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Maternal stress and social support prospectively predict infant inflammation
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Brain, Behavior, and Immunity journal homepage: www.elsevier.com/locate/ybrbi
Maternal stress and social support prospectively predict infant inflammation ⁎
Benjamin W. Nelsona, , Dorianne B. Wrighta, Nicholas B. Allena, Heidemarie K. Laurenta,b a b
Department of Psychology, University of Oregon, Eugene, OR, USA Department of Psychology, University of Illinois Urbana-Champaign, Champaign, IL, USA
A R T I C LE I N FO
A B S T R A C T
Keywords: C-reactive protein Infant Inflammation Maternal parenting stress Maternal social support Telomere length
Maternal stress has been suggested to be a risk factor for offspring health, while social support has been shown to be a protective factor for offspring functioning. Currently, research has yet to investigate how both of these factors may relate to infant inflammatory processes and associated biological aging in the first years of life. In 48 mother-infant dyads, we investigated whether maternal parenting stress and social support when infants were 12 and 18 months of age were cross-sectionally associated with infant salivary C-reactive protein (sCRP) during these times. In addition, we investigated whether parenting stress and social support were prospectively associated with later sCRP and changes in sCRP from 12 to 18 months of age, as well as whether those changes in sCRP were associated with subsequent infant salivary telomere length (sTL), a marker of biological aging. Analyses revealed that while there were no cross-sectional associations between maternal factors and infant sCRP, maternal parenting stress and social support when infants were 12 months of age predicted infant sCRP at 18 months of age. Further, maternal social support predicted changes in infant sCRP from 12 to 18 months of age. We observed a null association between infant sCRP and sTL. Implications for the ways that maternal mental health and social support may impact biological mechanisms related to disease processes in infants are discussed.
1. Introduction
1.1. Psychosocial stress and health
The mechanistic origins of adult disease and psychopathology can often be traced back to early psychosocial and biological disturbances (Gluckman et al., 2008; McEwen, 2012; Shonkoff et al., 2009). Different forms of early life psychosocial stress has been shown to predict a host of negative health outcomes across the lifespan (Danese and McEwen, 2012), including increased inflammation (David et al., 2017; Measelle and Ablow, 2018; Measelle et al., 2017; Miller et al., 2011; Taylor et al., 2006), shortened telomere length (TL; Kananen et al., 2010; KiecoltGlaser et al., 2011; Nelson et al., 2018; Tyrka et al., 2010), and ultimately, general morbidity (Price et al., 2013) and premature mortality (Anda et al., 2009; Fagundes et al., 2013; Miller et al., 2011). In contrast, social relationships and support have been shown to be associated with decreased inflammation (Ford et al., 2006; Mezuk et al., 2010), longer TL (Drury et al., 2012), and reduced morbidity and mortality (Heffner et al., 2011; Holt-Lunstad et al., 2015; Holt-Lunstad et al., 2010). Therefore, it is important to identify the association between early environmental psychosocial variables and biological markers of health during infancy to better understand the etiology of the emergence of negative health outcomes.
Elevated levels of c-reactive protein (CRP), a marker of inflammation, and shorter TL, a marker of cellular aging, are two potentially important biological mechanisms that are susceptible to psychosocial factors and that may influence health and disease processes across the lifespan. Currently, there are well established literatures connecting adult retrospective self-reported early life stress with inflammatory processes (Danese et al., 2008; Danese et al., 2013; Miller et al., 2011; Taylor et al., 2006) and TL (Kananen et al., 2010; Kiecolt-Glaser et al., 2011; Tyrka et al., 2010). A recent meta-analysis with over 16,000 adults confirmed that a form of retrospectively reported early life stress (i.e., childhood trauma) was significantly associated with a number of inflammatory variables, including CRP, in adulthood (Baumeister et al., 2016), while another meta-analysis with over 30,000 individuals found this same form of retrospectively reported early life stress to predict shorter TL in adulthood (Li et al., 2017). Yet, there is a dearth of research exploring these associations during the important developmental period of infancy. The few prior studies addressing the association between parental stress and inflammation during infancy have shown that maternal psychosocial stress, particularly stress related to parenting, is associated
Abbreviations: BMI, body mass index; PSS, parental stress scale; sCRP, salivary C-Reactive Protein; SSQ, social support questionnaire; sTL, salivary telomere length ⁎ Corresponding author at: Department of Psychology, 1227 University of Oregon, Eugene, OR 97403, USA. E-mail address: [email protected] (B.W. Nelson). https://doi.org/10.1016/j.bbi.2019.05.010 Received 27 June 2018; Received in revised form 4 May 2019; Accepted 7 May 2019 0889-1591/ © 2019 Elsevier Inc. All rights reserved.
Please cite this article as: Benjamin W. Nelson, et al., Brain, Behavior, and Immunity, https://doi.org/10.1016/j.bbi.2019.05.010
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with higher infant CRP levels (David et al., 2017). In addition, higher family stress, greater socioeconomic disadvantage, maternal depression, and disorganized attachment have all been associated with greater infant CRP (David et al., 2017; Measelle and Ablow, 2018; Measelle et al., 2017). These findings during infancy can be supplemented with additional research that has found that greater adversity between birth and age eight is associated with increased CRP from ages 10–15 (Danese et al., 2013). Regarding TL, maternal stress both prior to and following birth appears to matter. For example, maternal stress during pregnancy has been shown to predict newborn TL (Send et al., 2017), and exposure to increasing levels of maternal depressive symptoms—which may be conceptualized as a form of psychosocial stress—has been shown to be associated with shorter salivary telomere length (sTL) during infancy in this sample (Nelson et al., 2018).
Table 1 Sample Descriptive Statistics. Variable
Number
Percent of Sample
Race/Ethnic Identification Caucasian Latina Asian American Native American
38 5 3 2
79.2 10.4 6.3 4.2
Infant Gender Female Male
29 19
60.4 39.6
2 2 17
4.2 4.2 35.4
23 4
47.9 8.3
Relationship Length < 1 year 1–2 years 2–5 years 5–10 years > 10 years Missing
1 2 11 4 1 29
2.1 4.2 22.9 8.3 2.1 60.4
Education High school Vocational/technical school (2-year) Some college College graduate (4-year) Master’s degree Other
11 6 20 6 4 1
22.9 12.5 41.7 12.5 8.3 2.1
Employment Self-employed Part-time paid work Full-time paid work On leave Unemployed Full-time homemaker Student
4 6 6 6 7 16 3
8.3 12.5 12.5 12.5 14.6 33.3 6.3
Household Income < $4,999 $5,000-$9,999 $10,000-$19,999 $20,000-$29,999 $30,000-$39,999 $40,000-$49,999 $50,000-$74,999 $75,000-$99,999
12 4 3 9 6 5 7 2
25.0 8.3 6.3 18.8 12.5 10.4 14.6 4.2
Relationship Status Single Dating Living with Someone (not a legal domestic partnership) Married Legal/Registered Domestic Partnership
1.2. Social support and health There is even less research to date investigating the association between social support and inflammation during infancy. While no studies have directly assessed the association between parental social support and infant CRP, one study found that lower levels of maternal social support in the third trimester of pregnancy was associated with greater serum levels of CRP in mothers (Coussons-Read et al., 2007), although it is unknown if this translates to higher CRP in their infants. Overall, no studies have yet investigated whether maternal parenting stress and social support during infancy are associated with concurrent salivary c-reactive protein (sCRP), later sCRP, or changes in sCRP over time, and whether these changes in sCRP relate to subsequent TL. These research questions have potentially important implications as higher childhood CRP levels are associated with higher CRP levels in adulthood (Juonala et al., 2006), which may increase susceptibility to disease. It is important to have prospective infant research, as opposed to simply relying on adult retrospective reporting, to determine whether early life stress-related inflammation is already detectable in infancy or whether it is a phenomenon that only develops later in life. If the former is true, stress-related inflammation in infancy may be used as an early risk marker for future negative health trajectories. 1.3. Current study The current study (preregistered at Open Science Framework osf.io/ tw49z) investigated whether maternal parenting stress and social support are associated with infant sCRP—concurrently, as prospective predictors of sCRP six months later, and for changes in sCRP across those six months—and whether changes in sCRP are associated with infant TL. First, we hypothesized that greater maternal parenting stress and lower social support when infants were 12 months and 18 months of age would be cross-sectionally associated with higher infant sCRP during these times. Second, we hypothesized that greater maternal parenting stress and lower social support when infants were 12 months old would predict both higher infant sCRP at 18 months and a greater increase in sCRP from 12 to 18 months of age. Finally, we hypothesized that increasing infant sCRP from 12 and 18 months of age would be associated with shorter TL at 18 months of age.
sample. Of the 91 mother-infant dyads who began the study at Time 1 (T1), 48 dyads (53%) participated at all four assessments and provided a saliva samples for telomere and sCRP assay, resulting in the final sample size. Compared to non-completers, study completers tended to be older (M = 28.40 vs. 25.38, F[1, 88] = 7.66, p = .007, be in a longer-term romantic relationship (M = 3.11 years, SD = 0.88 vs. 2.19 years, SD = 0.60, F[1,38] = 15.09, p < .001), have more biological children (M = 2.94, SD = 0.94 vs. M = 2.56, SD = 0.83, F [1,88] = 4.07, p = .047), and report a higher household income, χ2(7) = 14.36, p = .045. Although there were no overall differences in attrition between white and non-white participants, differences between specific racial categories were found, χ2(5) = 13.70, p = .018, with African American participants more likely to drop out than other groups. There were no differences in infant sex, likelihood of being in a relationship with the target child’s biological father or degree of contact with the father, education, or employment status. Of the mental healthrelated variables reported at T1, the only difference that emerged was for current maternal depressive symptoms (M = 7.68 for completers vs. 11.70 for non-completers, F[1, 86] = 5.33, p = .020), indicating that
2. Methods and materials 2.1. Participants and recruitment Mothers were recruited from the Women Infants Children program and other community agencies serving low-income families in a midsized city in the Pacific Northwest region of the United States. To be eligible, mothers had to speak English, have a < 12-week-old infant, and anticipate remaining in the area until this target child was 18 months of age. Table 1 provides demographic information about the 2
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Fig. 1. Flowchart of participation across Times 1 through 4 (T1-T4, respectively). Note: at T1 average infant age was slightly younger than 3 months, as mothers completed questionnaires online prior to the first session.
Expanded Range High Sensitivity Cortisol Enzyme Immunoassay kit by Dr. Elizabeth Shirtcliff’s lab. The inter-assay CV was 2.34 and the intraassay CV was 3.10.
mothers who experienced the highest levels of depressive symptoms may have been lost in this study due to attrition. 2.2. Procedure
2.3.2. Salivary telomere length (sTL) At T4, one saliva sample was collected at the start of the session from the infant (assisted collection using DNA Genotek Oragene DISCOVER [OGR-575]) by a trained graduate student or research assistant to capture sTL according to DNA Genotek instructions. Saliva was collected by placing an absorbent sponge in the cheek pouch of infants’ mouths for a total of 1 min in order to collect 2 ML of saliva. If any of the conditions had been violated (e.g., if the infant had eaten recently or was sick with a fever), the participants were rescheduled. Samples were stored at room temperature. The Blackburn Lab at University of California San Francisco performed the salivary telomere assay by adapting the original method by Cawthon (2002), (Lin et al., 2010). Genomic DNA was extracted from saliva collected using the Oragene DNA kit (DNA Genotek cat# OG-575) with Agencourt DNAdvance kit (Beckman Coulter, cat# A48705). DNA samples were quantified by measuring OD260. The average concentration was 60.3 ng/ul (SD = 38.5 ng/ul). All DNA samples passed the quality control criteria of OD260/OD280 between 1.7 and 2.0. Additionally, DNA samples were run on agarose gels to check DNA integrity, and all samples appeared intact on gels. The average CV for this study was 3–4% (for more information on the telomere assay method see (Nelson et al., 2018).
Prior to study participation, mothers gave written informed consent to all study procedures, which had been approved by the Institutional Review Board. Mothers completed study assessments at 3 months at home (T1) and in the afternoon during three laboratory visits: at 6 months (T2), 12 months (T3), and 18 months (T4) postnatal. The rate of participation, relevant measures collected, infant age and sex, and maternal age at each wave are outlined in Fig. 1. At T2-T4 sessions, the mother and infant participated in laboratory psychosocial stress tasks. Because the saliva samples used in the current analyses were collected prior to the stress tasks, these tasks are not discussed further here. 2.3. Measures 2.3.1. Salivary c-reactive protein (sCRP) At T3 and T4, one saliva sample (Salimetrics Child’s Swab) was collected from infants by a trained graduate student or research assistant to capture sCRP according to Salimetrics instructions. Saliva was collected by placing the swabs in infants’ mouths for two minutes in order to collect a total of 2 mL of saliva. Prior to saliva collection mothers completed a saliva collection checklist. If any of several conditions had been violated (e.g., if the infant had eaten recently or was sick with a fever), the participants were rescheduled. Samples were stored at −20° C until shipment on dry ice for assay. Infants’ saliva samples were assayed in duplicate with the commercially available Salimetrics
2.3.3. Social support questionnaire 6 (SSQ6) The SSQ6 (Sarason et al., 1987) is a 6-item self-report questionnaire designed to measure both the number of individuals one can go to for 3
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age, β = −0.307, SE = 0.112, p = .009, 95% CI [−0.534, −0.081], and explained a significant amount of variance in sCRP, R2 = 0.123, F (1, 45) = 7.475, p = .009 (see Fig. 3a). Similarly, greater maternal social support when infants were 12 months of age was significantly associated with decreasing infant sCRP from 12 to 18 months of age, β = −0.211, SE = 0.103, p = .047, 95% CI [−0.419, −0.003], and explained a significant amount of variance in sCRP change scores, R2 = 0.064, F(1, 45) = 4.155, p = .047. Maternal parenting stress when infants were 12 months of age was significantly associated with infant sCRP at 18 months of age, β = 0.053, SE = 0.025, p = .042, 95% CI [0.002, 0.104], and explained a significant amount of variance in sCRP, R2 = 0.042, F(1, 43) = 4.392, p = .042 (see Fig. 3b). The association between maternal parenting stress when infants were 12 months of age and changes in infant sCRP from 12 to 18 months of age was marginally significant, β = 0.040, SE = 0.023, p = .090, 95% CI [−0.007, 0.087], and explained a marginal amount of variance in sCRP, R2 = 0.044, F(1, 43) = 3.002, p = .090. Finally, change in infant sCRP was not significantly associated with infant sTL at 18 months, β = −0.035, SE = 0.044, p = .433, 95% CI [−0.122, 0.053].
social support under different circumstances and one’s satisfaction with that social support. The former part of the measure, which taps quantity or extent of social support, was used in the current analyses. 2.3.4. The parental stress scale (PSS) The PSS (Berry and Jones, 1995) is an 18-item self-report questionnaire designed to measure parental stress both in terms of the presence of negative experiences (e.g., “The major source of stress in my life is my child (ren)”) and the absence of positive experiences (e.g., “I enjoy spending time with my child/ren” [reversed]). This measure has been shown to have good internal (0.83) and test-retest (0.81) reliability. Furthermore, the validity of this measure has been supported by various studies (see Berry and Jones, 1995; Zelman and Ferro, 2018). 2.3.5. Covariates A number of variables proposed to be related to infant sTL and/or sCRP were examined as potential control variables. These included infant age and weight, maternal and paternal age, infant sex and race, maternal socioeconomic status (SES) markers (education, employment, and income), and maternal smoking status. In order to preserve power and avoid overfitting, only covariates that are significantly associated with biomarker outcomes were included in analyses. None of these variables showed a significant association with infant sCRP or sTL, so they were not included in further model testing (see Fig. 2).
3.3. Post-hoc exploratory analyses Correlational analyses showed that maternal stress (r[45] = 0.095, p = .526, 95% CI [−0.198, 0.372]) and maternal social support (r [45] = 0.081, p = .586, 95% CI [−0.211, 0.360]) at 18 months were not cross-sectionally associated with infant sTL. In addition, regression analyses showed that maternal social support (β = −0.031, SE = 0.032, p = .327, 95% CI [−0.095, 0.032]) and maternal parenting stress (β = 0.004, SE = 0.007, p = .551, 95% CI [−0.010, 0.018]) at 12 months were not associated with infant sTL at 18 months. Last, neither sCRP at T3 (β = −0.032, SE = 0.055, p = .558, 95% CI [−0.142, 0.079] nor sCRP at T4 (r[45] = −.144p = .333, 95% CI [−0.414, 0.149]) were associated with infant sTL. In addition, as shown in Table 2, there was one high value of sTL even though sTL was winsorized to +/− 3 SD to correct for outliers. We performed sensitivity analyses by removing this value and rerunning analyses. Results indicated that all sTL results remained the same.
2.4. Statistical analyses All statistical analyses were conducted with R, version 3.3.2. Statistical significance was defined using 95% confidence intervals. Histograms as well as skew and kurtosis statistics were examined for each variable to check for normality. sTL and sCRP were winsorized to +/− 3 SD to correct for outliers (this impacted 1 sTL sample) or, in the case of sCRP, undetectable values (this impacted 4 samples each at the 12- and 18-month assessments). sCRP (log-transformed) concentrations when infants were 12 months of age (M = 4.76 pg/ML, SD = 0.97) ranged from 3.06 pg/ML to 6.86 pg/ML and at 18 months of age (M = 4.33 pg/ML, SD = 1.36) ranged from 1.61 pg/ML to 7.34 pg/ML. Change scores for sCRP were created by using T3 sCRP to predict T4 sCRP and saving the unstandardized residual. See Table 2 for sTL and sCRP descriptive statistics. Correlations were run to investigate cross-sectional associations between both maternal parenting stress and social support with sCRP at each time point. Linear regressions were performed to assess whether maternal parenting stress and social support when infants were 12 months of age predicted infant sCRP at 18 months of age and changes in infants’ sCRP between 12 and 18 months of age. Finally, a regression was run to examine whether changes in sCRP predicted sTL.
4. Discussion The current study was designed to investigate how maternal parenting stress and social support relate to infant inflammation from 12 to 18 months of age, and whether changes in inflammation in turn relate to infants’ cellular aging. This study is the first to examine cross-sectional and prospective associations between these maternal risk/protective factors and infant sCRP and changes in sCRP, as well as potential links with infant sTL. Study results provide partial support for hypothesized associations. Consistent with our hypotheses, higher maternal social support and lower parenting stress when infants were 12 months old predicted lower levels of infant sCRP six months later. This finding provides the first evidence that maternal parenting stress may act as a risk factor for infant inflammatory processes, while maternal social support may provide protection against higher inflammation. Furthermore, higher maternal social support predicted decreasing levels of sCRP from 12 to 18 months of age, indicating that the level of social support a mother has when her child is in early infancy may have an influence on inflammatory dynamics across infancy. One possible explanation for these associations is that mothers with more social support experience lower stress, as was found in our study at both 12 months (r = −0.42, p = .001) and 18 months (r = −0.27, p = .048), and therefore are able to express more positive parental behaviors toward their infants. This, in turn, could buffer against heightened sympathetic physiology in the child, which have been associated with higher sCRP during adolescence (Nelson et al., 2017). Indeed, greater social support has been shown to be a protective factor
3. Results 3.1. Cross-sectional correlation analyses Maternal social support and infant sCRP were marginally associated when infants were both 12 months of age (r(45) = −0.260, p = .077, 95% CI [−0.509, 0.029]) and 18 months of age (r(45) = −0.259, p = .078, 95% CI [−0.509, 0.030]). Maternal parenting stress and infant sCRP were not significantly associated when infants were 12 months of age (r(43) = 0.165, p = .279, 95% CI [−0.135, 0.437]) or when infants were 18 months of age (r(44) = 0.235, p = .117, 95% CI [−0.060, 0.491]). 3.2. Prospective regression analyses Greater maternal social support when infants were 12 months of age was significantly inversely associated with infant sCRP at 18 months of 4
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Fig. 2. Correlation Matrix. Note: Correlation coefficients may be different from Results Section as this figure was made with complete observations. T3 = time 3, T4 = time 4.
The effects for parenting stress in our study were not as consistent as those for social support. One reason for this may be that our measure of parental stress collapsed two different forms of stress—i.e., the presence of negative experiences and the absence of positive ones—into one variable. Researchers have argued that positive and negative affect are asymmetrical and may be distinct variables that differentially predict outcomes. For example, in a recent study of over 5000 participants, positive affect (but not negative affect) was associated with mortality (Petrie et al., 2018). Therefore, a more “pure” measure of stress that delineates positive and negative aspects of parental stress may provide a better measure for assessing how parenting stress is associated with infant inflammation. Inconsistent with our hypotheses, there were no cross-sectional associations between maternal variables and infant sCRP when infants were 12 months or 18 months of age and a null association between infant sCRP change and sTL. One potential reason for these null findings is that sCRP and sTL are relatively stable biological markers, and there may be a delay (Tilders et al., 1999) or lag effect (Shonkoff et al., 2009)
Table 2 Descriptive Statistics of sCRP and sTL. Variable
Mean (SD)
Range
sCRP log T3 sCRP log T4 sCRP Change sTL
4.76 (0.97) 4.33 (1.36) 0 (1.21) 1.76 (0.36)
3.06–6.86 1.61–7.34 −2.97 to 2.35 1.06–3.27
Note: sCRP = salivary C-Reactive Protein, sTL = salivary telomere length, T3 = time 3, T4 = time 4.
associated with lower levels of CRP (Ford et al., 2006; Heffner et al., 2011; Mezuk et al., 2010). In contrast, mothers who experience more parenting stress may display more negative parental behaviors (e.g., anger, such as expressed harshness) toward their offspring, a pattern associated with both greater sympathetic response in children (ElSheikh et al., 1989) and higher levels of sCRP in adolescence (Byrne et al., 2016). 5
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Fig. 3. Social Support (top) and Parenting Stress (bottom) predicting subsequent sCRP. Note: sCRP = salivary C-Reactive Protein.
4.1. Limitations and future directions
for current levels of psychosocial stress to influence stable inflammatory and aging processes. In other words, there may need to be a more cumulative effect of a buildup of psychosocial risk factors that “get under the skin” to influence biological processes related to disease. Consistent with this idea, T3 and T4 parental stress (r = 0.80) and parental social support (r = 0.62) were highly correlated, suggesting that that the level of stress and support in the family was fairly consistent across this period of time. If infants continued to be exposed to highly stressful or supportive family environments over time, we might expect that these environments would eventually have an influence on these more stable biological processes of inflammation and aging as has been shown in adult populations (Danese et al., 2008; Danese et al., 2013; Kananen et al., 2010; Kiecolt-Glaser et al., 2011; Miller et al., 2011; Taylor et al., 2006; Tyrka et al., 2010). More reactive measures of inflammation, such as Interleukin-6, might be better suited to index cross-sectional associations between maternal risk and protective factors, especially if those factors are changing over time. The non-significant association between sCRP—whether at 12 months, 18 months, or change from 12 to 18 months—and sTL adds to the mixed literature in this area, with some studies demonstrating an association between higher CRP and shorter TL (Fitzpatrick et al., 2011; Révész et al., 2014; Rode et al., 2014; Solorio et al., 2011), and others failing to find such an association (Brouilette et al., 2007; O’Donovan et al., 2011). In the current study, the lack of an association might be due to the relatively short time scale (six months) during which the study took place and/or low power due to the small N. It might take a longer period of time for higher levels of inflammatory markers to influence cell turnover to result in shorter TL, a hypothesis that should be tested in future research.
Although the present study has some notable strengths, such as using a longitudinal design with a high-risk (low-income) sample to provide initial evidence for prospective associations between maternal risk/protective factors and infant inflammation, there were a number of limitations that reduce the generalizability of these findings. Full study measures were only available for 48 mother-infant dyads, which provided a small scale test of the hypothesized associations between both maternal parenting stress and social support and infant inflammation, as well as the association of inflammation with infant biological aging. Future research should replicate this study with a larger and more diverse sample. In addition, we did not address the role of potential mechanisms (e.g., parenting behaviors, sympathetic activity) that may have accounted for the association between maternal variables and infant inflammation. Future studies should investigate the role of the autonomic nervous system and parenting behaviors, which have been shown to respond to stress and influence inflammatory processes (Kemeny and Schedlowski, 2007; Jänig, 2014; Nelson et al., 2017). In addition, this study did not collect prenatal stress measures, which could be important gestational predictors that may account for variance in infant sCRP and sTL. Future studies incorporating such measures would allow researchers to disentangle prenatal and postnatal environmental contributions to processes of disease. Similarly, the current study utilized measures of parental stress and social support that were highly correlated across the six months – suggesting that they prominently tap into trait like aspects of stressful experiences. Future studies should attempt to capture these variables with measures that may be more sensitive to proximal changes in environmental stress and 6
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social support. Finally, we collected sCRP, rather than circulating CRP in infants, because this entails a noninvasive and painless procedure. The tradeoff with this method is that it may have introduced some noise. For example, research is mixed on whether sCRP is associated with CRP collected in blood, with some studies finding no correlation (Dillon et al., 2010; Kopanczyk et al., 2010) and others finding that these two measures correlate with medium to large effect sizes (O’Brien-Simpson et al., 2013; Out et al., 2012). There is also evidence that many inflammatory markers can have higher detection rates in saliva when compared to blood (O’Brien-Simpson et al., 2013). One possible reason for this difference is that CRP can pass from blood to saliva through gingival crevicular fluid, which indicates that sCRP can be indicative of both local and systemic inflammation (Megson et al., 2010). While saliva samples are preferred with infants based on the invasiveness/pain considerations noted above, future studies might consider utilizing blood spots to detect CRP in infants. In contrast, this is not likely to be an issue with sTL; research has shown that while sTL is significantly longer than whole blood TL, they are highly correlated (Mitchell et al., 2014; Stout et al., 2017).
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Effect of in utero and early-life conditions on adult health and disease. N. Engl. J. Med. 359 (1), 61–73. Heffner, K.L., Waring, M.E., Roberts, M.B., Eaton, C.B., Gramling, R., 2011. Social isolation, C-reactive protein, and coronary heart disease mortality among communitydwelling adults. Soc. Sci. Med. 72 (9), 1482–1488. https://doi.org/10.1016/j. socscimed.2011.03.016. Holt-Lunstad, J., Smith, T.B., Baker, M., Harris, T., Stephenson, D., 2015. Loneliness and social isolation as risk factors for mortality: a meta-analytic review. Perspect. Psychol. Sci. https://doi.org/10.1177/1745691614568352. Holt-Lunstad, J., Smith, T.B., Layton, J.B., 2010. Social relationships and mortality risk: a meta-analytic review. PLoS Med. 7 (7), e1000316. https://doi.org/10.1371/journal. pmed.1000316. Jänig, W., 2014. Sympathetic nervous system and inflammation: a conceptual view. Auton. Neurosci. 182, 4–14. Juonala, M., Viikari, J.S.A., Rönnemaa, T., Taittonen, L., Marniemi, J., Raitakari, O.T., 2006. Childhood C-reactive protein in predicting CRP and carotid intima-media thickness in adulthood: the Cardiovascular Risk in Young Finns Study. Arterioscler. Thromb. Vasc. Biol. 26 (8), 1883–1888. https://doi.org/10.1161/01.ATV. 0000228818.11968.7a. Kananen, L., Surakka, I., Pirkola, S., Suvisaari, J., Lönnqvist, J., Peltonen, L., Hovatta, I., 2010. Childhood adversities are associated with shorter telomere length at adult age both in individuals with an anxiety disorder and controls. PLoS One 5 (5), e10826. Kemeny, M.E., Schedlowski, M., 2007. Understanding the interaction between psychosocial stress and immune-related diseases: a stepwise progression. Brain Behav. Immun. 21 (8), 1009–1018. https://doi.org/10.1016/j.bbi.2007.07.010. Kiecolt-Glaser, J.K., Gouin, J.-P., Weng, N.-P., Malarkey, W.B., Beversdorf, D.Q., Glaser, R., 2011. Childhood adversity heightens the impact of later-life caregiving stress on telomere length and inflammation. Psychosom. Med. 73 (1), 16–22. https://doi.org/ 10.1097/PSY.0b013e31820573b6. Kopanczyk, R., Opris, D.C., Lickliter, J., Bridges, E.G., Nazar, A.M., Bridges, K.G., 2010. Creactive protein levels in blood and saliva show no correlation in young, healthy adults. FASEB 24 (1), b409-lb409. Li, Z., He, Y., Wang, D., Tang, J., Chen, X., 2017. Association between childhood trauma and accelerated telomere erosion in adulthood: a meta-analytic study. J. Psychiatr. Res. 93, 64–71. Lin, J., Epel, E.S., Cheon, J., Kroenke, C.H., Sinclair, E., Bigos, M., Blackburn, E., 2010. Analyses and comparisons of telomerase activity and telomere length in human T and B cells: Insights for epidemiology of telomere maintenance. J. Immunol. Methods 352 (1–2), 71–80. https://doi.org/10.1016/j.biotechadv.2011.08.021.Secreted. McEwen, B.S., 2012. Brain on stress: how the social environment gets under the skin. PNAS 109 (Supplement 2), 17180–17185. https://doi.org/10.1073/pnas. 1121254109. Measelle, J.R., Ablow, J.C., 2018. Contributions of early adversity to pro-inflammatory phenotype in infancy: the buffer provided by attachment security. Attachment Human Dev. 20 (1), 1–23. https://doi.org/10.1080/14616734.2017.1362657. Measelle, J.R., David, J., Ablow, J.C., 2017. Increased levels of inflammation among infants with disorganized histories of attachment. Behav. Brain Res. 325, 260–267.
5. Conclusion This study investigated whether maternal psychosocial stress—particularly as it relates to parenting—and social support relate both cross-sectionally and prospectively to infant inflammation (sCRP), whether these maternal factors predict changes in infant sCRP across 6 months, and whether changes in infant inflammation relate to cellular aging (sTL). These findings indicate that maternal parenting stress may heighten infant inflammatory processes during the first year and a half of life, while maternal social support may protect or buffer against these effects. By examining these processes as they occur during infancy, the current investigation takes an important step toward identifying how early stressful environments can give rise to long-term disease risk. Acknowledgments This research was supported by grants from The Mind and Life Institute (1440 Research Award 2015-1440-Nelson) awarded to the first author and The Society for Research in Child Development Victoria Levin Award and the University of Oregon College of Arts and Sciences issued to the last author. The funding sources had no role in the study design, data collection and analysis, or submission process. We thank Elissa Epel, Ph.D. for her consultation on our study design and Jue Line, Ph.D. and Elizabeth Blackburn, Ph.D. for their expertise in assaying the telomere samples. We also thank Elizabeth Shirtcliff, Ph.D. for her expertise in assaying the c-reactive protein samples. References Anda, R.F., Dong, M., Brown, D.W., Felitti, V.J., Giles, W.H., Perry, G.S., Valerie, E.J., Dube, S.R., 2009. The relationship of adverse childhood experiences to a history of premature death of family members. BMC Public Health 9 (1), 106. https://doi.org/ 10.1186/1471-2458-9-106. Baumeister, D., Akhtar, R., Ciufolini, S., Pariante, C.M., Mondelli, V., 2016. Childhood trauma and adulthood inflammation: a meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-α. Mol. Psychiatry 21 (5), 642–649. Berry, J.O., Jones, W.H., 1995. The parental stress scale: initial psychometric evidence. J. Soc. Pers. Relat. 12 (3), 463–472. https://doi.org/10.1177/0265407595123009. Brouilette, S.W., Moore, J.S., McMahon, A.D., Thompson, J.R., Ford, I., Shepherd, J., Samani, N.J., 2007. Telomere length, risk of coronary heart disease, and statin treatment in the West of Scotland Primary Prevention Study: a nested case-control study. Lancet 369 (9556), 107–114. https://doi.org/10.1016/S0140-6736(07) 60071-3. Byrne, M.L., Badcock, P.B., Simmons, J.G., Whittle, S., Pettitt, A., Olsson, C.A., Mundy, L.K., Patton, G.C., Allen, N.B., 2016. Self-reported parenting style is associated with children’s inflammation and immune activation. J. Fam. Psychol. 31 (3), 374. O’Brien-Simpson, M.L.N.M., Reynolds, E.C., Walsh, K.A., Laughton, K., Waloszek, J.M., ... Allen, N.B., 2013. Acute phase protein and cytokine levels in serum and saliva: a comparison of detectable levels and correlations in a depressed and healthy adolescent sample. Brain, Behav. Immu. 34, 164–175. https://doi.org/10.1016/j.bbi.2013. 08.010.
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B.W.J.H., 2014. Dysregulated physiological stress systems and accelerated cellular aging. Neurobiol. Aging 35 (6), 1422–1430. https://doi.org/10.1016/j. neurobiolaging.2013.12.027. Rode, L., Nordestgaard, B.G., Weischer, M., Bojesen, S.E., 2014. Increased body mass index, elevated c-reactive protein, and short telomere length. J. Clin. Endocrinol. Metab. 99 (9), E1671–E1675. https://doi.org/10.1210/jc.2014-1161. Sarason, I.G., Sarason, B.R., Shearin, E.N., Pierce, G.R., 1987. A brief measure of social support: practical and theoretical implications. J. Soc. Pers. Relat. 4 (4), 497–510. https://doi.org/10.1177/0265407587044007. Send, T., Gilles, M., Codd, V., Wolf, I.A.C., Bardtke, S., Streit, F., Witt, S.H., 2017. Telomere length in newborns is related to maternal stress during pregnancy. Neuropsychopharmacology 42 (12), 2407–2413. https://doi.org/10.1038/npp. 2017.73. Shonkoff, J.P., Boyce, W.T., McEwen, B.S., 2009. Neuroscience, molecular biology, and the childhood roots of health disparities: building a new framework for health promotion and disease prevention. JAMA 301 (21), 2252–2259. https://doi.org/10. 1001/jama.2009.754. Solorio, S., Murillo-Ortíz, B., Hernández-González, M., Guillén-Contreras, J., ArenasAranda, D., Solorzano-Zepeda, F.J., Malacara-Hernández, J.M., 2011. Association between telomere length and c-reactive protein and the development of coronary collateral circulation in patients with coronary artery disease. Angiology 62 (6), 467–472. https://doi.org/10.1177/0003319710398007. Stout, S.A., Lin, J., Hernandez, N., Davis, E.P., Blackburn, E., Carroll, J.E., Glynn, L.M., 2017. Validation of minimally-invasive sample collection methods for measurement of telomere length. Front. Aging Neurosci. 9 (DEC), 1–6. https://doi.org/10.3389/ fnagi.2017.00397. Taylor, S.E., Lehman, B.J., Kiefe, C.I., Seeman, T.E., 2006. Relationship of early life stress and psychological functioning to adult C-reactive protein in the coronary artery risk development in young adults study. Biol. Psychiatry 60 (8), 819–824. Tilders, F.J.H., Schmidt, E.D., Hoogedijk, W.J.G., Swaab, D.F., 1999. Delayed effects of stress and immune activation. Bailliere’s Best Pract. Res. Clin. Endocrinol. Metab. 13 (4), 523–540. https://doi.org/10.1053/beem.1999.0040. Tyrka, A.R., Price, L.H., Kao, H.T., Porton, B., Marsella, S.A., Carpenter, L.L., 2010. Childhood maltreatment and telomere shortening: preliminary support for an effect of early stress on cellular aging. Biol. Psychiatry 67 (6), 531–534. Zelman, J.J., Ferro, M.A., 2018. The parental stress scale: psychometric properties in families of children with chronic health conditions. Fam. Relat. 67 (2), 240–252.
https://doi.org/10.1016/j.bbr.2016.12.001. Megson, E., Fitzsimmons, T., Dharmapatni, K., Mark Bartold, P., 2010. C-reactive protein in gingival crevicular fluid may be indicative of systemic inflammation. J. Clin. Periodontol. 37 (9), 797–804. https://doi.org/10.1111/j.1600-051X.2010.01603.x. Mezuk, B., Diez Roux, A.V., Seeman, T., 2010. Evaluating the buffering vs. direct effects hypotheses of emotional social support on inflammatory markers: the Multi-Ethnic Study of Atherosclerosis. Brain Behav. Immun. 24 (8), 1294–1300. https://doi.org/ 10.1016/j.bbi.2010.06.006. Miller, G.E., Chen, E., Parker, K.J., 2011. Psychological stress in childhood and susceptibility to the chronic diseases of aging: moving toward a model of behavioral and biological mechanisms. Psychol. Bull. 137 (6), 959–997. https://doi.org/10.1037/ a0024768. Mitchell, C., Hobcraft, J., McLanahan, S.S., Siegel, S.R., Berg, A., Brooks-Gunn, J., Notterman, D., 2014. Social disadvantage, genetic sensitivity, and children’s telomere length. PNAS 111 (16), 5944–5949. https://doi.org/10.1073/pnas.1404293111. Nelson, B.W., Allen, N.B., Laurent, H., 2018. Infant HPA axis as a potential mechanism linking maternal mental health and infant telomere length. Psychoneuroendocrinology 88 (June 2017), 38–46. https://doi.org/10.1016/j. psyneuen.2017.11.008. Nelson, B.W., Byrne, M.L., Simmons, J.G., Whittle, S., Schwartz, O.S., Reynolds, E.C., ... Allen, N.B., 2017. Adolescent sympathetic activity and salivary c-reactive protein: the effects of parental behavior. Health Psychol. 36 (10), 955–965. https://doi.org/10. 1037/hea0000516. O’Donovan, A., Pantell, M.S., Puterman, E., Dhabhar, F.S., Blackburn, E.H., Yaffe, K., Epel, E.S., 2011. Cumulative inflammatory load is associated with short leukocyte telomere length in the health, aging and body composition study. PLoS One 6 (5). https://doi.org/10.1371/journal.pone.0019687. Out, D., Hall, R.J., Granger, D.A., Page, G.G., Woods, S.J., 2012. Assessing salivary Creactive protein: longitudinal associations with systemic inflammation and cardiovascular disease risk in women exposed to intimate partner violence. Brain, Behav. Immunity 26 (4), 543–551. https://doi.org/10.1016/j.bbi.2012.01.019. Petrie, K.J., Pressman, S.D., Pennebaker, J.W., Øverland, S., Tell, G.S., Sivertsen, B., 2018. Which aspects of positive affect are related to mortality? results from a general population longitudinal study. Ann. Behav. Med. 52 (7), 571–581. Price, L.H., Kao, H.-T.T., Burgers, D.E., Carpenter, L.L., Tyrka, A.R., 2013. Telomeres and early-life stress: an overview. Biol. Psychiatry 73 (1), 15–23. https://doi.org/10. 1016/j.biopsych.2012.06.025. Révész, D., Verhoeven, J.E., Milaneschi, Y., De Geus, E.J.C.N., Wolkowitz, O.M., Penninx,
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Contents lists available at ScienceDirect
Brain, Behavior, and Immunity journal homepage: www.elsevier.com/locate/ybrbi
Maternal stress and social support prospectively predict infant inflammation ⁎
Benjamin W. Nelsona, , Dorianne B. Wrighta, Nicholas B. Allena, Heidemarie K. Laurenta,b a b
Department of Psychology, University of Oregon, Eugene, OR, USA Department of Psychology, University of Illinois Urbana-Champaign, Champaign, IL, USA
A R T I C LE I N FO
A B S T R A C T
Keywords: C-reactive protein Infant Inflammation Maternal parenting stress Maternal social support Telomere length
Maternal stress has been suggested to be a risk factor for offspring health, while social support has been shown to be a protective factor for offspring functioning. Currently, research has yet to investigate how both of these factors may relate to infant inflammatory processes and associated biological aging in the first years of life. In 48 mother-infant dyads, we investigated whether maternal parenting stress and social support when infants were 12 and 18 months of age were cross-sectionally associated with infant salivary C-reactive protein (sCRP) during these times. In addition, we investigated whether parenting stress and social support were prospectively associated with later sCRP and changes in sCRP from 12 to 18 months of age, as well as whether those changes in sCRP were associated with subsequent infant salivary telomere length (sTL), a marker of biological aging. Analyses revealed that while there were no cross-sectional associations between maternal factors and infant sCRP, maternal parenting stress and social support when infants were 12 months of age predicted infant sCRP at 18 months of age. Further, maternal social support predicted changes in infant sCRP from 12 to 18 months of age. We observed a null association between infant sCRP and sTL. Implications for the ways that maternal mental health and social support may impact biological mechanisms related to disease processes in infants are discussed.
1. Introduction
1.1. Psychosocial stress and health
The mechanistic origins of adult disease and psychopathology can often be traced back to early psychosocial and biological disturbances (Gluckman et al., 2008; McEwen, 2012; Shonkoff et al., 2009). Different forms of early life psychosocial stress has been shown to predict a host of negative health outcomes across the lifespan (Danese and McEwen, 2012), including increased inflammation (David et al., 2017; Measelle and Ablow, 2018; Measelle et al., 2017; Miller et al., 2011; Taylor et al., 2006), shortened telomere length (TL; Kananen et al., 2010; KiecoltGlaser et al., 2011; Nelson et al., 2018; Tyrka et al., 2010), and ultimately, general morbidity (Price et al., 2013) and premature mortality (Anda et al., 2009; Fagundes et al., 2013; Miller et al., 2011). In contrast, social relationships and support have been shown to be associated with decreased inflammation (Ford et al., 2006; Mezuk et al., 2010), longer TL (Drury et al., 2012), and reduced morbidity and mortality (Heffner et al., 2011; Holt-Lunstad et al., 2015; Holt-Lunstad et al., 2010). Therefore, it is important to identify the association between early environmental psychosocial variables and biological markers of health during infancy to better understand the etiology of the emergence of negative health outcomes.
Elevated levels of c-reactive protein (CRP), a marker of inflammation, and shorter TL, a marker of cellular aging, are two potentially important biological mechanisms that are susceptible to psychosocial factors and that may influence health and disease processes across the lifespan. Currently, there are well established literatures connecting adult retrospective self-reported early life stress with inflammatory processes (Danese et al., 2008; Danese et al., 2013; Miller et al., 2011; Taylor et al., 2006) and TL (Kananen et al., 2010; Kiecolt-Glaser et al., 2011; Tyrka et al., 2010). A recent meta-analysis with over 16,000 adults confirmed that a form of retrospectively reported early life stress (i.e., childhood trauma) was significantly associated with a number of inflammatory variables, including CRP, in adulthood (Baumeister et al., 2016), while another meta-analysis with over 30,000 individuals found this same form of retrospectively reported early life stress to predict shorter TL in adulthood (Li et al., 2017). Yet, there is a dearth of research exploring these associations during the important developmental period of infancy. The few prior studies addressing the association between parental stress and inflammation during infancy have shown that maternal psychosocial stress, particularly stress related to parenting, is associated
Abbreviations: BMI, body mass index; PSS, parental stress scale; sCRP, salivary C-Reactive Protein; SSQ, social support questionnaire; sTL, salivary telomere length ⁎ Corresponding author at: Department of Psychology, 1227 University of Oregon, Eugene, OR 97403, USA. E-mail address: [email protected] (B.W. Nelson). https://doi.org/10.1016/j.bbi.2019.05.010 Received 27 June 2018; Received in revised form 4 May 2019; Accepted 7 May 2019 0889-1591/ © 2019 Elsevier Inc. All rights reserved.
Please cite this article as: Benjamin W. Nelson, et al., Brain, Behavior, and Immunity, https://doi.org/10.1016/j.bbi.2019.05.010
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with higher infant CRP levels (David et al., 2017). In addition, higher family stress, greater socioeconomic disadvantage, maternal depression, and disorganized attachment have all been associated with greater infant CRP (David et al., 2017; Measelle and Ablow, 2018; Measelle et al., 2017). These findings during infancy can be supplemented with additional research that has found that greater adversity between birth and age eight is associated with increased CRP from ages 10–15 (Danese et al., 2013). Regarding TL, maternal stress both prior to and following birth appears to matter. For example, maternal stress during pregnancy has been shown to predict newborn TL (Send et al., 2017), and exposure to increasing levels of maternal depressive symptoms—which may be conceptualized as a form of psychosocial stress—has been shown to be associated with shorter salivary telomere length (sTL) during infancy in this sample (Nelson et al., 2018).
Table 1 Sample Descriptive Statistics. Variable
Number
Percent of Sample
Race/Ethnic Identification Caucasian Latina Asian American Native American
38 5 3 2
79.2 10.4 6.3 4.2
Infant Gender Female Male
29 19
60.4 39.6
2 2 17
4.2 4.2 35.4
23 4
47.9 8.3
Relationship Length < 1 year 1–2 years 2–5 years 5–10 years > 10 years Missing
1 2 11 4 1 29
2.1 4.2 22.9 8.3 2.1 60.4
Education High school Vocational/technical school (2-year) Some college College graduate (4-year) Master’s degree Other
11 6 20 6 4 1
22.9 12.5 41.7 12.5 8.3 2.1
Employment Self-employed Part-time paid work Full-time paid work On leave Unemployed Full-time homemaker Student
4 6 6 6 7 16 3
8.3 12.5 12.5 12.5 14.6 33.3 6.3
Household Income < $4,999 $5,000-$9,999 $10,000-$19,999 $20,000-$29,999 $30,000-$39,999 $40,000-$49,999 $50,000-$74,999 $75,000-$99,999
12 4 3 9 6 5 7 2
25.0 8.3 6.3 18.8 12.5 10.4 14.6 4.2
Relationship Status Single Dating Living with Someone (not a legal domestic partnership) Married Legal/Registered Domestic Partnership
1.2. Social support and health There is even less research to date investigating the association between social support and inflammation during infancy. While no studies have directly assessed the association between parental social support and infant CRP, one study found that lower levels of maternal social support in the third trimester of pregnancy was associated with greater serum levels of CRP in mothers (Coussons-Read et al., 2007), although it is unknown if this translates to higher CRP in their infants. Overall, no studies have yet investigated whether maternal parenting stress and social support during infancy are associated with concurrent salivary c-reactive protein (sCRP), later sCRP, or changes in sCRP over time, and whether these changes in sCRP relate to subsequent TL. These research questions have potentially important implications as higher childhood CRP levels are associated with higher CRP levels in adulthood (Juonala et al., 2006), which may increase susceptibility to disease. It is important to have prospective infant research, as opposed to simply relying on adult retrospective reporting, to determine whether early life stress-related inflammation is already detectable in infancy or whether it is a phenomenon that only develops later in life. If the former is true, stress-related inflammation in infancy may be used as an early risk marker for future negative health trajectories. 1.3. Current study The current study (preregistered at Open Science Framework osf.io/ tw49z) investigated whether maternal parenting stress and social support are associated with infant sCRP—concurrently, as prospective predictors of sCRP six months later, and for changes in sCRP across those six months—and whether changes in sCRP are associated with infant TL. First, we hypothesized that greater maternal parenting stress and lower social support when infants were 12 months and 18 months of age would be cross-sectionally associated with higher infant sCRP during these times. Second, we hypothesized that greater maternal parenting stress and lower social support when infants were 12 months old would predict both higher infant sCRP at 18 months and a greater increase in sCRP from 12 to 18 months of age. Finally, we hypothesized that increasing infant sCRP from 12 and 18 months of age would be associated with shorter TL at 18 months of age.
sample. Of the 91 mother-infant dyads who began the study at Time 1 (T1), 48 dyads (53%) participated at all four assessments and provided a saliva samples for telomere and sCRP assay, resulting in the final sample size. Compared to non-completers, study completers tended to be older (M = 28.40 vs. 25.38, F[1, 88] = 7.66, p = .007, be in a longer-term romantic relationship (M = 3.11 years, SD = 0.88 vs. 2.19 years, SD = 0.60, F[1,38] = 15.09, p < .001), have more biological children (M = 2.94, SD = 0.94 vs. M = 2.56, SD = 0.83, F [1,88] = 4.07, p = .047), and report a higher household income, χ2(7) = 14.36, p = .045. Although there were no overall differences in attrition between white and non-white participants, differences between specific racial categories were found, χ2(5) = 13.70, p = .018, with African American participants more likely to drop out than other groups. There were no differences in infant sex, likelihood of being in a relationship with the target child’s biological father or degree of contact with the father, education, or employment status. Of the mental healthrelated variables reported at T1, the only difference that emerged was for current maternal depressive symptoms (M = 7.68 for completers vs. 11.70 for non-completers, F[1, 86] = 5.33, p = .020), indicating that
2. Methods and materials 2.1. Participants and recruitment Mothers were recruited from the Women Infants Children program and other community agencies serving low-income families in a midsized city in the Pacific Northwest region of the United States. To be eligible, mothers had to speak English, have a < 12-week-old infant, and anticipate remaining in the area until this target child was 18 months of age. Table 1 provides demographic information about the 2
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Fig. 1. Flowchart of participation across Times 1 through 4 (T1-T4, respectively). Note: at T1 average infant age was slightly younger than 3 months, as mothers completed questionnaires online prior to the first session.
Expanded Range High Sensitivity Cortisol Enzyme Immunoassay kit by Dr. Elizabeth Shirtcliff’s lab. The inter-assay CV was 2.34 and the intraassay CV was 3.10.
mothers who experienced the highest levels of depressive symptoms may have been lost in this study due to attrition. 2.2. Procedure
2.3.2. Salivary telomere length (sTL) At T4, one saliva sample was collected at the start of the session from the infant (assisted collection using DNA Genotek Oragene DISCOVER [OGR-575]) by a trained graduate student or research assistant to capture sTL according to DNA Genotek instructions. Saliva was collected by placing an absorbent sponge in the cheek pouch of infants’ mouths for a total of 1 min in order to collect 2 ML of saliva. If any of the conditions had been violated (e.g., if the infant had eaten recently or was sick with a fever), the participants were rescheduled. Samples were stored at room temperature. The Blackburn Lab at University of California San Francisco performed the salivary telomere assay by adapting the original method by Cawthon (2002), (Lin et al., 2010). Genomic DNA was extracted from saliva collected using the Oragene DNA kit (DNA Genotek cat# OG-575) with Agencourt DNAdvance kit (Beckman Coulter, cat# A48705). DNA samples were quantified by measuring OD260. The average concentration was 60.3 ng/ul (SD = 38.5 ng/ul). All DNA samples passed the quality control criteria of OD260/OD280 between 1.7 and 2.0. Additionally, DNA samples were run on agarose gels to check DNA integrity, and all samples appeared intact on gels. The average CV for this study was 3–4% (for more information on the telomere assay method see (Nelson et al., 2018).
Prior to study participation, mothers gave written informed consent to all study procedures, which had been approved by the Institutional Review Board. Mothers completed study assessments at 3 months at home (T1) and in the afternoon during three laboratory visits: at 6 months (T2), 12 months (T3), and 18 months (T4) postnatal. The rate of participation, relevant measures collected, infant age and sex, and maternal age at each wave are outlined in Fig. 1. At T2-T4 sessions, the mother and infant participated in laboratory psychosocial stress tasks. Because the saliva samples used in the current analyses were collected prior to the stress tasks, these tasks are not discussed further here. 2.3. Measures 2.3.1. Salivary c-reactive protein (sCRP) At T3 and T4, one saliva sample (Salimetrics Child’s Swab) was collected from infants by a trained graduate student or research assistant to capture sCRP according to Salimetrics instructions. Saliva was collected by placing the swabs in infants’ mouths for two minutes in order to collect a total of 2 mL of saliva. Prior to saliva collection mothers completed a saliva collection checklist. If any of several conditions had been violated (e.g., if the infant had eaten recently or was sick with a fever), the participants were rescheduled. Samples were stored at −20° C until shipment on dry ice for assay. Infants’ saliva samples were assayed in duplicate with the commercially available Salimetrics
2.3.3. Social support questionnaire 6 (SSQ6) The SSQ6 (Sarason et al., 1987) is a 6-item self-report questionnaire designed to measure both the number of individuals one can go to for 3
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age, β = −0.307, SE = 0.112, p = .009, 95% CI [−0.534, −0.081], and explained a significant amount of variance in sCRP, R2 = 0.123, F (1, 45) = 7.475, p = .009 (see Fig. 3a). Similarly, greater maternal social support when infants were 12 months of age was significantly associated with decreasing infant sCRP from 12 to 18 months of age, β = −0.211, SE = 0.103, p = .047, 95% CI [−0.419, −0.003], and explained a significant amount of variance in sCRP change scores, R2 = 0.064, F(1, 45) = 4.155, p = .047. Maternal parenting stress when infants were 12 months of age was significantly associated with infant sCRP at 18 months of age, β = 0.053, SE = 0.025, p = .042, 95% CI [0.002, 0.104], and explained a significant amount of variance in sCRP, R2 = 0.042, F(1, 43) = 4.392, p = .042 (see Fig. 3b). The association between maternal parenting stress when infants were 12 months of age and changes in infant sCRP from 12 to 18 months of age was marginally significant, β = 0.040, SE = 0.023, p = .090, 95% CI [−0.007, 0.087], and explained a marginal amount of variance in sCRP, R2 = 0.044, F(1, 43) = 3.002, p = .090. Finally, change in infant sCRP was not significantly associated with infant sTL at 18 months, β = −0.035, SE = 0.044, p = .433, 95% CI [−0.122, 0.053].
social support under different circumstances and one’s satisfaction with that social support. The former part of the measure, which taps quantity or extent of social support, was used in the current analyses. 2.3.4. The parental stress scale (PSS) The PSS (Berry and Jones, 1995) is an 18-item self-report questionnaire designed to measure parental stress both in terms of the presence of negative experiences (e.g., “The major source of stress in my life is my child (ren)”) and the absence of positive experiences (e.g., “I enjoy spending time with my child/ren” [reversed]). This measure has been shown to have good internal (0.83) and test-retest (0.81) reliability. Furthermore, the validity of this measure has been supported by various studies (see Berry and Jones, 1995; Zelman and Ferro, 2018). 2.3.5. Covariates A number of variables proposed to be related to infant sTL and/or sCRP were examined as potential control variables. These included infant age and weight, maternal and paternal age, infant sex and race, maternal socioeconomic status (SES) markers (education, employment, and income), and maternal smoking status. In order to preserve power and avoid overfitting, only covariates that are significantly associated with biomarker outcomes were included in analyses. None of these variables showed a significant association with infant sCRP or sTL, so they were not included in further model testing (see Fig. 2).
3.3. Post-hoc exploratory analyses Correlational analyses showed that maternal stress (r[45] = 0.095, p = .526, 95% CI [−0.198, 0.372]) and maternal social support (r [45] = 0.081, p = .586, 95% CI [−0.211, 0.360]) at 18 months were not cross-sectionally associated with infant sTL. In addition, regression analyses showed that maternal social support (β = −0.031, SE = 0.032, p = .327, 95% CI [−0.095, 0.032]) and maternal parenting stress (β = 0.004, SE = 0.007, p = .551, 95% CI [−0.010, 0.018]) at 12 months were not associated with infant sTL at 18 months. Last, neither sCRP at T3 (β = −0.032, SE = 0.055, p = .558, 95% CI [−0.142, 0.079] nor sCRP at T4 (r[45] = −.144p = .333, 95% CI [−0.414, 0.149]) were associated with infant sTL. In addition, as shown in Table 2, there was one high value of sTL even though sTL was winsorized to +/− 3 SD to correct for outliers. We performed sensitivity analyses by removing this value and rerunning analyses. Results indicated that all sTL results remained the same.
2.4. Statistical analyses All statistical analyses were conducted with R, version 3.3.2. Statistical significance was defined using 95% confidence intervals. Histograms as well as skew and kurtosis statistics were examined for each variable to check for normality. sTL and sCRP were winsorized to +/− 3 SD to correct for outliers (this impacted 1 sTL sample) or, in the case of sCRP, undetectable values (this impacted 4 samples each at the 12- and 18-month assessments). sCRP (log-transformed) concentrations when infants were 12 months of age (M = 4.76 pg/ML, SD = 0.97) ranged from 3.06 pg/ML to 6.86 pg/ML and at 18 months of age (M = 4.33 pg/ML, SD = 1.36) ranged from 1.61 pg/ML to 7.34 pg/ML. Change scores for sCRP were created by using T3 sCRP to predict T4 sCRP and saving the unstandardized residual. See Table 2 for sTL and sCRP descriptive statistics. Correlations were run to investigate cross-sectional associations between both maternal parenting stress and social support with sCRP at each time point. Linear regressions were performed to assess whether maternal parenting stress and social support when infants were 12 months of age predicted infant sCRP at 18 months of age and changes in infants’ sCRP between 12 and 18 months of age. Finally, a regression was run to examine whether changes in sCRP predicted sTL.
4. Discussion The current study was designed to investigate how maternal parenting stress and social support relate to infant inflammation from 12 to 18 months of age, and whether changes in inflammation in turn relate to infants’ cellular aging. This study is the first to examine cross-sectional and prospective associations between these maternal risk/protective factors and infant sCRP and changes in sCRP, as well as potential links with infant sTL. Study results provide partial support for hypothesized associations. Consistent with our hypotheses, higher maternal social support and lower parenting stress when infants were 12 months old predicted lower levels of infant sCRP six months later. This finding provides the first evidence that maternal parenting stress may act as a risk factor for infant inflammatory processes, while maternal social support may provide protection against higher inflammation. Furthermore, higher maternal social support predicted decreasing levels of sCRP from 12 to 18 months of age, indicating that the level of social support a mother has when her child is in early infancy may have an influence on inflammatory dynamics across infancy. One possible explanation for these associations is that mothers with more social support experience lower stress, as was found in our study at both 12 months (r = −0.42, p = .001) and 18 months (r = −0.27, p = .048), and therefore are able to express more positive parental behaviors toward their infants. This, in turn, could buffer against heightened sympathetic physiology in the child, which have been associated with higher sCRP during adolescence (Nelson et al., 2017). Indeed, greater social support has been shown to be a protective factor
3. Results 3.1. Cross-sectional correlation analyses Maternal social support and infant sCRP were marginally associated when infants were both 12 months of age (r(45) = −0.260, p = .077, 95% CI [−0.509, 0.029]) and 18 months of age (r(45) = −0.259, p = .078, 95% CI [−0.509, 0.030]). Maternal parenting stress and infant sCRP were not significantly associated when infants were 12 months of age (r(43) = 0.165, p = .279, 95% CI [−0.135, 0.437]) or when infants were 18 months of age (r(44) = 0.235, p = .117, 95% CI [−0.060, 0.491]). 3.2. Prospective regression analyses Greater maternal social support when infants were 12 months of age was significantly inversely associated with infant sCRP at 18 months of 4
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Fig. 2. Correlation Matrix. Note: Correlation coefficients may be different from Results Section as this figure was made with complete observations. T3 = time 3, T4 = time 4.
The effects for parenting stress in our study were not as consistent as those for social support. One reason for this may be that our measure of parental stress collapsed two different forms of stress—i.e., the presence of negative experiences and the absence of positive ones—into one variable. Researchers have argued that positive and negative affect are asymmetrical and may be distinct variables that differentially predict outcomes. For example, in a recent study of over 5000 participants, positive affect (but not negative affect) was associated with mortality (Petrie et al., 2018). Therefore, a more “pure” measure of stress that delineates positive and negative aspects of parental stress may provide a better measure for assessing how parenting stress is associated with infant inflammation. Inconsistent with our hypotheses, there were no cross-sectional associations between maternal variables and infant sCRP when infants were 12 months or 18 months of age and a null association between infant sCRP change and sTL. One potential reason for these null findings is that sCRP and sTL are relatively stable biological markers, and there may be a delay (Tilders et al., 1999) or lag effect (Shonkoff et al., 2009)
Table 2 Descriptive Statistics of sCRP and sTL. Variable
Mean (SD)
Range
sCRP log T3 sCRP log T4 sCRP Change sTL
4.76 (0.97) 4.33 (1.36) 0 (1.21) 1.76 (0.36)
3.06–6.86 1.61–7.34 −2.97 to 2.35 1.06–3.27
Note: sCRP = salivary C-Reactive Protein, sTL = salivary telomere length, T3 = time 3, T4 = time 4.
associated with lower levels of CRP (Ford et al., 2006; Heffner et al., 2011; Mezuk et al., 2010). In contrast, mothers who experience more parenting stress may display more negative parental behaviors (e.g., anger, such as expressed harshness) toward their offspring, a pattern associated with both greater sympathetic response in children (ElSheikh et al., 1989) and higher levels of sCRP in adolescence (Byrne et al., 2016). 5
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Fig. 3. Social Support (top) and Parenting Stress (bottom) predicting subsequent sCRP. Note: sCRP = salivary C-Reactive Protein.
4.1. Limitations and future directions
for current levels of psychosocial stress to influence stable inflammatory and aging processes. In other words, there may need to be a more cumulative effect of a buildup of psychosocial risk factors that “get under the skin” to influence biological processes related to disease. Consistent with this idea, T3 and T4 parental stress (r = 0.80) and parental social support (r = 0.62) were highly correlated, suggesting that that the level of stress and support in the family was fairly consistent across this period of time. If infants continued to be exposed to highly stressful or supportive family environments over time, we might expect that these environments would eventually have an influence on these more stable biological processes of inflammation and aging as has been shown in adult populations (Danese et al., 2008; Danese et al., 2013; Kananen et al., 2010; Kiecolt-Glaser et al., 2011; Miller et al., 2011; Taylor et al., 2006; Tyrka et al., 2010). More reactive measures of inflammation, such as Interleukin-6, might be better suited to index cross-sectional associations between maternal risk and protective factors, especially if those factors are changing over time. The non-significant association between sCRP—whether at 12 months, 18 months, or change from 12 to 18 months—and sTL adds to the mixed literature in this area, with some studies demonstrating an association between higher CRP and shorter TL (Fitzpatrick et al., 2011; Révész et al., 2014; Rode et al., 2014; Solorio et al., 2011), and others failing to find such an association (Brouilette et al., 2007; O’Donovan et al., 2011). In the current study, the lack of an association might be due to the relatively short time scale (six months) during which the study took place and/or low power due to the small N. It might take a longer period of time for higher levels of inflammatory markers to influence cell turnover to result in shorter TL, a hypothesis that should be tested in future research.
Although the present study has some notable strengths, such as using a longitudinal design with a high-risk (low-income) sample to provide initial evidence for prospective associations between maternal risk/protective factors and infant inflammation, there were a number of limitations that reduce the generalizability of these findings. Full study measures were only available for 48 mother-infant dyads, which provided a small scale test of the hypothesized associations between both maternal parenting stress and social support and infant inflammation, as well as the association of inflammation with infant biological aging. Future research should replicate this study with a larger and more diverse sample. In addition, we did not address the role of potential mechanisms (e.g., parenting behaviors, sympathetic activity) that may have accounted for the association between maternal variables and infant inflammation. Future studies should investigate the role of the autonomic nervous system and parenting behaviors, which have been shown to respond to stress and influence inflammatory processes (Kemeny and Schedlowski, 2007; Jänig, 2014; Nelson et al., 2017). In addition, this study did not collect prenatal stress measures, which could be important gestational predictors that may account for variance in infant sCRP and sTL. Future studies incorporating such measures would allow researchers to disentangle prenatal and postnatal environmental contributions to processes of disease. Similarly, the current study utilized measures of parental stress and social support that were highly correlated across the six months – suggesting that they prominently tap into trait like aspects of stressful experiences. Future studies should attempt to capture these variables with measures that may be more sensitive to proximal changes in environmental stress and 6
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social support. Finally, we collected sCRP, rather than circulating CRP in infants, because this entails a noninvasive and painless procedure. The tradeoff with this method is that it may have introduced some noise. For example, research is mixed on whether sCRP is associated with CRP collected in blood, with some studies finding no correlation (Dillon et al., 2010; Kopanczyk et al., 2010) and others finding that these two measures correlate with medium to large effect sizes (O’Brien-Simpson et al., 2013; Out et al., 2012). There is also evidence that many inflammatory markers can have higher detection rates in saliva when compared to blood (O’Brien-Simpson et al., 2013). One possible reason for this difference is that CRP can pass from blood to saliva through gingival crevicular fluid, which indicates that sCRP can be indicative of both local and systemic inflammation (Megson et al., 2010). While saliva samples are preferred with infants based on the invasiveness/pain considerations noted above, future studies might consider utilizing blood spots to detect CRP in infants. In contrast, this is not likely to be an issue with sTL; research has shown that while sTL is significantly longer than whole blood TL, they are highly correlated (Mitchell et al., 2014; Stout et al., 2017).
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5. Conclusion This study investigated whether maternal psychosocial stress—particularly as it relates to parenting—and social support relate both cross-sectionally and prospectively to infant inflammation (sCRP), whether these maternal factors predict changes in infant sCRP across 6 months, and whether changes in infant inflammation relate to cellular aging (sTL). These findings indicate that maternal parenting stress may heighten infant inflammatory processes during the first year and a half of life, while maternal social support may protect or buffer against these effects. By examining these processes as they occur during infancy, the current investigation takes an important step toward identifying how early stressful environments can give rise to long-term disease risk. Acknowledgments This research was supported by grants from The Mind and Life Institute (1440 Research Award 2015-1440-Nelson) awarded to the first author and The Society for Research in Child Development Victoria Levin Award and the University of Oregon College of Arts and Sciences issued to the last author. The funding sources had no role in the study design, data collection and analysis, or submission process. We thank Elissa Epel, Ph.D. for her consultation on our study design and Jue Line, Ph.D. and Elizabeth Blackburn, Ph.D. for their expertise in assaying the telomere samples. We also thank Elizabeth Shirtcliff, Ph.D. for her expertise in assaying the c-reactive protein samples. References Anda, R.F., Dong, M., Brown, D.W., Felitti, V.J., Giles, W.H., Perry, G.S., Valerie, E.J., Dube, S.R., 2009. The relationship of adverse childhood experiences to a history of premature death of family members. BMC Public Health 9 (1), 106. https://doi.org/ 10.1186/1471-2458-9-106. Baumeister, D., Akhtar, R., Ciufolini, S., Pariante, C.M., Mondelli, V., 2016. Childhood trauma and adulthood inflammation: a meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-α. Mol. Psychiatry 21 (5), 642–649. Berry, J.O., Jones, W.H., 1995. The parental stress scale: initial psychometric evidence. J. Soc. Pers. Relat. 12 (3), 463–472. https://doi.org/10.1177/0265407595123009. Brouilette, S.W., Moore, J.S., McMahon, A.D., Thompson, J.R., Ford, I., Shepherd, J., Samani, N.J., 2007. Telomere length, risk of coronary heart disease, and statin treatment in the West of Scotland Primary Prevention Study: a nested case-control study. Lancet 369 (9556), 107–114. https://doi.org/10.1016/S0140-6736(07) 60071-3. Byrne, M.L., Badcock, P.B., Simmons, J.G., Whittle, S., Pettitt, A., Olsson, C.A., Mundy, L.K., Patton, G.C., Allen, N.B., 2016. Self-reported parenting style is associated with children’s inflammation and immune activation. J. Fam. Psychol. 31 (3), 374. O’Brien-Simpson, M.L.N.M., Reynolds, E.C., Walsh, K.A., Laughton, K., Waloszek, J.M., ... Allen, N.B., 2013. Acute phase protein and cytokine levels in serum and saliva: a comparison of detectable levels and correlations in a depressed and healthy adolescent sample. Brain, Behav. Immu. 34, 164–175. https://doi.org/10.1016/j.bbi.2013. 08.010.
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