Michele L. Okun

How Disturbed Sleep May Be a Risk Factor for Adverse Pregnancy Outcomes A Hypothesis

Adverse pregnancy outcomes associated with significant maternal and infant morbidity are on the rise in Western society despite advances of medical technology. Current risk factors are insufficient to identify women at greatest risk of developing an adverse outcome. An attempt to identify novel contributors to increased risk is warranted. Sleep disturbances are frequent during pregnancy, yet are often dismissed as irrelevant. Emerging evidence indicates that sleep disturbances are associated with poor health outcomes, including cardiovascular disease. Disturbed sleep is also linked with an increased inflammatory response. Increased inflammation is proposed as a key biological pathway through which chronic disease and adverse pregnancy outcomes develop. In this paper, we propose a model and a testable hypothesis of how disturbed sleep in the first 20 weeks of pregnancy could contribute to adverse pregnancy outcomes such as preeclampsia, intrauterine growth restriction, and preterm birth via increased inflammation. Target Audience: Obstetricians & Gynecologists, Family Physicians Leaning Objectives: After completion of this article, the reader should be able to outline data linking sleep disturbances with an increased risk of some systemic disorders, recall characteristics of pregnancy complications which support the hypothesis that sleep disturbances may be related to these pregnancy outcomes, and summarize the likelihood and types of sleep disturbances that are common in pregnant women.

Sleep disruption during pregnancy: how does it influence serum cytokines?

Women report their sleep to be disrupted during pregnancy. Sleep deprivation has been linked to elevations in pro-inflammatory cytokine levels. No information currently addresses the sleep-immune relationship during pregnancy. This study explores the relationship between subjectively reported sleep variables and circulating serum cytokine levels. Pregnant women (n=35; mean age=31.0+/-3.7 years) seen once a trimester completed sleep questionnaires, gave blood and recorded their sleep on a sleep diary at home for 2 weeks. Nonpregnant women (n=43; mean age=28.2+/-5.2 years) underwent the same protocol once. Subjective sleep variables were compared to serum cytokine levels for IL-4, -6, -10 and TNF-alpha as well as C-reactive protein (CRP) determined by ELISA. Nonparametric analyses and linear regression were performed to explore relationships between the sleep and immune variables. Pregnant women subjectively reported their sleep to be worse than in the nonpregnant group. Serum cytokine levels differed between the two groups and varied by trimester. As anticipated, IL-10 was significantly higher in all trimesters; however CRP, an indicator of systemic inflammation, was higher in all trimesters compared to the nonpregnant sample. Subjectively reported sleep disruption was associated with increases in TNF-alpha in the pregnant sample and CRP in the nonpregnant sample. These data confirm that disrupted sleep experienced during pregnancy, as well as during the nonpregnant state, is related to increases in inflammatory markers. Future exploration of these relationships should include functional assessments of immunity as well as polysomnographically recorded sleep.

Poor Sleep Quality is Associated with Preterm Birth

STUDY OBJECTIVES Preterm birth (PTB) is a major public health priority and the most common adverse pregnancy outcome. Several risk factors have been identified, but a gap in the understanding of the underlying etiology of PTB persists. Poor sleep quality is a correlate of adverse health outcomes. Therefore, we evaluated whether sleep quality during pregnancy was a clinically relevant risk factor for PTB. DESIGN Observational. MEASUREMENTS AND RESULTS Participants included 166 pregnant women (mean age = 28.6 ± 5.5 years). Self-report questionnaires, including the Pittsburgh Sleep Quality Index (PSQI), were administered at 14-16, 24-26, and 30-32 weeks gestation. Logistic regression models were used to evaluate whether sleep quality was associated with preterm delivery. Poor sleep quality was a predictor of preterm birth, with the largest effects in early pregnancy (14-16 weeks) (OR: 1.25 95% CI [1.04-1.50], P = 0.02) and more modest effects in later pregnancy (30-32 weeks) (OR: 1.18 95% CI [0.98-1.42], P = 0.07). With every one-point increase on the PSQI, the odds of preterm birth increase 25% in early pregnancy and 18% in later pregnancy. CONCLUSIONS Poor sleep quality, in both early and late pregnancy, is associated with an increased risk of delivering preterm. Currently the specific pathway(s) through which disturbed sleep contributes to PTB are unknown. We suggest that poor sleep may contribute to increased risk for PTB both independently, as well as in conjunction with other established risk factors, such as stress.

What constitutes too long of a delay? Determining the cortisol awakening response (CAR) using self-report and PSG-assessed wake time.

The cortisol awakening response (CAR) is a burst of cortisol in response to awakening from sleep that is superimposed on the circadian rhythm of cortisol. Determination of the CAR is contingent on the timing of sample collection: a delay between waking and collection of the first sample may affect the rise of the CAR, and could explain equivocal findings reported in the literature. We evaluated the impact of a delay between wake time and collection of waking cortisol samples on the CAR. Two methods were used to identify wake time: polysomnography (PSG) and self-report (S-R). Participants (total n=207, mean age 74.0+/-7.2 years) included bereaved older adults (n=35), caregivers (n=50), patients with insomnia and co-morbid medical disorders (n=68), and the healthy older adults (n=54). We used ANOVA to test if a delay >15 min affected the CAR. We also fitted cubic spline models to assess expected cortisol levels, the expected CAR, and the expected decrease in CAR. Wake times measured by PSG and S-R did not differ significantly. Large delays were observed (for both PSG and S-R) between wake time and collection of the waking cortisol sample (24.8+/-32.2 min for PSG and 28.3+/-49.2 min for S-R). Both statistical methods indicated that a delay >15 min between wake time and first cortisol sample collection significantly affected the CAR (ps<.005); later collection times were associated with smaller CAR values. Later collection times and reduced CAR values may affect the interpretation of clinical associations. Our data also show that S-R assessments of wake time perform equally well to PSG for evaluating adherence with CAR sampling procedures.

Disturbed sleep is associated with increased C-reactive protein in young women.

Evidence links disturbed sleep with an exaggerated inflammatory response and increased risk of adverse health outcomes. An emerging risk factor for many adverse health outcomes is chronic, low-grade inflammation. An exaggerated inflammatory response could provide a biological link between disturbed sleep and adverse health outcomes. The relationship between sleep and chronic, low-grade inflammation has been sparsely examined in otherwise healthy, young women. We evaluated cross-sectional relationships between self-reported sleep and three inflammatory markers. Participants were community dwelling nonpregnant women (N=43, 28.2+/-5.2 years of age). Measures included the Pittsburgh Sleep Quality Index (PSQI), sleep diaries, and serum levels of IL-6, TNF-alpha and C-reactive protein. Poor sleep quality and continuity were associated with higher CRP levels after controlling for covariates. No significant relationships were observed between PSQI scores and IL-6 or TNF-alpha; sleep duration was not related to any of the inflammatory markers. Poor sleep, in young adulthood, may contribute to the chronic, low-grade inflammation associated with an increased risk for future adverse health outcomes. Future work should longitudinally evaluate how these relationships may affect development of gender-specific diseases in apparently healthy young women.

Sleep Complaints in Late Pregnancy and the Recurrence of Postpartum Depression

This study evaluated the relationship between sleep quality in late pregnancy and recurrence of postpartum major depression (PPMD) through 28 weeks postpartum. The Pittsburgh Sleep Quality Index (PSQI) at 36 weeks gestation was assessed in 51 non-depressed women with a history of PPMD; recurrence was determined by the 21-item Hamilton Rating Scale for Depression and the Schedule for Affective Disorders and Schizophrenia. Sleep quality in late pregnancy was not related to recurrence per se, but it was related to timing of recurrence (Kruskal–Wallace = 9.78, p = .008). Rapid recurrence (within 4 weeks post delivery) was preceded by fewer sleep complaints (mean PSQI for early recurrers = 4.8 vs. 7.3 for non-recurrers, p = .09). Recurrence after 4 weeks postpartum was preceded by more sleep complaints in late pregnancy (mean PSQI for late recurrers = 9.9 vs. 7.3 for non-recurrers, p = .02). Sleep quality in late pregnancy may help in identifying women at risk for a PPMD recurrence.

Sleep variability, health-related practices, and inflammatory markers in a community dwelling sample of older adults.

Objective: To explore relationships between wake- and sleep-related health behaviors and circulating concentrations of inflammatory markers (interleukin [IL]-6 and tumor necrosis factor [TNF]-&agr;) in a cohort of community dwelling older adults. Low-grade chronic inflammation is an important risk factor for age-related morbidity. Health behaviors, including average aggregate measures of sleep, have been linked to increased inflammation in older adults. Variability in sleep timing may also be associated with increased inflammation. Method: Participants were community dwelling older adults ≥60 years (n = 222: 39 bereaved, 55 caregivers, 52 with insomnia, and 76 good sleepers). Mean values and intraindividual variability in sleep, as well as caffeine and alcohol use, exercise, and daytime napping, were assessed by sleep diaries. Blood samples were obtained in the morning. Results: Several interactions were noted between sleep behaviors, inflammatory markers, and participant group. Greater variability in wake time and time in bed was associated with higher IL-6 among good sleepers relative to caregivers and older adults with insomnia. Good sleepers who consumed moderate amounts of alcohol had the lowest concentrations of IL-6 compared with the other three groups who consumed alcohol. Insomnia subjects, but not good sleepers, showed increased concentrations of IL-6 associated with caffeine use. Caregivers showed increased concentrations of TNF-&agr; with alcohol use relative to good sleepers. Greater variability in bedtime, later wake times, and longer time in bed was associated with higher TNF-&agr; regardless of group. Conclusions: Moderation and regularity in the practice of certain health behaviors, including sleep practices, were associated with lower plasma levels of inflammatory markers in older adults. Life circumstances and specific sleep disorders may modify these associations. WT = wake time; BT = bed time; TIB = time in bed.

Disturbed sleep and inflammatory cytokines in depressed and nondepressed pregnant women: an exploratory analysis of pregnancy outcomes.

Objective Disturbed sleep and depression are potential risk factors for pregnancy complications. Both conditions are known to dysregulate biological pathways responsible for maintaining homeostatic balance and pregnancy health. Depression during pregnancy is associated with poor sleep. Thus, we explored whether disturbed sleep was associated with inflammatory cytokines and risk for adverse pregnancy outcomes, as well as whether depression augmented the sleep-cytokine relationship, thereby additively contributing to risk for adverse outcomes. Methods Interview-assessed sleep and plasma cytokine concentrations were evaluated in a cohort of depressed and nondepressed pregnant women (n = 168) at 20 and 30 weeks’ gestation. Outcomes evaluated included preterm birth, birth weight, and peripartum events. Results Among depressed women, short sleep duration (<7 hours) was associated with higher interleukin (IL)-8 across time (&bgr; = 0.506, p = .001), poor sleep efficiency (<85%) was associated with higher IL-6 (&bgr; = 0.205, p = .006), and daytime naps were associated with higher tumor necrosis factor &agr; (&bgr; = 0.105, p = .024). Aspects of poor sleep were associated with having a lower weight baby (p values <.053). Among depressed women, interferon-&ggr; increased risk for preterm birth (odds ratio = 1.175, p = .032). Trends for IL-6 and higher birth weight (&bgr; = 105.2, p = .085), interferon-&ggr; and lower birth weight (&bgr; = −19.92, p < .069), and increased IL-8 and babies weighing less than 4000 grams (odds ratio = 0.72, p < .083) were observed. Conclusions Although speculative, disturbed sleep may disrupt normal immune processes and contribute to adverse pregnancy outcomes. Exploratory analyses indicate that depression modifies these relationships.

Disturbed sleep, a novel risk factor for preterm birth?

OBJECTIVE The etiology of preterm birth (PTB) is likely caused by multiple factors, which may include disturbed sleep. We evaluated whether sleep disturbance was associated with PTB and whether the association was affected by other psychosocial risk factors. METHODS Pregnant women (n=217) for whom we had depression and sleep data at 20 or 30 weeks gestation and delivery information were evaluated. Logistic models were used to test the hypotheses that disturbed sleep was associated with PTB. RESULTS Time in bed at 20 weeks was significantly associated with risk for preterm delivery (odds ratio [OR] 1.43, 95% confidence interval [CI] 1.08-1.88). However, after controlling for depression/selective serotonin reuptake inhibitors (SSRI) status, history of PTB, age, employment, and marital status, this relationship was no longer significant (OR 1.26, 95% CI .92-1.71). No other relationships were significant. CONCLUSIONS We report preliminary evidence suggesting that poor sleep may contribute to risk for PTB. Although it is speculative and additional work is needed to confirm or refute whether sleep is an independent or mediating risk factor for PTB, disturbed sleep does appear to play a role in adverse pregnancy outcomes.

Subjective sleep disturbance during a smoking cessation program: Associations with relapse

BACKGROUND Sleep disturbance may affect smoking cessation efforts. We describe sleep changes across three months among women in a smoking cessation program and tested whether sleep disturbances at baseline and 1 month post-quit attempt predicted smoking status at three months. METHODS Participants (N=322) were women in a randomized, clinical trial for smoking cessation. Sleep disturbances, as well as, insomnia, drowsiness, and sleep quality were evaluated prior to and during three months of cessation treatment. Repeated measures mixed models evaluated change in sleep over time by smoking outcome status. Logistic regression analyses determined whether sleep disturbances at baseline and 1 month post-quit were associated with smoking status at 3 months. RESULTS Sleep disturbances were reported by more than 25% of women. Drowsiness, insomnia, and sleep quality changed over time. However, contrary to our hypotheses, none of the sleep variables at either baseline or 1 month post-quit attempt was associated with relapse (ps>.05). CONCLUSIONS Although mild to severe drowsiness was reported by more women who relapsed than those who remained abstinent, none of the sleep disturbance symptoms predicted smoking relapse. Given high rates of sleep disturbances among women smokers, better prospective evaluations of the relationship of sleep disturbances to smoking cessation treatment outcome are needed.