The Impact of Perceived Stress during Pregnancy on Placental Disease-related Adverse Pregnancy Outcomes; the Mechanism by which Stress is Associated with these Outcomes; and Modifying Constructs of that Mechanism.
Open Access DepositedBackground: Perinatal outcomes such as preterm birth and low birth weight remain major public health issues of concern both in the United States as well as globally. Placental disease-related conditions, such as hypertensive disorders of pregnancy (including preeclampsia), placental abruption, preterm birth, and low birth weight, contribute to a majority of perinatal morbidities and mortality. There is strong biological evidence in support of the negative consequences of maternal stress during pregnancy. Research has shown that psychosocial support and race/ethnicity can act as modifying factors in the relationship between stress and adverse maternal and perinatal outcomes. Additionally, resilience has been shown to act as a modifier on the relationship between stress and depression and stress and anxiety. Furthermore, stress and depression have been found to be associated with placental disease-related adverse outcomes, such as preterm birth, low birth weight, and small for gestational age. The role of depression and anxiety with maternal stress has not yet been explored in this context; this offers an opportunity to better understand the mechanism by which these three components impact adverse maternal and perinatal outcomes. Objectives: The first objective of the proposed study is to evaluate the association between perceived maternal stress at Visit 1 and placental disease-related outcomes (preterm birth (PTB), small for gestational age (SGA), placental abruption, and hypertensive disorder of pregnancy) and perceived maternal stress at Visit 3 and these outcomes. Next, race/ethnicity, psychosocial support, and resilience will be explored as effect modifiers of the association between perceived maternal stress at Visit 1 and Visit 3 and significant outcomes from the first objective. Finally, the role of depression and anxiety (serial mediation) in the association between perceived stress at Visit 1 and significant outcomes from the first objective and the role of depression in mediating the association between perceived stress at Visit 3 and significant outcomes from the first objective. If there are significant moderators and mediators of the association between perceived maternal stress at Visit 1 or Visit 3 and one or more of the outcomes of interest, moderated-mediation will be explored. Methods: Data from the Nulliparous Pregnancy Outcome Study: Monitoring Mothers-to-Be (nuMoM2b) study will be utilized to carry out these analyses. The nuMoM2b study gathered data throughout the duration of pregnancy of women who had never given birth to a child before (nulliparas) from eight clinical research sites and affiliated hospitals across the United States between October 2010 and September 2013. This study population is a racially, ethnically, and geographically diverse cohort of 10,038 nulliparous pregnant women with singleton pregnancies. Multivariable logistic regression will be used to explore the relationship between perceived maternal stress at Visit 1 and Visit 3 and the composite of placental disease-related outcomes as well as the individual components. Multivariable logistic regression will also be utilized to assess race/ethnicity, psychosocial support, and resilience as potential effect modifiers of the relationship between perceived maternal stress at Visit 1 and each significant outcome from the first objective as well as perceived maternal stress at Visit 3 and each significant outcome from the first objective. Covariates will be adjusted for as appropriate. PROCESS macro will be used to test for mediation by depression and anxiety in the appropriate models. Covariates will be included as exogenous variables in each model. If there are significant moderators from the second objective and significant mediators in the models from the third objective, conditional process analyses will be used to explore moderated-mediation utilizing PROCESS macro. Results: After adjusting for maternal BMI, education, comorbidities, and marital status, there were no significant associations between perceived stress at Visit 1 and the outcomes of interest. When exploring perceived stress at Visit 3, perceived stress at this timepoint in pregnancy was a significant predictor of PTB as well as SGA after adjusting for the covariates noted previously. There was a 1.6% increased odds of SGA for each unit increase in perceived stress score at Visit 3 (OR=1.016, 95% CI: 1.004, 1.029). In the PTB models, perceived stress at Visit 3 had a curvilinear relationship with PTB. A protective effect was seen at lower levels of perceived stress, and an increased odds of PTB was demonstrated as stress increased. Moderation analyses were carried out for perceived stress at Visit 3 as a predictor of SGA and PTB outcomes. There was no moderation of the association between perceived stress at Visit 3 and SGA or perceived stress at Visit 3 and PTB by race, psychosocial support, or resilience. Finally, the indirect effects of perceived stress at Visit 3 on SGA and PTB outcomes through depression measured at Visit 3 were evaluated using separate simple mediation models. There was no statistically significant mediation of the effect of perceived stress at Visit 3 on either outcome through depression. In the adjusted model, the direct effect of perceived stress at Visit 3 on SGA was borderline not significant (Z=1.9002, p=0.0574), and the indirect effect through depression was not significant. In the adjusted model with the PTB outcome, the direct effect demonstrated a significant inverse relationship between perceived stress at Visit 3 and PTB (Z= -2.9787, p=0.0029); the inverse association may be explained by the curvilinear relationship between perceived stress at this timepoint and PTB. Conclusions: The results of this secondary analysis confirmed the association between perceived maternal stress in the third trimester and two placental disease-related outcomes: SGA and PTB. A curvilinear association between perceived maternal stress in the third trimester and PTB outcome was noted. At low levels of perceived maternal stress, there was an evident protective effect. At higher levels of perceived maternal stress, there was an increased odds of PTB. No moderation by race/ethnicity, resilience, or psychosocial support was demonstrated. Additionally, there was no significant mediation of the relationship between perceived maternal stress during the third trimester and SGA or PTB by depression measured at Visit 3. No significant association between perceived maternal stress at Visit 1 and the placental disease-related outcomes of interest were found. These analyses supported that psychological measures later in pregnancy are more predictive of adverse pregnancy outcomes, such as SGA and PTB.
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