Abstract
Objective
The purpose of this study was to examine the association of short sleep duration among women in the first year postpartum with inflammation at 3-years postpartum.
Methods
We studied 479 women in Project Viva, a prospective cohort. At 6 months and 1 year postpartum, women reported the number of hours they slept in a 24-hour period, from which we calculated a weighted average of daily sleep. We used multivariable median regression analyses to predict the independent effects of short sleep duration (≤ 5 h/d v.> 5 h/d) on markers of inflammation, e.g. interleukin-6 [IL6] and C-reactive protein [CRP] at 3-years postpartum.
Results
Women's mean (SD) hours of daily sleep in the first year postpartum was 6.7 (0.96) hours. After adjusting for age, race/ethnicity, education, parity, pre-pregnancy body mass index, excessive gestational weight gain and gestational age at delivery, we found that postpartum sleep ≤ 5 h/d was associated with elevated IL6 (β 0.25 pg/mL; 95% CI: 0.14, 0.43) compared with > 5 h/d. Although postpartum sleep ≤ 5 h/d appeared to also be associated with elevated CRP (β 0.15 mg/dL; 95% CI: −0.08, 0.52), these results did not reach statistical significance.
Conclusion
Short sleep duration in the first year postpartum is associated with elevated levels of the pro-inflammatory marker, IL6, at 3-years postpartum.
Keywords: Sleep, Inflammation, Postpartum women
INTRODUCTION
Mounting epidemiologic evidence indicates that short (< 5 hrs/day) duration of sleep is a risk factor for obesity, type 2 diabetes, coronary heart disease, hypertension, and all-cause mortality in adults independent of other measured risk factors.1–7 Sleep loss8 and circadian misalignment9 have also been associated with markers of metabolic dysfunction and with adverse levels of adipokines. A group that may be at particularly high risk for the adverse effects of short sleep duration and sleep loss is women in the postpartum period.
Substantial sleep restriction and reduced sleep quality in the postpartum period have been well documented and found to be associated with women's physical and mental health.10, 11 Emerging evidence also suggests that postpartum sleep restriction is associated with greater adiposity and excessive postpartum weight retention 1- and 3-years after delivery.12, 13 While studies have found a cross-sectional association between sleep disturbances during pregnancy with increased markers of inflammation,14 no existing studies have prospectively examined the effects of postpartum short sleep duration on inflammatory status. Such information would help support interventions to improve sleep quality and quantity in the postpartum period.
The purpose of this study was to examine the longitudinal association of short sleep duration in the first year postpartum with markers of inflammation at 3-years postpartum. We hypothesized that short sleep duration would be associated with elevated markers of inflammation, measured as higher levels of C-reactive protein [CRP] and interleukin-6 [IL6].
METHODS AND PROCEDURES
Study subjects
The subjects for this study were participants in Project Viva, a prospective cohort study of gestational factors and offspring health.15 We recruited women who were attending their initial prenatal visit at 8 obstetrical offices of a multi-specialty group practice in Massachusetts. Eligibility criteria included fluency in English, gestational age less than 22 weeks at the initial prenatal clinical appointment, and singleton pregnancy. Details of recruitment and retention procedures are available elsewhere.15
Of the 2128 participating women who gave birth, 1579 were invited to a 3-year follow-up examination because they had completed dietary questionnaires during pregnancy. We excluded 818 women from the current analysis because they had delivered another child since the birth of the index child three years previously, they had type 1 or type 2 diabetes, or they did not attend the three year visit. Of the remaining 761 women, 586 had measures of sleep duration at 6 months and 1 year; 480 provided a blood sample at 3 years postpartum. We included 479 women with CRP or IL6 levels in the current analysis.
After obtaining informed consent, we performed in-person study visits with the mother immediately after delivery and at 6 months and 3 years postpartum. Mothers completed mailed questionnaires at 1 and 2 years postpartum. Institutional review boards of participating institutions approved the study.
Main Exposure: Maternal Postpartum Sleep Duration
At 6 months and 1 year postpartum, we asked women to report hours of sleep duration within a 24-hour period using the question: “In the past month, how many hours of sleep do you get in an average 24-hour period?”. Response options were in integers for hours of sleep at each time period. We calculated a weighted average of sleep duration from 6 months to 1 year as the mean of 6 month and 1 year values.
Main Outcomes: Markers of inflammation
We tested all blood samples for CRP and IL6. Blood samples were collected by trained phlebotomists and transferred within 24 hours for storage in liquid nitrogen freezers. Sample testing was performed at the Children's Hospital Boston Clinical Chemistry Laboratory. We assessed CRP using an immunoturbidimetric high-sensitivity assay on a Hitachi 911 analyzer and reagents and calibrators from Denka Seiken (Niigata, Japan). Plasma IL-6 was measured by ultrasensitive ELISA. Inter- and intra-assay coefficients of variation for our biosamples ranged from 2 to 10%.
Study covariates
Using a combination of self-administered questionnaires and interviews, we also collected information about maternal age, education, parity, household income, and race/ethnicity. Mothers reported their pre-pregnancy weight and height. We calculated gestational weight gain as the difference between the last weight prior to delivery and the self-reported pre-pregnancy weight. We categorized gestational weight gain as inadequate, adequate, or excessive for pre-pregnancy BMI categories using the new Institute of Medicine (IOM) guidelines.16 At 3 years postpartum, we measured women's weight to the nearest 0.1 kg using a research quality scale, measured height to the nearest 0.1 cm using a stadiometer, and calculated body mass index as kg/m2. At 3 years postpartum we also assessed maternal total physical activity (walking, moderate, and vigorous activity, hours per week) and television viewing (hours per week).
Statistical analysis
Our main exposure of interest was maternal short sleep duration defined as an average daily sleep duration from 6 months to 1 year ≤ 5 hours/day (v. > 5 hours/day).
We first performed univariate analyses to assess the distribution of all variables included in the analyses. We then used bivariate analyses to examine the association of our exposure of interest with study covariates and outcomes. We used multiple regression models to assess the independent effects of short sleep duration on our main outcomes. We used median regression17 because the distributions of the CRP and IL6 were non-Gaussian. In multivariable models, we included only those covariates that were of a priori interest or confounded associations of sleep duration with our outcomes. Model 1 was unadjusted. Model 2 was adjusted for maternal age, race/ethnicity, education, parity, pre-pregnancy BMI, excessive gestational weight gain and gestational age at delivery. To examine the confounding effects of maternal BMI, total physical activity, and television viewing at the time of cytokine measurement at 3 years postpartum, we also added these variables to Model 1 in subsequent models. We report regression estimates (β) and 95% confidence intervals for the main exposure. We performed data analyses with SAS version 9.2.
RESULTS
Characteristics of study participants are shown in Table 1. The mean (SD) of daily sleep duration from 6 months to 1 year was 6.7 (0.97) hours; 74 (13%) women were sleeping ≤ 5 hours/day. Mean (SD) for pre-pregnancy BMI was 24.9 kg/m2 (5.2). Means, standard deviations, medians, and inter-quartile range of CRP and IL6 are shown in Table 2.
Table 1.
Unadjusted and bivariate associations of maternal characteristics with short sleep duration from 6 months to 1 year postpartum. Data from 479 participants in Project Viva who presented for follow-up at three years postpartum without an intervening birth.
| Sociodemographic Characteristic | N | Overall | Average Daily Sleep Duration (hrs/d), 6 Months to 1 Year Postpartum | ||
|---|---|---|---|---|---|
| ≤ 5 hours (N = 68) | > 5 hours (N = 411) | p-value* | |||
| Mean (SD) or % | |||||
| Maternal age at 3 years postpartum, years | 479 | 37.8 (5.1) | 38.7 (4.1) | 37.7 (5.3) | 0.09 |
| Gestational age at delivery, weeks | 479 | 39.4 (2.0) | 39.4 (2.6) | 39.5 (1.9) | 0.80 |
| Pre-pregnancy BMI, kg/m2 | 479 | 24.9 (5.2) | 25.3 (5.6) | 24.9 (5.2) | 0.55 |
| BMI at 3 years postpartum, kg/m2 | 470 | 26.3 (6.2) | 27.2 (6.5) | 26.2 (6.2) | 0.21 |
| Total physical activity at 3 years postpartum, hrs/week | 452 | 7.1 (6.8) | 6.9 (6.7) | 7.1 (6.9) | 0.79 |
| Television viewing at 3 years postpartum, hrs/week | 452 | 9.7 (8.4) | 10.3 (9.3) | 9.6 (8.2) | 0.54 |
| Institute of Medicine gestational weight gain category | 0.95 | ||||
| Adequate/inadequate | 218 | 46 | 46 | 46 | |
| Excessive | 257 | 54 | 54 | 54 | |
| Race/ethnicity | 0.04 | ||||
| White | 356 | 74 | 71 | 75 | |
| Black | 55 | 11 | 10 | 12 | |
| Hispanic | 30 | 6 | 10 | 6 | |
| Asian | 19 | 4 | 0 | 5 | |
| Other | 19 | 4 | 9 | 3 | |
| Parity | 0.15 | ||||
| 1 | 132 | 28 | 24 | 28 | |
| 2 | 236 | 49 | 44 | 50 | |
| 3+ | 111 | 23 | 32 | 22 | |
| College graduate | 0.49 | ||||
| No | 145 | 30 | 34 | 30 | |
| Yes | 334 | 70 | 66 | 70 | |
| Household income | 0.34 | ||||
| < $40,000/year | 52 | 11 | 15 | 11 | |
| ≥ $40,000/year | 401 | 89 | 85 | 89 | |
P-value from t-test for continuous and chi-square for categorical characteristics.
Table 2.
Unadjusted and bivariate associations of maternal inflammatory markers at 3-years postpartum with short sleep duration from 6 months to 1 year postpartum among 479 participants.
| Inflammatory Markers at 3 Years Postpartum | Overall | Average Daily Sleep Duration (hrs/d), 6 Months to 1 Year Postpartum | |||||
|---|---|---|---|---|---|---|---|
| ≤ 5 hours | > 5 hours | p† | |||||
| Mean (SD) | Median (IQR) | Mean (SD) | Median (IQR) | Mean (SD) | Median (IQR) | ||
| C-reactive protein, mg/dl | 2.3 (5.7) | 0.7 (0.3, 2.1) | 2.4 (4.3) | 0.9 (0.4, 2.4) | 2.3 (5.9) | 0.7 (0.3,2.1) | 0.25 |
| IL6, pg/mL | 1.6 (3.0) | 0.9 (0.5, 1.5) | 2.1 (3.4) | 1.1 (0.7, 1.8) | 1.5 (2.9) | 0.8 (0.5,1.4) | 0.01 |
P-value are from Wilcoxon rank-sum test for non-normally distributed variables.
Sleep duration ≤ 5 hours/day was associated with higher levels of IL6 at 3-years postpartum (Table 2). In multivariable analyses adjusted for maternal age, race/ethnicity, education, parity, pre-pregnancy BMI, excessive gestational weight gain and gestational age at delivery, we found that postpartum sleep ≤ 5 h/d was associated with elevated IL6 (β 0.25 pg/mL; 95% CI: 0.14, 0.43) at 3-years postpartum (Table 3). Although postpartum sleep ≤ 5 h/d appeared to also be associated with elevated CRP (β 0.15 mg/dL; 95% CI: −0.08, 0.52), these results did not reach statistical significance (Table 3).
Table 3.
Inflammatory markers at three-years postpartum, by average daily sleep duration from 6 months to 1 year postpartum among 479 participants.
| Average Daily Sleep Duration (hours/day), 6 Months to 1 Year Postpartum | P-value | ||
|---|---|---|---|
| ≤ 5 hours | > 5 hours | ||
| Effect Estimate (95% Confidence Interval) | |||
| C-reactive protein, mg/dL * | |||
| Model 1. Unadjusted | 0.12 (−0.10, 0.88) | 0.00 (ref) | 0.60 |
| Model 2. Multivariable Adjusted† | 0.15 (−0.08, 0.52) | 0.00 (ref) | 0.39 |
| IL6, pg/mL * | |||
| Model 1. Unadjusted | 0.29 (−0.02, 0.68) | 0.00 (ref) | 0.12 |
| Model 2. Multivariable Adjusted† | 0.25 (0.14, 0.43) | 0.00 (ref) | 0.01 |
Effect estimates are from multivariable median regression. Estimates reflect the difference from the median of each outcome associated with sleep duration ≤ 5 hours/day.
Model 2 is adjusted for maternal age, race/ethnicity, education, parity, pre-pregnancy BMI, excessive gestational weight gain, and gestational age at delivery.
Models adjusted for maternal BMI at 3 years postpartum instead of pre-pregnancy BMI and excessive gestational weight gain showed similar effect estimates for IL6 (β 0.21 pg/mL; 95% CI: 0.09, 0.40) and CRP (β 0.07 pg/mL; 95% CI: −0.04, 0.35). Further adjustment for total physical activity and TV viewing at 3 years postpartum minimally changed the effect estimates for IL6 (β 0.32 pg/mL; 95% CI: 0.05, 0.57) and CRP (β 0.20 pg/mL; 95% CI: −0.15, 0.87).
DISCUSSION
In this prospective study of women, we found that short sleep duration in the first year postpartum was associated with higher levels of the pro-inflammatory marker, IL6, and appeared to also be associated with higher CRP levels at 3 years postpartum independent of maternal sociodemographic characteristics. Our observed estimates were independent of pre-pregnancy BMI and excessive gestational weight gain.
Previous studies have found that short sleep duration is associated with increased risk of coronary heart disease18 and incident diabetes.1 The mechanisms relating sleep duration to adverse cardio-metabolic outcomes are not clear but one possible explanation is the effects of sleep restriction on inflammation. Experimental studies and prospective cohort studies of adults have shown associations of sleep restriction with increases in the pro-inflammatory cytokines, IL6 and CRP.4, 19–21 Studies among pregnant women have also related short sleep duration and poor sleep efficiency in both mid and late pregnancy to higher stimulated levels of IL-6.14 Elevations in both CRP and IL6 predict an increased risk for adverse cardio-metabolic outcomes such as myocardial infarction and diabetes.22, 23 However, it is not known if the associations of sleep duration and inflammation extend to women in the postpartum period. In this study we found that short sleep duration in the first postpartum year was associated with higher IL6 at three years postpartum. The association was robust to adjustment for a wide range of potential confounders. Thus, it is possible that sleep curtailment in the first year postpartum might lead to elevations in inflammatory markers that could increase women's risks of adverse cardio-metabolic outcomes. To our knowledge, our study is the first to report associations of maternal postpartum sleep duration and inflammation.
While we found that short sleep duration was associated with higher levels of CRP, these results did not reach statistical significance. Plasma CRP is a marker of systemic inflammation induced by proinflammatory cytokines in the liver.24 Its production is influenced by TNF-a and IL6, both of which are upstream of CRP.25 Thus, the levels of CRP depend on both TNF-a and IL6 activity. We observed a relationship between short sleep duration and higher levels of IL6 but did not have data on TNF-a or circulating soluble TNF-a receptor II (sTNF-aRII), the circulating levels of which reflect TNF-a activity. Thus, it is possible that the effects of short sleep duration on IL6 are proportionally stronger than those on TNF-a and / or that their effects on CRP lag behind the IL6 elevations. Longer term follow up could reveal stronger associations.
Several limitations of this study deserve mention. First, although we had measures of total sleep duration, we did not have direct measures of sleep (e.g. from actigraphs) nor did we have measures of snoring or of other signs of obstructive sleep apnea (OSA). Thus, we are not able to determine whether our observed effects were independent of snoring and OSA, both of which have been found to be associated with adverse inflammatory biomarkers.4, 26 Second, we did not have measures of sleep during pregnancy or beyond 1 year postpartum. Thus, it is possible that postpartum sleep is a marker of sleep at 3 years. Also, we did not measure inflammatory biomarkers before pregnancy to control for differences in these measures that may have preceded changes in postpartum sleep. Fourth, although women in the study had diverse racial/ethnic backgrounds, their education and income levels were relatively high. Our results may not be generalizable to more socioeconomically disadvantaged populations. Finally, in any observational study it is possible that unmeasured characteristics might explain the observed associations between exposure and outcome.
Conclusions
Short sleep duration in the first year postpartum is associated with higher levels of inflammatory markers at 3-years postpartum. Given the adverse physiological effects of chronic inflammation, our findings suggest that there is significant public health impact among the sizable number of women who experience prolonged sleep curtailment in the first postpartum year.
Acknowledgments
We would like to thank the participants and research staff of Project Viva.
Funding Sources: This study was supported in part by grants from the U.S. National Institutes of Health (HD 34568, HL 64925, HL 68041, DK 053539). CSM received funding from the National Institute of Diabetes and Digestive and Kidney Diseases (grants DK058785, DK079929, and DK081913), and the National Institute on Aging (grant AG032030).
Footnotes
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Disclosures: The authors have no conflicts of interest to declare.
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