Shannon L. Gillespie

Outcomes of nulliparous women with spontaneous labor onset admitted to hospitals in preactive versus active labor.

INTRODUCTION The timing of when a woman is admitted to the hospital for labor care following spontaneous contraction onset may be among the most important decisions that labor attendants make because it can influence care patterns and birth outcomes. The aims of this study were to estimate the percentage of low-risk, nulliparous women at term who are admitted to labor units prior to active labor and to evaluate the effects of the timing of admission (ie, preactive vs active labor) on labor interventions and mode of birth. METHODS Data from low-risk, nulliparous women with spontaneous labor onset at term gestation were merged from 2 prospective studies conducted at 3 large Midwestern hospitals. Baseline characteristics, labor interventions, and outcomes were compared between groups using Fishers exact and Mann-Whitney U tests, as appropriate. Likelihoods for oxytocin augmentation, amniotomy, and cesarean birth were assessed by logistic regression. RESULTS Of the sample of 216 low-risk nulliparous women, 114 (52.8%) were admitted in preactive labor and 102 (47.2%) were admitted in active labor. Women who were admitted in preactive labor were more likely to undergo oxytocin augmentation (84.2% and 45.1%, respectively; odds ratio [OR], 6.5; 95% confidence interval [CI], 3.43-12.27) but not amniotomy (55.3% and 61.8%, respectively; OR, 0.8; 95% CI, 0.44-1.32) when compared to women admitted in active labor. The likelihood of cesarean birth was higher for women admitted before active labor onset (15.8% and 6.9%, respectively; OR, 2.6; 95% CI, 1.02-6.37). DISCUSSION Many low-risk nulliparous women with regular, spontaneous uterine contractions are admitted to labor units before active labor onset, which increases their likelihood of receiving oxytocin and giving birth via cesarean. An evidence-based, standardized approach for labor admission decision making is recommended to decrease inadvertent admissions of women in preactive labor. When active labor cannot be diagnosed with relative certainty, observation before admission to the birthing unit is warranted.

Differences in inflammatory markers between nulliparous women admitted to hospitals in preactive vs active labor

OBJECTIVE To determine whether labor-associated inflammatory markers differ between low-risk, nulliparous women in preactive vs active labor at hospital admission and over time. STUDY DESIGN Prospective comparative study of low-risk, nulliparous women with spontaneous labor onset at term (n = 118) sampled from 2 large Midwestern hospitals. Circulating concentrations of inflammatory markers were measured at admission and again 2 and 4 hours later: namely, neutrophil, and monocyte counts; and serum inflammatory cytokines (interleukin -1β, interleukin-6, tumor necrosis factor-α, interleukin-10) and chemokines (interleukin-8). Biomarker concentrations and their patterns of change over time were compared between preactive (n = 63) and active (n = 55) labor admission groups using Mann-Whitney U tests. RESULTS Concentrations of interleukin-6 and interleukin-10 in the active labor admission group were significantly higher than concentrations in the preactive labor admission group at all 3 time points. Neutrophil levels were significantly higher in the active group at 2 and 4 hours after admission. The rate of increase in neutrophils and interleukin-10 between admission and 2 hours later was faster in the active group (P < .001 and P = .003, respectively). CONCLUSION Circulating concentrations of several inflammatory biomarkers are higher and their rate of change over time since admission is faster among low-risk, nulliparous women admitted to hospitals in active labor, as compared with those admitted in preactive labor. More research is needed to determine if progressive changes in inflammatory biomarkers might be a useful adjunct to improving the assessment of labor progression and determining the optimal timing of labor admission.

Adaptation of the inflammatory immune response across pregnancy and postpartum in Black and White women

Pregnancy is a period of considerable physiological adaption in neuroendocrine, cardiovascular, as well as immune function. Understanding of typical changes in inflammatory immune responses during healthy pregnancy is incomplete. In addition, despite considerable racial difference in adverse pregnancy outcomes, data are lacking on potential racial differences in such adaptation. This repeated measures prospective cohort study included 37 Black and 39 White women who provided blood samples during early, mid-, and late pregnancy and 8-10 weeks postpartum. Peripheral blood mononuclear cells were incubated with lipopolysaccharide (LPS) for 24h and supernatants assayed by electrochemiluminescence to quantify interleukin(IL)-6, tumor necrosis factor(TNF)-α, IL-1β, and IL-8 production. While no changes were observed in IL-8 production over time, significant increases in IL-6, TNF-α, and IL-1β production were observed from early to late pregnancy, with subsequent declines approaching early pregnancy values at postpartum (ps<0.05). Overall, inflammatory response patterns were highly similar among Black versus White women. However, Black women had greater TNF-α production during mid-pregnancy (p=0.002) and marginally lower IL-1β production at postpartum (p=0.054). These data show a clear trajectory of change in the inflammatory immune response across pregnancy and postpartum. In this cohort of generally healthy women, Black and White women exhibited minimal differences in LPS-stimulated cytokine production across the perinatal period. Future prospective studies in Black and White women with healthy versus adverse outcomes (e.g., preeclampsia, preterm birth) would inform our understanding of the potential role of immune dysregulation in pregnant women and in relation to racial disparities in perinatal health.

Serum brain-derived neurotrophic factor (BDNF) across pregnancy and postpartum: Associations with race, depressive symptoms, and low birth weight

BACKGROUND Brain-derived neurotrophic factor (BDNF) is implicated as a causal factor in major depression and is critical to placental development during pregnancy. Longitudinal data on BDNF across the perinatal period are lacking. These data are of interest given the potential implications for maternal mood and fetal growth, particularly among Black women who show ∼2-fold greater risk for delivering low birth weight infants. METHODS Serum BDNF, serum cortisol, and depressive symptoms (per CES-D) were assessed during each trimester and 4-11 weeks postpartum among 139 women (77 Black, 62 White). Low birth weight (<2500g) was determined via medical record. RESULTS Serum BDNF declined considerably from 1st through 3rd trimesters (ps≤0.008) and subsequently increased at postpartum (p<0.001). Black women exhibited significantly higher serum BDNF during the 1st trimester, 2nd trimester, and postpartum (ps≤0.032) as well as lower serum cortisol during the 2nd and 3rd trimester (ps≤0.01). Higher serum cortisol was concurrently associated with lower serum BDNF in the 2nd trimester only (p<0.05). Controlling for race, serum BDNF at both the 2nd and 3rd trimester was negatively associated with 3rd trimester depressive symptoms (ps≤0.02). In addition, women delivering low versus healthy weight infants showed significantly lower serum BDNF in the 3rd trimester (p=0.004). Women delivering low versus healthy weight infants did not differ in depressive symptoms at any time point during pregnancy (ps≥0.34). CONCLUSIONS Serum BDNF declines considerably across pregnancy in Black and White women, with overall higher levels in Blacks. Lower serum BDNF in late pregnancy corresponds with higher depressive symptoms and risk for low birth weight in Black and White women. However, the predictive value of serum BDNF in pregnancy is specific to within-race comparisons. Potential links between racial differences in serum BDNF and differential pregnancy-related cortisol adaptation require further investigation.

Interleukin-1 Receptor Antagonist Polymorphism and Birth Timing: Pathway Analysis Among African American Women

Background Timing of birth is a major determinant of newborn health. African American women are at increased risk for early birth, particularly via the inflammatory pathway. Variants of the IL1RN gene, which encode the interleukin-1 receptor antagonist (IL-1Ra) protein, are implicated in early birth. The biological pathways linking these variables remain unclear. Evidence also suggests that inflammatory pathways differ by race; however, studies among African American women are lacking. Objectives We assessed whether an IL1RN variant was associated with timing of birth among African American women and whether this relationship was mediated by lower anti-inflammatory IL-1Ra production or related to a decrease in inhibition of proinflammatory IL-1&bgr; production. Methods A candidate gene study using a prospective cohort design was used. We collected blood samples at 28–32 weeks of gestation among African American women experiencing an uncomplicated pregnancy (N = 89). IL1RN single-nucleotide polymorphism (SNP) rs2637988 was genotyped, and lipopolysaccharide-stimulated IL-1Ra and IL-1&bgr; production was quantified. Medical record review determined timing of birth. Results Women with GG genotype gave birth earlier than women with AA/AG genotypes (b* = .21, p = .04). There was no indirect effect of IL1RN SNP rs2637988 allele status on timing of birth through IL-1Ra production, as evidenced by a nonsignificant product of coefficients in mediational analyses (ab = .006, 95% CI [−0.05, 0.13]). Women with GG genotype showed less inhibition of IL-1&bgr; production for a unit positive difference in IL-1Ra production than women with AA/AG genotypes (b* = .93, p = .03). Greater IL-1&bgr; production at 28–32 weeks of pregnancy was marginally associated with earlier birth (b* = .21, p = .05). Discussion Women with GG genotype may be at risk for earlier birth because of diminished IL-1&bgr; inhibition, allowing for initiation of a robust inflammatory response upon even mild immune challenge. Study of inflammatory contributions to early birth among African American women may be key to identifying potential prognostic markers of risk and targeted preventive interventions.

A proposed bio-panel to predict risk for spontaneous preterm birth among African American women.

Preterm birth (PTB), or birth prior to 37 weeks gestation, impacts 11.5% of U.S. deliveries. PTB results in significant morbidity and mortality among affected children and imposes a large societal financial burden. Racial disparities in PTB are alarming. African American women are at more than 1.5 times the risk for PTB than white women. Unfortunately, the medical communitys ability to predict who is at risk for PTB is extremely limited. History of a prior PTB remains the strongest predictor during a singleton gestation. Cervical length and fetal fibronectin measurement are helpful tools. However, usefulness is limited, particularly among the 95% of U.S. women currently pregnant and lacking a history of PTB. Therefore, preventive therapies do not reach a great number of women who may benefit from them. This manuscript, in response to the pressing need for predictors of PTB risk and elimination of racial disparities in PTB, presents a proposed bio-panel for use in predicting risk for spontaneous PTB among African American women. This bio-panel, measured each trimester, includes stimulated production of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-1 receptor antagonist (Ra), soluble(s) TNF receptor(R) 1, and sTNFR2, and cortisol responsiveness. We hypothesize that greater IL-1β and TNF-α production, decreased IL-1Ra, sTNFR1, and sTNFR2 production, and decreased cortisol responsiveness at each time point as well as a more expedient alignment with this unfavorable profile over time will be associated with PTB. The choice to focus on inflammatory parameters is supported by data highlighting a crucial role for inflammation in labor. Specific inflammatory mediators have been chosen due to their potential importance in preterm labor among African American women. The bio-panel also focuses on inflammatory regulation (i.e., cytokine production upon ex vivo stimulation), which is hypothesized to provide insight into potential in vivo leukocyte responses and potential for initiation of a preterm inflammatory cascade. Production of receptor antagonists is also considered, as pro-inflammatory mediator effects can be greatly influenced by their balance with respective antagonists. Finally, leukocyte responsiveness to cortisol is included as a measure of cortisols ability to convey anti-inflammatory signals. The development of a bio-panel predictive of risk for spontaneous PTB among African American women would represent a significant advancement. Available preventive therapies, namely progesterone supplementation, could be delivered to women deemed at risk. Further, the identification of biological predictors of PTB may uncover novel targets for preventive therapies.

Childhood stress and birth timing among African American women: Cortisol as biological mediator

Preterm birth (PTB) occurs among 1:11U.S. white women and 1:7.5 African American women and is a significant driver of racial disparities in infant mortality. Maternal stress is the most common clinical phenotype underlying spontaneous PTB. Specific patterns of stress and biological mediators driving PTB remain unclear. We examined the effect of childhood stress on birth timing among African American women and evaluated maternal cortisol elevation as a biological mediator. A prospective observational design was employed, with a single study visit at 28-32 weeks gestation and medical record review. The Stress and Adversity Inventory was administered, which provides a comprehensive estimate of childhood stress, stress in adulthood, and five core characteristic subscales (interpersonal loss, physical danger, humiliation, entrapment, role disruption). Venipuncture was performed between 11:00am and 4:00pm and plasma cortisol quantified by ELISA. Analyses controlled for stress in adulthood. Among a final sample of 89, cumulative childhood stress predicted birth timing (p=0.01). The association was driven by stress related to interpersonal loss and physical danger, with support for maternal cortisol as a biological mediator (ab=0.02, 95% CI [0.001, 0.045]; ab=0.02, 95% CI [0.001, 0.043], respectively). Results were similar, overall, in sub-group analyses among spontaneously laboring women (n=53); however, role disruption arose as an additional predictor, as mediated by cortisol elevations (ab=0.03, 95% CI [0.005, 0.074]). Of note, cortisol was no longer supported as a mediator linking physical danger to birth timing after adjusting for sleep quality and hours awake prior to venipuncture (ab=0.02, 95% CI [-0.0001, 0.046]). We provide preliminary evidence that, independent of stress in adulthood, childhood stress of specific core characteristics may shape birth timing, with cortisol elevation as a biological mediator. Further investigation is warranted and may bolster the development of biologically-informed screening tools for the prediction and targeted prevention of stress-related PTB.

Effects of Maternal Vitamin D Supplementation on the Maternal and Infant Epigenome

INTRODUCTION Mothers and infants are at high risk for inadequate vitamin D status. Mechanisms by which vitamin D may affect maternal and infant DNA methylation are poorly understood. OBJECTIVE This study quantified the effects of vitamin D3 supplementation on DNA methylation in pregnant and lactating women and their breastfed infants. MATERIALS AND METHODS In this randomized controlled pilot study, pregnant women received vitamin D3 400 international units (IU) (n = 6; control) or 3,800 IU (n = 7; intervention) daily from late second trimester through 4-6 weeks postpartum. Epigenome-wide DNA methylation was quantified in leukocytes collected from mothers at birth and mother-infant dyads at 4-6 weeks postpartum. RESULTS At birth, intervention group mothers showed DNA methylation gain and loss at 76 and 89 cytosine-guanine (CpG) dinucleotides, respectively, compared to controls. Postpartum, methylation gain was noted at 200 and loss at 102 CpGs. Associated gene clusters showed strongest biologic relevance for cell migration/motility and cellular membrane function at birth and cadherin signaling and immune function at postpartum. Breastfed 4-6-week-old infants of intervention mothers showed DNA methylation gain and loss in 217 and 213 CpGs, respectively, compared to controls. Genes showing differential methylation mapped most strongly to collagen metabolic processes and regulation of apoptosis. CONCLUSIONS Maternal vitamin D supplementation during pregnancy and lactation alters DNA methylation in mothers and breastfed infants. Additional work is needed to fully elucidate the short- and long-term biologic effects of vitamin D supplementation at varying doses, which could hold important implications for establishing clinical recommendations for prenatal and offspring health promotion.

An IL1RN Polymorphism Predicts Early Birth Among African American Women

Early birth negatively affects neonatal health and is disproportionately experienced by African American women. Etiology may be related to premature initiation of an inflammatory cascade, including enhanced interleukin (IL)– 1β activity, which is influenced by its competitive inhibitor, IL-1 receptor antagonist (Ra). Guided by Glass and McAtee’s multilevel framework of nested hierarchies, we sought to determine whether IL-1Ra–related genetic variants predicted early birth and test potential pathways by which this may occur. This prospective cohort study collected blood samples at 28 to 32 weeks gestation from 92 low-risk African American women. Genotype at single nucleotide polymorphisms (SNPs) IL1RN rs2637988, CHAT rs1917805, and SLC26A11 rs12452028 was determined. Ex vivo lipopolysaccharide-stimulated whole blood production of IL-1β and IL-1Ra was quantified. Early birth was classified per the U.S. definition of full-term (39 weeks) and proposed physiologic full-term among African American women (38 weeks); models were run assessing both outcomes. The joint significance test assessed mediation, controlling for education, age, parity, and induction/ cesarean in the absence of labor. Women with GG genotype for IL1RN rs2637988 had 3.09 times greater odds of birth before 39 weeks than women with AA/AG genotypes (95% confidence interval [CI] = [1.07, 8.92]). IL-1Ra production did not mediate this relationship. The SNP did modify the association between IL-1β and IL-1Ra production; women with GG genotype demonstrated less inhibition of IL-1β production for a unit positive difference in IL-1Ra production than women with AA/AG genotypes (β = −1.23, p = 0.004). This pathway met criteria for mediation in predicting birth before 38 weeks; however, significance relied on moderately influential data points. The models did reveal that greater IL-1β production was associated with earlier birth (odds ratio [OR]39weeks = 1.18, 95% CI = [1.01, 1.38]; OR38weeks = 1.45, 95% CI = [1.10, 1.91]), with no influential observations identified. Results lend support to the theory of an inflammatory etiology to early birth. African American women with IL1RN rs2637988 GG genotype may be at risk for early birth due to diminished inhibition of IL-1β during the 658201WJNXXX10.1177/0193945916658201Western Journal of Nursing ResearchGillespie et al research-article2016

Racial discrimination and leukocyte glucocorticoid sensitivity: Implications for birth timing

RATIONALE Psychological stress-induced cortisol elevations appear to contribute to preterm birth. Yet, some studies suggest that the biological ramifications of racial discrimination-associated stress are unique and may involve development of decreased glucocorticoid sensitivity despite normalized cortisol levels. OBJECTIVE In this study, we examined the effects of racial discrimination on maternal cortisol output, leukocyte glucocorticoid sensitivity, and the degree of correspondence between cortisol levels and birth timing in an African American cohort. METHOD A generally healthy prospective cohort was enrolled at 28-32 weeks gestation (n = 91). The Experiences of Discrimination scale was administered, whole blood collected, and plasma cortisol levels, cytokine levels, and leukocyte counts quantified for examination of patterns of endogenous feedback. RESULTS Racial discrimination in the mid-tertile was associated with greater maternal cortisol levels than the bottom tertile among women reporting internalizing responses (b* = 0.68, p = 0.001). Decreased leukocyte glucocorticoid sensitivity was witnessed at greater frequencies of experiences of racial discrimination, as evidenced by decreased correspondence between maternal cortisol levels and plasma IL-8 levels, monocyte counts, and lymphocyte counts (p values ≤ 0.043). The association between maternal cortisol levels and birth timing differed by discrimination tertile (p values ≤ 0.005), with greater cortisol levels predictive of earlier birth among women without (b* = -0.59, p < 0.001) but not with racial discrimination (ps ≥ 0.497). CONCLUSION We provide novel evidence of decreased glucocorticoid sensitivity at increasing frequency of exposure to racial discrimination. Our findings suggest that the biology of preterm birth may depend upon racial discriminatory exposures, favoring pathways dependent upon glucocorticoid-induced increases in leukocyte tissue surveillance versus glucocorticoid resistance-associated inflammatory aberrations at increasing levels of exposure. Precision approaches to prenatal care are sorely needed to combat preterm birth, particularly among African American women, with efforts dependent upon further research examining the pathways contributing to the syndrome dependent upon the totality of an individuals exposures.