Effect of maternal sleep in late pregnancy on leptin and lipid levels in umbilical cord blood

Journal Pre-proof Effect of maternal sleep in late pregnancy on leptin and lipid levels in umbilical cord blood Min Meng, Yanrui Jiang, Lixia Zhu, Guanghai Wang, Qingmin Lin, Wanqi Sun, Yuanjin Song, Shumei Dong, Yujiao Deng, Tingyu Rong, Qi Zhu, Hao Mei, Fan Jiang PII:

S1389-9457(19)31572-2

DOI:

https://doi.org/10.1016/j.sleep.2019.11.1194

Reference:

SLEEP 4227

To appear in:

Sleep Medicine

Received Date: 13 August 2019 Revised Date:

31 October 2019

Accepted Date: 5 November 2019

Please cite this article as: Meng M, Jiang Y, Zhu L, Wang G, Lin Q, Sun W, Song Y, Dong S, Deng Y, Rong T, Zhu Q, Mei H, Jiang F, Effect of maternal sleep in late pregnancy on leptin and lipid levels in umbilical cord blood, Sleep Medicine, https://doi.org/10.1016/j.sleep.2019.11.1194. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V.

Effect of maternal sleep in late pregnancy on leptin and lipid levels in umbilical cord blood Min Menga,b#, Yanrui Jianga,b#, Lixia Zhua,b, Guanghai Wanga,b,Qingmin Lina,b, Wanqi Suna,b, Yuanjin Songa,b, Shumei Donga,b, Yujiao Denga,b, Tingyu Ronga,b, Qi Zhua,b, Hao Mei a,c,d, Fan Jianga,b* a

Department of Developmental and Behavioral Pediatrics, Pediatric Translational Medicine

Institution, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; b

Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health,

Shanghai, China c

Pediatric Translational Medicine Institute, Shanghai Children’s Medical Center, Shanghai

Jiao Tong University School of Medicine, Shanghai, China d

Department of Data Science, School of Population Health, University of Mississippi Medical

Center, Jackson, MS, the United States #

Min Meng and Yanrui Jiang contributed equally to this article.

*Corresponding Author: Fan Jiang Department of Developmental and Behavioral Pediatrics, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, 1678 Dongfang Road, Shanghai 200127, China. Tel.: +86 21 38626012; fax: +86 2158706129. E-mail address: [email protected] Conflict of interest: The authors declare no conflict of interest.

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Abbreviations: SSBC

Shanghai Sleep Birth Cohort Study;

NST

Night sleep time;

SE

Sleep efficiency;

SOL

Sleep onset latency;

WASO

Wake after sleep onset;

MSF

Midpoint of sleep;

GDM

Gestational diabetes mellitus;

TG

Triglycerides;

TC

Total cholesterol;

LDL-C

Low-density lipoprotein cholesterol;

HDL-C

High-lipoprotein cholesterol;

OSA

Obstructive sleep apnea;

LMP

Last menstrual period;

GWG

Gestational weight gain;

IOM

Institute of Medicine;

GA

Gestational age;

BW/GA

Birth weight for gestational age.

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Abstract Objectives: To study the impact of maternal sleep in late pregnancy on birth weight (BW) and leptin and lipid levels in umbilical cord blood. Study Design: A total of 277 healthy and singleton pregnancy women were recruited for participation in the Shanghai Sleep Birth Cohort Study (SSBC) during their 36–38 weeks of pregnancy, from May 2012 to July 2013. Maternal night sleep time (NST), sleep efficiency (SE), sleep onset latency (SOL) and the percentage of wake after sleep onset (WASO) in NST and midpoint of sleep (MSF) were measured by actigraphy for seven consecutive days. The leptin and lipid levels were determined in cord blood samples collected from the umbilical vein immediately after delivery. Birth information (birth weight, gender, delivery type, etc.) was extracted from medical records. A multivariable linear regression model was applied to examine the effect of maternal sleep in late pregnancy on newborn leptin and lipid levels in umbilical cord blood. Results: A total of 177 women and their infants were included in the analysis. Maternal mean NST was 7.03 ± 1.10 h in late pregnancy, and 48% had a shorter sleep time (NST < 7 h). The average maternal SE was 72.54% ± 9.66%. The mean percentage WASO/NST was 21.62%± 9.98%; the average MSF was about 3:34 (0:53); and the SOL was 46.78±36.00 minutes. After adjustment for confounders, both maternal NST and SE were found to be significantly associated with triglyceride levels (β = -0.219, p = 0.006; β = -0.224, p = 0.006) in umbilical cord blood; and maternal NST was also observed to have positive association with newborn leptin levels (β = 0.146, p = 0.047). However, we did not find significant association between other maternal sleep parameters in late pregnancy and leptin and lipid levels and birth weight. Conclusions: Short sleep duration and poor sleep quality during late pregnancy were associated 3

with newborn leptin and lipid levels, and efforts on improving maternal sleep during late pregnancy should be advocated for children’s health. Keywords: Late pregnancy, sleep, umbilical cord blood, leptin, lipid, birth weight.

1. Introduction

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Sleep changes during pregnancy have been well recognized [1]. Sleep disturbances, shorter sleep duration, and poorer sleep quality are common during pregnancy, especially in its late stages [2-5]. The estimated prevalence of the sleep problems during late pregnancy is diverse, ranging from 39% to 76% [4]. Sleep problems may have short- and long-term negative effects on both the mother and the infant. Most prior studies established that short sleep duration and poor sleep quality led to maternal metabolism disorder and adiposity [5,6], but only few investigations explored the effect on fetal metabolism, most of which focused on birth weight [7] and obtained inconsistent results. For example, an earlier cohort study reported that sleeping eight hours or less during pregnancy was a risk factor of low birth weight [8]. Conversely, a cross-sectional study found that sleep duration of less than eight hours was associated with a risk of an increase in the birth weight to more than 3500 grams [9]. Furthermore, other examinations did not find any association between maternal sleep duration and quality and birth weight [10]. However, apart from adiposity, short sleep duration and poor sleep quality were associated with reduced leptin levels [11,12] and poorer lipid profile [13,14] in children and adolescents. However, whether the association between sleep and leptin and lipid levels has already occurred in the uterus was not known. To date, no study has explored the association between maternal sleep and the newborn leptin and lipid levels. Only one animal study discovered that sleep fragmentation during late pregnancy exerted adverse and long-lasting metabolic consequences in the next generation [15]. Increased insulin resistance and reduced adiponectin expression were observed in the offspring mice subjected to sleep fragmentation [15]. Leptin and lipid levels have important functions in energy homeostasis [16] and the prediction of hyperlipidemia [17]. Importantly, certain changes in umbilical cord blood leptin and lipid levels were reported to have long-term adverse effects in the later years [17,18]. Therefore, the investigations of the effect of maternal sleep on the leptin and lipid levels of newborns are of critical importance.

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The developmental origin of the health and disease (DOHaD) hypothesis suggests that intrauterine developmental phases of high plasticity influence the metabolic pathways involved in the development of certain chronic diseases in childhood and adulthood [19,20]. Thus, we hypothesized that maternal sleep in late pregnancy can influence the leptin and lipid levels in umbilical cord blood by the alteration of intra-uterine environment. Furthermore, sleep include multiple dimensions, and these different dimensions of sleep may provide a more comprehensive understanding of the relationship between sleep and metabolism. However, many studies consider only one of these sleep parameters at a time, or at most two or three of them simultaneously [11-14]. Here, we aimed to explore multiple dimensions of maternal sleep in late pregnancy and its effect on birth weight and leptin and lipid levels in the umbilical cord blood. 2. Methods 2.1 Study Design and Participants Study subjects were participants in the SSBC, an ongoing prospective cohort study aimed to determine the effects of early‐life environmental and behavioral factors on child growth and development. All the mothers included were recruited in Renji Hospital from May 2012 to July 2013. The first contact was made during 36–38 weeks of gestation. Women with the following medical conditions were excluded: premature signs during pregnancy, gestational diabetes mellitus (GDM), pregnancy-induced hypertension (PIH) during late pregnancy, heart disease, chronic hypertension, chronic lung disease, and chronic renal disease. Second, upon delivery of the baby, only full-term infants were included in the study. Infants with the following conditions were excluded: history of apnea at birth, 7 or Apgar scores below 1 minute or 5 minutes, sent to Neonatal Intensive Care Units after birth. In sum, 431 candidate pregnant women were contacted at first, 277 participants were eligible 6

and recruited into this study, and 10 women withdrew before their deliveries. Then, among 267 eligible mothers, 194 completed actigraphy (wearing of a wristwatch to detect movement during sleep) and the sleep logs for at least three continuous days. A total number of 236 cord blood samples were obtained after delivery. The birth cohort protocol was approved by the Shanghai Children's Medical Center Human Ethics Committee (SCMCIRB-2012033), and written informed consent was obtained from each participant. 2.2 Maternal sleep in late pregnancy Maternal sleep was assessed using an actigraph (Actiwatch2, AW2, Phillips- Respironics Co., Inc., Bend, OR, USA), which determines the wake and sleep state by a sensitive accelerometer. Previous work has established the reliability and validity of actigraph measurements in sleep-wake detection [21]. The participants enrolled in the study were asked to wear the device on their non-dominant wrist for seven consecutive days. The wrist actigraphy was set to record 30-second epochs using the medium threshold set by the manufacturer (40 activity counts/min) for detection of wake and sleep periods, and the sleep onset time and offset time were determined by the manufacturer default setting of 10 minutes immobile [22]. Meanwhile, the participants were asked to keep a daily sleep diary to record their bed time, get-up time and off-wrist period [23]. The sleep diary was used to facilitate the interpretation of the actigraphy data. An actigraph recording was considered successful if, during seven-day study, data were recorded for at least three days, and the actigraph data matched those of the sleep diary. Then, the actigraphy data combined with those of the sleep diaries were analyzed using Actiware 6.0.0 software. The main measures of sleep-related outcomes were generated by the software: (1) NST: obtained by averaging the total time in hours scored as sleep by the Actiware algorithm during all available nights; Short sleep time was defined as sleeping less than seven hours per night (NST < 7 h), based on the recommendations of National Sleep Foundation [24]; (2) Sleep efficiency (SE): 7

proportion of NST from bedtime to get-up time; (3) Sleep onset latency (SOL): the period from bedtime to sleep onset time; (4) wake after sleep onset (WASO)/NST: the percentage of night waking time in NST; (5) Midpoint of sleep (MSF): the clock time that represent the midpoint between the clock time of sleep onset and the clock time of sleep offset. 2.3 Cord blood leptin and lipids measurement and birth weight Cord blood samples were collected from the umbilical vein immediately after delivery, then were stored at 4 °C for a maximum of 4 h. They were then centrifuged, aliquoted, and stored in liquid nitrogen (-80 °C) until assayed. Total serum leptin levels were measured using Human Radioimmunoassay (RIA) Kit (Northern Biotech Inc., Beijing, China) with a sensitivity of 0.45 ng/mL. The inter- and intra-assay coefficients of variation (CV) were ≤15% and ≤10%, respectively. The levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-lipoprotein cholesterol (HDL-C) were measured by an automatic biochemical analyzer (Hitachi 7600, Japan), following a standard operating procedure. Infant birth weight was extracted from the hospital clinical records. 2.4 Covariates Each participant enrolled in this study was asked to fill in a sociodemographic questionnaire for obtaining general information. The information included maternal age, pre-pregnancy weight, height, and medical and family history. The STOP-Bang questionnaire was used for collecting information about maternal obstructive sleep apnea (OSA) in late pregnancy women [25]. The Stop-Bang questionnaire shows a high probability of OSA if the score is ≥ 3 [26]. The last menstrual period (LMP), mothers’ weight at the last prenatal care, infants’ gender and other birth information was extracted from the hospital clinical records. Maternal pre-pregnancy BMI was calculated from the self-reported weight and height. We calculated gestational weight gain 8

(GWG) as the pre-pregnancy weight subtracted from the last clinically recorded weight within two weeks after delivery. Then, we categorized GWG into inadequate, adequate, and excessive GWG according to the 2009 Institute of Medicine (IOM) guidelines [27]. Gestational age (GA) was calculated from the LMP to the delivery. United States national reference was used for the measurements of infant birth weight (BW) for GA z‐value [28]. 2.5 Statistical analyses Maternal NST, SE, SOL， WASO/NST and MSF and other continuous variables are expressed as means ± standard deviation (SD), except for leptin, which was presented as median and range. Categorical variables are presented as numbers and percentages. In the analyses, the log10-transformed cord blood leptin level was utilized to normalize its distribution, which has been tested by the Kolmogorov-Smirnov test. The t-test was applied to compare leptin and lipids levels in umbilical cord blood between short and long sleeper groups. Pearson correlation analysis was performed to test the relationship between maternal sleep and cord blood log leptin and lipid levels and birth weight. We employed a multiple linear regression analysis to adjust the covariates those were of a priori interest or confounded the main association, including maternal age at delivery, parity, pre-pregnancy BMI, GWG, maternal education level, delivery type, infant gender and birth weight for GA. Two-sided P-values < 0.05 (two sides) were considered statistically significant. All analyses were performed using the Statistical Package for the Social Sciences for Windows (version 21.0.0.0, SPSS, Inc., Chicago, IL, USA). 3. Results 3.1 Descriptive statistics Finally, a total number of 177 mother-child pairs were included in the analysis. No

9

significant differences were detected in the cord blood leptin and lipid levels between infants delivered by mothers with or without the sleep variables. The STOP-Bang score of the women included in the study all below 3, which indicated that women included had minimal risk of OSA. The participants wore the actigraphy for an average of 6.41 nights with nearly two-thirds (63.3%) wearing the actigraphy device for full seven days and nights. Table 1 represents the characteristics of mother-child pairs in the cohort. The mean age of the mothers at delivery was 29.47 ± 3.27 years, and 92.1% of them were nulliparas. Most of the mothers were college-educated or above (91.5%) and with an appropriate pre-pregnancy BMI (18.5–23 kg/m2, 62.1%) [29]. The average NST during late pregnancy was 7.03 ± 1.10 h, and 48% mothers slept shorter than seven hours per night. The average SE of the mothers during late pregnancy was 72.54 ± 9.66%. The mean percentage WASO/NST was 21.62%±9.98% and the average MSF was about 3:34 (0:53). The period from bedtime to asleep was about 46.78±36.00 minutes. Among the infants, 53.1% were girls, the mean GA was 39.77 ± 0.98 weeks, and the mean birth weight of the infants was 3372.13 ± 375.20 grams. Approximately 82.5% of the infants had a normal BW/GA z score. The median levels of leptin in the umbilical cord blood samples were 4.78 ng/mL. The mean levels of TG, TC, HDL, and LDL were 0.43 ± 0.49 mmol/L, 1.87 ± 0.48 mmol/L, 1.00 ± 0.29 mmol/L, and 0.71 ± 0.29 mmol/L, respectively. No differences were observed in the baseline characteristics between the included and excluded mother-infant pairs in the analysis (Supplement profile tableS1). 3.2 Association between maternal sleep and newborn leptin and lipid levels and birth weight Bivariate analysis showed a positive association between maternal NST and log-transformed leptin levels (r = 0.173, P = 0.022) (Table 2). Compared with newborns born by mothers in the long-sleep group (NST ≥ 7 h), those born by mothers in the short-sleep group had significantly 10

lower log leptin levels (0.68 ng/mL vs 0.57 ng/mL; t = -2.182, P = 0.030), but maternal SE, SOL， WASO/NST and MSF were not associated with newborn log-transformed leptin levels. In addition, the leptin level was higher in female newborns than male newborns. An association between a higher newborn BW/GA z‐value was found with the increase of 0.307 ng/mL in the leptin levels detected in the umbilical cord blood samples. After adjustment for confounding factors, including maternal age at delivery, parity, maternal education levels, infant gender, and birth weight for GA, which may exert effects on cord blood leptin, there was still a positive association between maternal NST and infant log leptin levels (β = 0.148, P = 0.043) (Table 3). Both maternal NST and SE were negatively associated with triglyceride levels (r = -0.202, P = 0.007, and r = -0.193, P = 0.011) (Table 2). Compared with newborns born by mothers in the long-sleep group, those born by mothers in the short-sleep group had higher triglyceride levels in umbilical cord blood (0.43 mmol/L vs 0.36 mmol/L; t = 2.030, P = 0.044). Multiple linear regression revealed a significant negative association between maternal NST, SE, and triglyceride levels (β = -0.219, P = 0.006; β = -0.224, P = 0.006) (Table 3). We did not observe a significant association between maternal sleep during late pregnancy and birth weight (Table 2). 4. Discussion In this prospective study, we used objective measures of maternal habitual sleep and found an average NST of women in the third trimester of 7.03 h, SE of 72.54%. Nearly half of the pregnant women (48%) included in the present study slept less than seven hours. In addition, the newborns of shorter sleep mothers had lower leptin levels and higher triglyceride levels in umbilical cord blood. Moreover, a negative association between maternal SE in late pregnancy and cord triglyceride levels was found, but no association between maternal sleep and newborn birth weight was established in our study. 11

4.1 Maternal sleep in late pregnancy The use of objective measures to evaluate habitual NST during late pregnancy and its outcomes is critical. Subjective sleep time appears to be a less reliable index as according to recent reports showed little agreement between objective and subjective assessments of sleep time among pregnant women [30]. Using actigraphy in our study, we explored maternal sleep during late pregnancy, which had an overall 91% agreement with polysomnography (PSG) [31] (even in pregnancy [32,33]). Sleep quality (SE, SOL,WASO/NST) or quantity (NST) was measured using actigraphy, which has been widely applied in many late-pregnancy studies [34-39]. Our findings of maternal NST are similar to those of the study of Lee and Gay conducted in the USA, in which the authors measured sleep by actigraphy; the average sleep time of 131 women in their ninth month of pregnancy was 7.1 h [34]. Notably, the sleep of 7.04 hours was lower than the 7.2-h sleep measured by actigraphy in 29 Australian women in late pregnancy [40]. In addition, in a small Taiwanese study by Tsai et al., found that the mean sleep time of 38 women in the third trimester was 6.44 h [36]. Another study on 19 late-pregnancy women in New Zealand revealed a mean SE of 83.41% [35], which is higher than the SE of 72.54% established in our investigation. Overall, the sleep duration during late pregnancy in our study was poorer than that in western countries, which may reflect cultural differences and the stress during pregnancy. In addition, studies showed that nullipara was one of the risk factors of shorter sleep duration and worse insomnia severity in pregnancy [3,41], but in our study, over 90% were nullipara, so it is possible to bias the influence of parity. 4.2 The association between maternal sleep and birthweight Previous studies on the effect of maternal sleep on newborn’s birth weight obtained 12

inconsistent results [7]. In the present investigation, we didn’t find any association between maternal sleep and birthweight. In our cohort, there were only six infants with the birthweight larger than 4000g, and none were lower than 2500g. So, the lack of variance of birthweight may bias the association between maternal sleep and birthweight. Nevertheless, we established that poorer sleep quality during late pregnancy was associated with a lower leptin level and a higher triglyceride level in umbilical cord blood. This finding implies that the effect of maternal sleep on metabolic changes before birth occurs even before it had no obvious effect on birthweight, which may be a risk factor for childhood and adulthood obesity, and the hypothesis needs a longer follow-up to confirm. 4.3 The association between maternal sleep and leptin level in cord blood It is well known that poorer sleep is associated with lower leptin levels in both adults and children [11,12,42-48]. Here, we also found an association cross generation (an earlier life stage). Shorter NST during late pregnancy was associated with lower newborn leptin levels. Leptin as an adipocyte-related hormone plays an important role in energy homeostasis that has been proposed as a potential programming modulator of obesity [16] acting by suppression of food intake and stimulation of energy expenditure [16]. Previous research found that cord blood leptin levels were statistically significantly associated with children’s growth trajectories from birth to early childhood [18,49]. Lower cord blood leptin levels were associated with a more rapid weight gain in the first six months [50] or the first 12 months [51] and higher BMI at three years of age [52]. Since cord blood leptin has long-term effect on children’s growth and metabolism, it is of great importance to explore the impact of maternal sleep on newborns leptin levels. As for the fetus, a majority of leptin is produced by the placenta [38] and fetal adipose tissues [39]; in addition, some leptin is actively transported across the placenta from mother [38]. However, the leptin produced by the placenta enters primarily the maternal circulation (95%) in comparison with its 13

entry into the fetal circulation (5%), suggesting that neonatal leptin levels truly reflect the production by the fetus itself [53]. Decreased fetal sleep time may be one of the pathways mediating effects of maternal sleep on cord leptin level. Studies in animals [54] and humans [55,56] have demonstrated an association between acute total or partial sleep deprivation and increased sympathetic nervous system (SNS) activity, which inhibits the leptin release. Besides, increased sympathetic nervous system outflow resulting from maternal high caffeine consumption could lead to spending similar time in quiet sleep by the fetus, less time in active sleep, and much greater time in arousal [57]. Since leptin levels are elevated during sleep [58-60], it is highly possible that short maternal sleep time might lead to an increased sympathetic nervous system outflow and decreased fetal sleep time and leptin levels in umbilical cord blood. The epigenetic alteration of umbilical cord blood may be another mechanism underlying the newborn metabolism disorder due to maternal sleep inadequacy. Epigenetic information is controlled by the genome sequence and environmental exposure and is considered to play the key role in the development of human diseases in recent years [61]. Most prenatal factors, including obesity [62], diabetes [63], mood disorders [64], and various exposures [65,66] have been confirmed to alter cord blood or placental DNA methylation profile at birth, and sleep loss may be associated with DNA methylation and the promotion of adiposity [67-69]. Poor maternal sleep during pregnancy may be one of the risk factors changing newborns metabolism by epigenetic alteration. 4.4 The association between maternal sleep and triglyceride level in cord blood We also found that both maternal NST and SE had a negative effect on newborn triglyceride levels. Accumulating cross-sectional studies examined the association, but the results of these studies are inconsistent. A National Health and Nutrition Survey in Japan reported a U-shaped 14

relationship between sleep duration and higher triglyceride level [70], both longer [71] and shorter [72] sleep duration was associated with higher triglyceride levels. However, Wu et al., did not find an association between a shorter sleep duration and a higher triglyceride level [73]. Apart from sleep duration, poor sleep quality may be another risk factor of increased triglyceride level. A longitudinal study, which measured children sleep with actigraphy, revealed that the poorer sleep quality at eight years of age was associated with higher TG at 12 years of age [74]. Similar results were obtained and an association was detected between maternal sleep and newborn lipid level in our cohort study, indicating that the effect on triglyceride levels of sleep might have already occurred in the uterus, which may have long-term influence. Since the importance of the impact of early life metabolism on health and disease risk in later life is widely appreciated and has been referred to as “early metabolic programming of adult health” [75], the effect of umbilical cord blood lipid levels on later health cannot be ignored. However, we did not find any association between other sleep parameters, especially SOL and WASO/NST, and triglyceride level. WASO/NST mainly reflect the sleep fragmentation of maternal sleep, and the only difference between SE and WASO is SOL. It may be due to SOL, which makes the different result for SE and WASO/NST. Therefore, as for triglyceride level in cord blood, the maternal sleeping time may be more influential than waking time. Previous research did not find such a relationship in adults [76]. The objective sleep fragmentation was not related to a poor lipid level over a 10-year follow up. All these inconsistencies may be influenced by age, race, and the alterations in the lipid metabolism with age. As is described before, besides epigenetic modification in umbilical cord blood, maternal metabolic status may mediate the effect of maternal sleep on newborns metabolism. A shorter sleep duration and poorer sleep quality were confirmed to increase the risk of obesity and metabolism disorder [6,11,77]. Meanwhile, it is well accepted that fetal growth and children 15

obesity are related to the maternal metabolic status [78,79] and anthropometric properties during pregnancy [80,81]. Therefore, maternal sleep may alter the newborn metabolism by changing the maternal metabolism itself. Another possibility is that the mothers with a short sleep duration or poor sleep quality is more likely to lead to unhealthy dietary habits. Such subjects prefer to choose fat-rich foods and have more meals [82]. The search for the potential mechanisms by which maternal sleep during late pregnancy may program the offspring metabolic status remains an area of active investigation. 5. Strengths and limitations This study has several strengths. First, to our knowledge, this is the first study to uncover the relationship between maternal sleep time during late pregnancy and newborns cord blood leptin and lipids levels. Second, we used a prospective cohort study design. Given recent notions that perturbation during gestation can increase the risk of offspring metabolic disease in adult life [19,20], a prospective study following mother-child pairs from late pregnancy is of considerable significance. Finally, maternal sleep during late pregnancy was objectively measured by actigraphy, whereas few investigations have utilized actigraphy to assess sleep in cohort studies of such a magnitude. Several potential limitations should also be taken into consideration when interpreting the results of our study. First, only 177 dyads had useful data among their total sample, so a biased sample toward women who could wear an actigraph may limit the generalizability. Second, the majority of the mothers were well educated and came from families of middle or high socioeconomic statuses. Thus, our sample can’t represent the whole population in Shanghai, and the cesarean rate of 50% in our study may differ from other populations across China. Third, because of the nature of the observational study design, we were unable to examine the 16

mechanism behind the sleep and lipid and leptin association, as well as to measure the long-term effect of maternal sleep on children’s growth and metabolism. Further research will provide new insights into that important association. 6. Conclusion In conclusion, the findings on the properties and effects of maternal sleep quality (ie, SE) and quantity (sleep time) during late pregnancy in our study are similar to those of previously published reports [34]. Specifically, maternal habitual short sleep time during late pregnancy was associated with lower cord leptin levels and higher cord triglyceride levels, and poor sleep quality in late pregnancy had a negative effect on cord blood triglyceride levels. While pregnant women may regard curtailed sleep duration during pregnancy as normal and a phase to be endured, our findings may motivate more increased efforts aimed at improving maternal sleep during late pregnancy. We recommend that healthcare providers should provide sleep counseling during pregnancy, particularly for pregnant women with short sleep duration and poor sleep quality.

7. Acknowledgments The authors express their gratitude to the children and the families that participated in this study.

8. funding The study was supported by the Chinese National Natural Science Foundation (81773443, 81728017,

81602868,

81601162);

Ministry

17

of

Science

and

Technology

of

China

(2016YFC1305203);

Science

and

Technology

Commission

(17XD1402800, 1741965300, 19QA1405800, 19411968800).

18

Shanghai

Municipality

9.

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24

Table1 Characteristics of 177 mother-child pairs in the cohort. Characteristic

N

% or Mean (SD)

177

29.47(3.27)

High school or below

15

8.5

College

133

75.1

Undergraduate and above

29

16.4

Nullipara

163

92.1%

Maternal factors Age at delivery(years) Education level

BMI before pregnancy(kg/m2) 2

<18.5kg/m

20.52(2.50) 36

20.3

110

62.1

31

17.5 16.42(4.32)

Inadequate

18

10.3

Adequate

75

42.9

82 85 92 177 177 177 177

46.9 7.03(1.10) 48.0 52.0 72.54(9.66) 46.78(36.00) 21.62(9.98) 3:34(0:53)

Boy

83

46.9

Girl

94

53.1

Vaginal

79

44.6

Cesarean

98

55.4

2

18.5-23kg/m

≥23kg/m2 Gestational weight gain (GWG)(kg)

Excessive Night sleep time (NST)(h) NST<7h NST≥7h Sleep efficiency (SE) (%) Sleep onset latency(SOL) WASO/NST(%) Midpoint of sleep (MSF) Newborn factors Gender

Delivery type

Gestational age(weeks)

177

39.77(0.98)

a

176

3372.13(375.20)

Birth weight for gestational age (BW/GA)

Birth weight(grams)

176

-0.18(0.78)

b

176

4.78(13.96)

Triglyceride(TG)（mmol/l）

175

0.43(0.49)

Total cholestenone (TC) (mmol/l)

175

1.87(0.48)

High-density lipoprotein cholestenone (HDL-C) (mmol/l)

175

1.00(0.29)

Leptin(ng/ml)

0.71(0.29) Low-density lipoprotein cholestenone (LDL-C) (mmol/l) 175 The range of birthweight was 2545g to 5080g, and there were only 6 infants whose birthweight was higher than 4000g. b Value was expressed as median (range) a

Table2 The correlation between maternal sleep and newborns’ leptin, lipids levels and birth weight.

Leptin a

TG

TC

HDL-C

LDL-C

Birth weight

r(p)

r(p)

r(p)

r(p)

r(p)

r(p)

NST

0.173(0.022)*

-0.202(0.007)*

0.043(0.568)

0.047(0.539)

0.074(0.332)

0.009(0.904)

SE

0.040(0.597)

-0.193(0.011)*

0.011(0.882)

0.064(0.397)

-0.003(0.974)

-0.080(0.291)

SOL

-0.015（0.846）

0.092（0.226）

-0.042（0.581）

-0.052（0.493）

-0.018（0.815）

0.032（0.672）

WASO/NST

-0.014（0.854）

0.008（0.911）

-0.018（0.816）

-0.040（0.601）

0.001（0.986）

0.140（0.064）

MSF

0.065(0.388)

0.036(0.633)

-0.020(0.791)

-0.070(0.357)

0.066(0.387)

0.014(0.852)

a

data was log transformed when entered into statistical analyses;

NST, night sleep time; SE, sleep efficiency; SOL，sleep onset latency; WASO/NST, the percentage of wake after sleep onset in night sleep time; MSF, midpoint of sleep; TG, triglyceride; TC, total cholesterol; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol. *p＜0.05

Table 3 Multiple regression analysis of the associations between maternal sleep and leptin and triglyceride levels in umbilical cord blood.

leptin a

triglyceride

β

（95%CI）

p

β

（95%CI）

p

Unadjusted

0.177

(0.009，0.099)

0.019*

-0.203

(-0.155, -0.024)

0.007*

Adjustedb

0.146

(0.001, 0.089)

0.047*

-0.219

(-0.165, -0.029)

0.006*

Unadjusted

0.043

(-0.004, 0.007)

0.570

-0.193

(-0.017, -0.002)

0.011*

Adjustedb

0.004

(-0.005, 0.005)

0.997

-0.224

(-0.019, -0.003)

0.006*

Model covariate

NST

SE

a

data was log transformed when entered into statistical analyses;

NST, night sleep time; SE, sleep efficiency; b

model was adjusted for maternal age at delivery, parity, maternal education level, delivery type,

maternal BMI before pregnancy, infant’s gender and BW/GA. *

p＜0.05

Highlight Pregnant women in late pregnancy are subjective to short sleep duration（<7 h, with the prevalence of about 48%. Short sleep duration and fragment sleep were both associated with leptin and triglyceride levels in umbilical cord blood. Efforts aimed at improving maternal sleep during late pregnancy should be advocated for children’s health.

NA