pregnancy. We expected greater variability in the dependent measures (eg, stress reactivity) among the experimental participants than the control patients. Thus, to optimize power to test the hypotheses, we enrolled a higher number of participants in the experimental group to adequately capture that variability. Women randomized to the study group received the supplement through two gel capsules providing: 450 mg DHA; 40 mg docosapentaenoic acid and eicosatetranoic acid; 90 mg eicosapentaenoic acid; and 15 international units of vitamin E supplied by Nordic Naturals. Women receiving the placebo received two capsules supplied by Nordic Naturals that were matched in size, color, and smell to the study drug. The pharmacist at the University of Pittsburgh used computer-generated random assignment of identification numbers to active supplement or placebo in blocks of nine: six identification numbers were randomized to active supplement and three to placebo. To maintain the double-blind, the pharmacist divided each randomization block of nine identification numbers into groups of three: three identification numbers were assigned to group A (placebo) and the remaining six were assigned to either group B or C, both of which received identical doses of active supplement. This approach allowed the pharmacist to randomize on a two-to-one ratio without having the unbalanced design break the blind. Once the study was complete, the blind was broken and the two groups receiving identical doses of active supplement were combined for analyses.
Cortisol response to a social evaluative stressor was measured at baseline and 24 and 30 weeks of gestation. Participants completed questionnaires covering stressful life events, perceived stress, and symptoms of depression at baseline and 24 and 30 weeks of gestation. Research assistants contacted participants by phone three times per week to ask the time of day that the supplement was taken and gathered data on perception of taste and possible gastrointestinal side effects to increase compliance.
Symptoms of depression were assessed using the Edinburgh Postnatal Depression Scale,30 a 10-item measure designed to assess pre- and postnatal depression without confounding the assessment of depression with somatic symptoms of pregnancy (eg, weight gain, loss of energy). Internal consistency in this sample was high: α=0.88 at baseline; 0.86 at 24 weeks of gestation; and 0.87 at 30 weeks. The Difficult Life Circumstances Scale31 is a set of 28 yes–no questions about difficult circumstances at home or work that may be a problem for the primary caregiver. The measure was designed to include items that would be applicable to women living in poverty such as difficulty with finances and housing. The internal consistency of the scale as measured by α ranged from 0.73 to 0.80. The Perceived Stress Scale32 is a 14-item scale designed to measure the degree to which situations in one's life are appraised as stressful. The internal consistency of the scale as measured by α was high: 0.85 at baseline; 0.88 at 24 weeks of gestation; and 0.87 at 30 weeks of gestation.
Following published recommendations for assessing physiologic stress reactivity during pregnancy,33 the Trier Social Stress Test34 was used as a psychological stressor. The Trier Social Stress Test procedure consists of a 2-minute preparation time followed by a 5-minute speech (as if for a job interview) and then a 5-minute mental arithmetic task. The latter two tasks are performed in front of a video camera and an audience. The Trier Social Stress Test typically elicits individual differences in cortisol reactivity, even during pregnancy.29,35
Saliva was collected at three time points at the baseline and 24 and 30 weeks of gestation assessments: 20 minutes after arrival to the laboratory and 20 and 45 minutes post-Trier Social Stress Test. To collect saliva samples, an absorbent, unflavored dental roll was applied to the tongue, cheek, and gums for several minutes. The dental roll was then placed in a labeled plastic salivette. Samples were immediately transferred to a freezer and stored at −20°C until assayed. On the day of testing, samples were thawed and centrifuged at 3,000 rpm for 10 minutes allowing for a clear sample to be pipetted into appropriate test wells. All samples from each participant were assayed in the same batch to minimize variability and assayed with reagents from the same lot. Samples with sufficient saliva were assayed in duplicate using the Salimetrics HS Salivary Cortisol EIA Kit for unbound cortisol. This assay has a lower limit of sensitivity from 0.007 to 1.2 micrograms per deciliter. The average between-assay variance is 3.9% and 7.1%, and the average within-assay variance is 6.7% and 6.9% for high and low concentrations, respectively. The correlation between saliva and serum using the Salimetrics HS Salivary Cortisol EIA Kit and the Coat-a-Count Serum Cortisol RIA kit is 0.96 (P<.001). Analyses were conducted with log10-transformed cortisol values but are presented as untransformed micrograms per deciliter for ease of interpretation.
Of the 64 participants who completed the baseline assessment, four (6.3%) withdrew from the study: two participants from each study arm. Two participants randomized to placebo withdrew as a result of adverse events: one miscarried, and the other withdrew as a result of mood changes. Two participants randomized to active supplement withdrew as a result of adverse events: one reported headaches and the other an upset stomach. Forty-seven participants (73.4%) attended all three sessions. Descriptive statistics are presented in Table 1 for depression, negative life events, and perceived stress at baseline and at 24 and 30 weeks of gestation. Data collected from all participants, including those who withdrew, are included in the analyses. Baseline self-report data for one participant in the active group were lost. One participant, with undetectable cortisol values for five of the nine samples, was not included in the analyses of cortisol response.
The first goal was to examine group differences in level of depression, negative life events, and perceived stress by conducting analyses of variance for each measure controlling for the other two measures. At baseline and 24 weeks of gestation, there were no group differences in any of the three measures. At 30 weeks of gestation, perceived stress was significantly lower among the participants receiving supplementation (mean 27.4) compared with those receiving placebo (mean 29.5) controlling for negative life events and depression scores at 30 weeks of gestation (F [1, 47] 5.06, P=.029, Cohen's d=0.65; Fig. 2), a difference of more than half of a standard deviation for the sample.
Cortisol response to the Trier Social Stress Test was examined as a function of group status (supplementation versus placebo) at baseline and 24 and 30 weeks of gestation by repeated-measures analysis of variance using a Greenhouse-Geisser correction to account for lack of sphericity. Time of day was significantly associated with initial cortisol levels at baseline but not at 24 and 30 weeks of gestation; time of day was controlled in analyses involving cortisol levels at baseline.
Cortisol levels before and after the Trier Social Stress Test did not vary as a function of supplementation at baseline or at 24 weeks of gestation. At 30 weeks of gestation, cortisol levels over time significantly differed as a function of supplementation (F [1.78, 83.85]=6.24, P=0.004, Cohen's d=0.76). As shown in Figure 3, women who received placebo had higher levels of cortisol on arrival to the laboratory compared with women receiving omega-3 supplementation. Levels for women receiving placebo were characterized by a relatively steep decline, whereas levels for women receiving omega-3 supplement evidenced a slight increase in response to the stressor, on average, followed by decline during the period of recovery. To further probe the differences in levels on arrival to the laboratory, the two groups were compared at baseline and 24 weeks and 30 weeks of gestation. As shown in Figure 4, cortisol levels on arrival to the laboratory were similar for the two groups at baseline but diverged over time such that by 30 weeks of gestation, women who received placebo had levels that were on average 20% higher than women receiving supplement (mean 0.35 compared with 0.27; F [1.74, 74.63] 3.51, P=.041, Cohen's d=0.56).
The present study was conducted from the perspective of the prenatal programming hypothesis.1 Specifically, a primary hypothesized mechanism by which prenatal stress affects offspring development is through exposure of the fetus to high levels of glucocorticoids released by the mother. This exposure, in turn, affects the fetal stress architecture in part by adjusting the set point for mounting a stress response and interfering with the feedback mechanisms for maintaining homeostasis. Although the postpartum environment continues to affect brain development, it is plausible that this initial insult sets the stage for a poor developmental trajectory that begins with poorly modulated response to stress in infancy.
Results from the present study provide preliminary evidence that changes in prenatal nutrition may be one way to interrupt the suboptimal prenatal programming of the fetus developing in the context of high levels of maternal stress. Pregnant women living in a high-stress, low-income, urban environment who received a fatty acid supplement reported lower levels of perceived stress than women who received placebo despite a lack of change in exposure to stressors. Moreover, the reduction of perceived stress was independent of depression, which was not associated with fatty acid supplementation. The lack of an association between DHA supplementation and depression symptoms is consistent with the literature on perinatal depression. In several randomized controlled trials, DHA was not associated with depression scores,36,37 but supplementation did appear to enhance the efficacy of psychopharmacologic treatment for depression,38 suggesting that systems associated with depressed mood and affect neurotransmission such as the hypothalamic–pituitary–adrenal axis are affected by fatty acid supplementation.
In fact, evidence from the present study suggests that DHA supplementation does affect the functioning of the hypothalamic–pituitary–adrenal axis by modulating response to a social stressor. This was demonstrated primarily through a lower cortisol response to arriving at the laboratory. By 30 weeks of gestation, participants who received DHA supplementation had lower levels of cortisol on arrival to the laboratory and on average demonstrated a slight increase in cortisol in response to the stressor, a pattern typically observed late in pregnancy.29,33 In contrast, participants who had received placebo evidenced high levels of cortisol on arrival to the laboratory followed by a steep decrease in cortisol levels during and after exposure to the Trier Social Stress Test. One interpretation of this pattern is that an exaggerated response to anticipatory stress leads to a less flexible response to the stressor. The high levels of cortisol on arrival to the laboratory followed by a lack of responsiveness to the stressor has been described as a pattern of dysregulated hypothalamic–pituitary–adrenal axis functioning associated with depression both in adults39 and children.40 Lack of cortisol response to a social stressor also has been observed among adults reporting high levels of early life adversity, especially females.41 Docosahexaenoic acid supplementation appears to protect pregnant women living in low-income environments from manifesting this type of dysregulation.
Demonstrating associations between of fatty acid supplementation and lower prenatal stress, however, is not sufficient. The next step will be to test the hypothesis that alterations in maternal stress levels through fatty acid supplementation improves developmental outcomes in the offspring. Data from other studies support the testing of this hypothesis. For example, Bolten and colleagues35 reported that cortisol reactivity to the Trier Social Stress Test at 32–34 weeks of gestation, but not basal cortisol levels, was associated with neonatal self-regulation. Similarly, Werner and colleagues42 found that neonates of women with high levels of maternal cortisol 25 minutes after arrival to the laboratory during late gestation were more likely to be classified as “high reactive” (ie, more motor activity and crying) in response to novel stimuli.
Thus, several important links among prenatal stress, cortisol levels, and neonate neurodevelopment have been demonstrated. Data from our preliminary study are compelling in terms of the potential effect on health disparities in maternal and neonatal health, a significant public health problem that is poorly understood. The findings, however, are in need of replication. In addition, a number of limitations should be noted. First, the small sample size and attrition of participants over time likely affect the reliability of the findings; thus, replication and timing of effects need to be explored in a larger study population. Although retention across study visits was comparable for the two groups, there may have been some differential selection bias across the two groups. Second, given the preliminary nature of the study, we did not control for multiple testing, and of the 13 tests of significance, we could expect that one may be the result of chance. The effect sizes for the significant results were medium to large, however, providing some indication that the results are not spurious. Third, we relied on maternal report of uptake as opposed to a rigorous assessment of blood levels of fatty acids across pregnancy. In addition to the possibility that uptake varied, blood levels may have varied among individuals with the same level of supplementation as a result of other dietary factors or individual differences in metabolism. Fourth, although we did not readminister the Trier Social Stress Test after 30 weeks of gestation, it would be important to examine whether differences in cortisol levels as a function of supplementation are maintained. Moreover, in the context of improving neonate outcomes, it may be important to supplement earlier in gestation. The third trimester is a period of fetal development that may be particularly sensitive to prenatal stress given the increase in maternal cortisol and decrease in placental corticosteroid 11β-hydroxysteroid dehydrogenase type 2, yet exposure earlier in gestation may also confer risk.43
In conclusion, the results reported here extend earlier work on the association between fatty acid supplementation and improved obstetric outcomes and complement existing research on prenatal stress and offspring neurodevelopment by providing preliminary evidence for nutritional moderation of prenatal stress.
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