Effect of Position on Sleep, Heart Rate Variability, and QT Interval in Preterm Infants at 1 and 3 Months’ Corrected Age

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Effect of Position on Sleep, Heart Rate Variability, and QT Interval in

Preterm Infants at 1 and 3 Months’ Corrected Age

Ronald L. Ariagno, MD*; Majid Mirmiran, MD*§; Marian M. Adams, MD*; Anna G. Saporito, MS*; Anne M. Dubin, MD‡; and Roger B. Baldwin, MA*

ABSTRACT. Objective. Prone sleeping position has a strong link to sudden infant death syndrome (SIDS), and the “Back to Sleep” campaign has played an important role in reducing SIDS. We tested the hypothesis that the mechanism of the sleep position effect is based on changes in sleep, arousal, heart rate variability (HRV), and the QT interval of the electrocardiogram.

Study Design. We studied 16 premature infants lon-gitudinally, at 1 and 3 months’ corrected age. Video-somnography recordings were made during the infants’ normal daytime naps. Each infant was recorded in both supine and prone positions. The recordings were ana-lyzed in 30-second epochs, which were classified as awake, active sleep (AS), quiet sleep (QS), or indetermi-nate sleep. Electrocardiogram data were sampled with an accuracy of 1 millisecond. Time domain analysis of HRV was measured by standard deviation of all R-R intervals and by the square root of the mean of the sum of the squares of the differences between adjacent R-R inter-vals. Frequency domain analysis was done for low fre-quency (0.04 – 0.14 Hz) and high frefre-quency (0.15– 0.5 Hz) HRV. We measured QT, JT, and R-R intervals during AS and QS for each position.

Results. We found no significant differences be-tween supine and prone position, either in total sleep time or in percentage of QS. Percentage of AS was sig-nificantly lower in the supine position, but only at 1 month corrected age. The incidence of short, spontane-ous, sleep transitions was significantly higher in supine, also only at 1 month corrected age. Time domain analysis of HRV showed a significantly lower variability in prone, but only during QS. Frequency domain analysis of HRV showed no differences between the 2 sleeping positions. Both QT and JT intervals were significantly longer in prone during QS, but only at 1 month corrected age.

Conclusions. Despite the commonly held belief, prone position did not substantially increase total sleep at these ages. On the other hand, prone sleeping de-creased the number of sleep transitions at 1 month cor-rected age, increased QT and JT intervals, and reduced HRV, thereby potentially increasing the vulnerability for SIDS. This study supports “Back to Sleep” as the posi-tion of choice not only for term but also for preterm infants after discharge home.Pediatrics 2003;111:622– 625;

sleep, QT interval, prone, supine, heart rate variability.

ABBREVIATIONS. SIDS, sudden infant death syndrome; QTc,

corrected QT interval; HRV, heart rate variability; PCA, postcon-ceptual age; W, awake; AS, active sleep; QS, quiet sleep; IS, inde-terminate sleep; ECG, electrocardiogram; SDNN, standard devia-tion of all R-R intervals; RMSSD, mean of the sum of the squares of differences between adjacent R-R; LF, low frequency; HF, high frequency, SD, standard deviation.

S

udden infant death syndrome (SIDS) has been independently associated with both prone sleeping position and prolonged QT interval.1,2 Since the “Back to Sleep” campaign, the frequency of prone sleeping position in the United States has de-creased from ⬎70% to only 24%.3_{The rate of SIDS} has concomitantly decreased by 38%. Despite this, a substantial number of infants continue to be placed in the prone sleeping position. The majority of care-givers, at home or in day care centers, who placed the infants in the prone sleeping position believe that the “infants sleep better that way.”4

There is substantial scientific evidence that the prone sleeping position increases the risk of SIDS, but the mechanism by which positioning and/or sleep states increase this risk has not been elucidated. A prolonged, corrected QT interval (QTc) has been hypothesized as a marker of cardiac electrical insta-bility, therefore increasing the likelihood of a lethal ventricular arrhythmia.2_{Schwartz et al}2_{have shown} significantly longer QTcin SIDS victims. They spec-ulated that prolongation of the QTcinterval may be attributable to developmental alterations in cardiac sympathetic innervation. An alternative possibility is that a prolonged QTcis a marker of a genetic abnor-mality, which predisposes the patient to lethal ar-rhythmias particularly when placed prone.5

Alterna-tively, we hypothesize a lower number of

spontaneous arousals, lower heart rate variability (HRV), and a prolonged QTcduring prone sleep may increase the likelihood for cardiorespiratory failure. In support of this hypothesis, a number of studies showed depressed arousal responses and HRV to external stimuli in prone versus supine in term in-fants.6 – 8

Preterm infants are at much higher risk of SIDS than term infants.9 –11_{The association between prone} sleeping and SIDS seems to be even stronger among low birth weight infants.12 _{Earlier, we had studied} preterm infants at discharge, around 36 weeks’ postconceptual age (PCA). We found fewer arousals and reduced HRV in prone position.13_{In the current} study, we extended the time period of the study to

From the Departments of *Pediatrics and ‡Pediatric Cardiology, Stanford University School of Medicine, Stanford, California; and §Netherlands In-stitute for Brain Research, Amsterdam, the Netherlands.

Received for publication Feb 12, 2002; accepted Jul 1, 2002.

Address correspondence to Ronald L. Ariagno, MD, Department of Pedi-atrics, Stanford University School of Medicine, 750 Welch Rd, Ste 315, Palo Alto, CA 94304. E-mail: [email protected]

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examine the effects of prone sleeping position at a later developmental period, ie, at 1 and 3 months’ corrected age. To better understand the mecha-nism(s) of SIDS, we have tested the hypothesis that sleep position may influence sleep transitions, HRV, and QTc in formerly premature infants at 1 and 3 months’ corrected age.

MATERIALS AND METHODS

Sixteen asymptomatic preterm infants (6 girls and 10 boys) with a mean gestational age of 34.4⫾2.2 weeks (range: 28 –36 weeks) and mean birth weight of 2326⫾493 g (range: 1172–3000 g) were studied longitudinally at 1 and 3 months’ corrected age at home. These infants did not have any medical problems and were not on medications at the time of the study. Each infant was recorded at their usual nap time, between 11 am and 4 pm. Sensors were placed on the infant before feeding and the recording was then started right after the completion of feeding. The initial sleeping position was randomized. After 1 to 1.5 hours of recording, the infant was gently, without awakening, placed in the complemen-tary position.

The protocol was approved by the Human Subjects Institu-tional Review Board at Stanford University. Informed parental consent was obtained before the study.

Polysomnographic recordings were performed with an ambu-latory digital recorder (Embla; Flaga hf. Medical Devices, Reykja-vik, Iceland, 4.5⫻8.3⫻13.3 cm). The following variables were recorded simultaneously: 2 channels electroencephalogram (C4/A1 and C3/A2), an electrocardiogram (lead II); air flow (BreathSensor; Model 976; Nellcor Puritan Bennett Inc, Minneap-olis, MN); thoracic respiratory effort (Crystal Trace Piezo Respi-ratory Effort Belt; Pro-Tech Services Inc, Woodinville, WA); and transcutaneous oxygen saturation and pulse rate (Pulse Oximeter Sensor, Models 8001J & 8008J; Nonin Medical Inc, Minneapolis, MN). All data were stored on hard disk and later analyzed using Somnologica software (Flaga hf. Medical Devices, Reykjavik, Ice-land). Synchronized time-lapse video recordings (Panasonic, model AG6730, Osaka, Japan) were made simultaneously with the digital recordings. The camera framed the infant’s face and upper body for interpretation of sleep behavior (see Goto et al13 _for

further details).

Sleep State Analysis

Each 30-second epoch of the recording was analyzed and clas-sified as Awake (W), Active Sleep (AS), Quiet Sleep (QS), or Indeterminate Sleep (IS) according to criteria in the literature.14

Percentages of each sleep state were calculated relative to the total sleep time in each position for each age. The number of transitions from one state to another was determined for each position. The number of transitions method was chosen rather than spontane-ous arspontane-ousals since, at this time, there is no consensus or univer-sally accepted criteria for defining spontaneous arousal.

Electrocardiogram (ECG) Analysis

ECG data were sampled at an effective accuracy of 1 millisec-ond. Artifacts on ECG traces were identified by visual inspection and periods with artifact were excluded from additional analysis. Somnologica software for HRV analysis was used to examine the data.15_{Time domain analyses included standard deviation of all}

R-R intervals (SDNN) and the square root of the mean of the sum of the squares of differences between adjacent R-R (RMSSD). Frequency domain analyses were done for low frequency (LF; 0.04 – 0.14 Hz) and high frequency (HF; 0.15– 0.5 Hz) HRV. These measurements were based on standard criteria.16_{All artifact-free}

episodes lasting at least 2 minutes during each sleep state, AS and QS, in each position were used for analysis.

An experienced pediatric cardiologist (A.M.D.) randomly se-lected 10 R-R intervals for each position and sleep state and manually measured QT, R-R, and JT intervals during AS and QS for each position.17 _{The JT interval, from the end of the QRS}

complex to the end of the T wave, was measured to account for any interventricular conduction delay.17_{These measures, QT and}

JT, were corrected for heart rate using Bazett’s formula, yielding QTcand JTc. Average QTcs and JTcs for each position and each

sleep state were then obtained. Any periods of apnea ⱖ10 s,

oxygen desaturation⬍90%, or bradycardia⬍80 beats per minute were also recorded.

Statistical Analysis

All values are expressed as mean⫾1 standard deviation (SD). Statistical analyses were done with pairedttests. Significance was accepted atPⱕ.05.

RESULTS

The sleep characteristics of both positions are sum-marized with means and SDs in Table 1. We found no significant differences in total sleeping time and %QS between the supine and prone positions (Table 1). The %AS was significantly lower in supine, but only at 1 month corrected age. The incidence of sleep transitions and %IS were significantly higher in su-pine, but only at 1 month corrected age.

Time domain analysis of the HRV showed signif-icant differences in the sleeping position during QS, but not in AS (Table 2). The RMSSD was significantly greater in the supine position at both 1 and 3 months’ corrected age, whereas the SDNN was significantly higher in the supine position, but only at 1 month corrected age. Frequency domain analysis of HRV, on the other hand, showed no differences between the 2 sleeping positions either in LF or HF except for higher HF during QS in supine at 1 month corrected age (Table 3). QTc and JTc were significantly longer in prone but only at 1 month corrected age (Table 4). No apnea, desaturation, or bradycardia episodes were found in any infant in either sleeping position. TABLE 1. Comparison of Sleep Characteristics Between Prone and Supine Sleep Positions

Variable Prone Supine Pairedt-Test Mean (SD) Mean (SD) PValue

%AS, 1 mo 52.8 (10.9) 27.1 (24.6) ⬍.01 %AS, 3 mo 39.9 (21.7) 35.9 (14.0) NS %QS, 1 mo 42.09 (9.3) 53.4 (23.9) NS %QS, 3 mo 47.8 (26.6) 56.2 (13.6) NS %IS, 1 mo 3.1 (2.6) 6.3 (4.6) ⬍.01

%IS, 3 mo 9 (18.6) 3.6 (3.4) NS

No. transitions, 1 mo 5.9 (4.0) 12.2 (10.1) .05 No. transitions, 3 mo 6.2 (3.8) 5.2 (1.8) NS Total sleep time, 1 mo 89 (24) 70 (42) NS Total sleep time, 3 mo 70 (24) 61 (20) NS

NS indicates not significant.

TABLE 2. Time Domain Analysis of HRV

QS Prone Supine Pairedt-Test

Mean (SD) Mean (SD) PValue

R-R, 1 mo 449 (20) 456 (29) NS

R-R, 3 mo 501 (27) 519 (36) ⬍.01

RMSSD, 1 mo 6.2 (2.3) 7.7 (4.1) .05 RMSSD, 3 mo 13.0 (7.0) 17.3 (6.8) .02 SDNN, 1 mo 10.5 (5.9) 15.1 (8.9) .03 SDNN, 3 mo 19.5 (9.3) 25.8 (10.6) NS

Prone Supine Pairedt-Test

AS Mean (SD) Mean (SD) PValue

R-R, 1 mo 449 (24) 432 (24) NS

R-R, 3 mo 473 (20) 521 (35) NS

RMSSD, 1 mo 8.7 (3.0) 6.0 (1.4) NS RMSSD, 3 mo 11.5 (5.0) 20.7 (11.2) NS SDNN, 1 mo 21 (7.1) 16.7 (4.6) NS SDNN, 3 mo 24.7 (10.3) 32.8 (13.1) NS

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DISCUSSION

At 1 month corrected age, we found a small but significant reduction in %AS in the supine sleeping position; however, this was accompanied by an in-creased %IS and no change in %QS or total sleep time. At 3 months’ corrected age, on the other hand, no significant differences were found between prone and supine sleeping positions. Although prone posi-tion may indeed increase duraposi-tion of QS right after feeding in preterm infants before discharge, there is no significant difference in overall sleep pattern at later age.18,19 _{These results contradict the common} belief that a preterm or term infant may sleep better/ longer when in the prone sleeping position.4,20_Our earlier study of preterm infants before discharge also failed to show any significant effect of position on amount of sleep.18_{The strength of our study is that} each infant served as its own control. Differences between prone and supine in this study could not be attributed to the typical large individual sleep differ-ences in infants. On the other hand, to record the infant in both positions on a single afternoon, we were not able to record each infant for longer than 1 to 1.5 hours in each position. A longer overnight home study was impractical, less acceptable to par-ents, and we wanted to avoid laboratory influences

on sleep pattern of the infant.20 _{Although daytime} naps may not be representative of nighttime sleep, we could not find evidence for substantial changes in amount of sleep based on position. We believe that although SIDS is associated with sleep, the amount of AS or QS per se may not be the determining factor in the occurrence of SIDS.

Prone position, by virtue of centrally increasing arousal threshold and upper airway resistance, may well serve as a potential independent risk factor in SIDS.21_{The decreased number of sleep transitions at} 1 month corrected age in our study supports this hypothesis. Because the tendency of infants to sleep during the day decreases by 3 months’ corrected age (because of the development of circadian rhythms22_), this may have influenced the number of sleep tran-sitions at this age. Investigators recording spontane-ous and evoked arspontane-ousals have shown the influence of sleep state and sleep position in term and preterm infants6,7,23–28_{). Galland et al}25 _{showed lower HRV} in prone versus supine in term infants at 1 and 3 months of age. Franco et al27 _{showed significantly} more intense stimuli were required to induce arousal during REM sleep in prone versus supine. Arousal threshold in response to air-jet stimulation was sig-nificantly higher in prone versus supine both in ac-tive and in quiet sleep.23 _{Skadberg and Markestad}26 found significantly less short arousals in prone ver-sus supine during REM sleep but not during QS.

Time domain analysis of HRV, particularly RMSSD, which is a measure of variability in succes-sive intervals, showed significant reduction of HRV in prone sleeping position both at 1 and 3 months’ corrected age. Both RMSSD and SDNN values dur-ing QS in prone were consistently lower than supine (Table 3). No significant differences in frequency do-main analysis of HRV were found. The reduction in HRV, particularly RMSSD, which is a measure of the degree of parasympathetic influences on heart rate over time, is interesting and is consistent with our earlier studies in preterm infants before discharge.13 Similar results have been reported by other investi-gators in term infants at 1 to 3 months’ corrected age and in preterm infants in the nursery.19,25_Reduction in HRV after cardiac arrest has been considered a potential risk factor for cardiac arrhythmia in adult patients. For the preterm infant, we speculate that a decrease in sleep transitions in combination with reduced autonomic function variability at a critical age could increase the risk for SIDS.29,30

Although the JTcand QTcintervals were within a normal clinical range, statistically significant in-creases were found during QS at 1 month corrected age. JTc and QTc were both shorter at 3 months’ corrected age compared with 1 month. Prolongation of the QTcinterval has been associated with imbal-ances of sympathetic and parasympathetic tone; these imbalances may permit lethal ventricular ar-rhythmias to develop in those patients who are at risk of long QT syndrome.2_{On the other hand, the} QT may not adequately reflect the autonomic state in this patient population. QT prolongation may be ev-ident only if the cellular substrate for prolonged QT syndrome is present. In the light of the provocative TABLE 3. Frequency Domain Analysis of HRV

HF, 1 mo 5.6 (6.0) 9.5 (14.9) .02

HF, 3 mo 35 (37) 49 (44) NS

LF, 1 mo 51 (70) 131 (194) NS

LF, 3 mo 147 (183) 269 (295) NS

LF/HF, 1 mo 9.8 (9.6) 21.4 (28.3) NS LF/HF, 3 mo 6.3 (5.6) 7.8 (9.2) NS HF/LF, 1 mo 0.23 (0.22) 0.14 (0.15) NS HF/LF, 3 mo 0.34 (0.34) 0.34 (0.40) NS

AS Prone Supine Pairedt-Test

HF, 1 mo 16.9 (14.8) 6.2 (4.4) NS

HF, 3 mo 30 (31) 72 (87) NS

LF, 1 mo 221 (168) 116 (70) NS

LF, 3 mo 274 (237) 388 (401) NS

LF/HF, 1 mo 17.1 (12.9) 25.4 (18.2) NS LF/HF, 3 mo 12.67 (13.1) 8.3 (7.2) NS HF/LF, 1 mo 0.10 (0.07) 0.06 (0.04) NS HF/LF, 3 mo 0.13 (0.09) 0.23 (0.22) NS

TABLE 4. QT and JT Intervals Compared With Sleep Position

JTcaverage, 1 mo 0.375 (0.019) 0.367 (0.025) .03

JTcaverage, 3 mo 0.341 (0.019) 0.343 (0.015) NS

QTcaverage, 1 mo 0.451 (0.023) 0.443 (0.025) .03

QTcaverage, 3 mo 0.418 (0.019) 0.422 (0.018) NS

AS Prone Supine Pairedt-Test

JTcaverage, 1 mo 0.364 (0.026) 0.364 (0.022) NS

JTcaverage, 3 mo 0.338 (0.016) 0.337 (0.020) NS

QTcaverage, 1 mo 0.443 (0.030) 0.440 (0.023) NS

QTcaverage, 3 mo 0.417 (0.021) 0.416 (0.021) NS

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results reported by Schwartz,2_{we may expect even} further increase of QT interval during QS in prone sleeping position in patients with long QT syndrome. Although both sleeping position and QT intervals are risk factors for sudden infant death syndrome, they do not appear to be related. Additional study of the relationship between sleeping position and the autonomic nervous system is warranted.

Beneficial influences of prone sleeping position have been found in critically ill preterm infants in the neonatal intensive care unit.31 _{We have found no} clinically significant apnea, oxygen desaturation, or bradycardia in asymptomatic preterm infants before discharge from the hospital13 _{or at 1 and 3 months’} corrected age at home. A recent study of 22 symp-tomatic preterm infants with gestational age ranging from 24 to 30 weeks, recorded at 28 to 36 weeks’ PCA in the neonatal intensive care unit failed to show any beneficial influence of prone position on apnea, bra-dycardia, or desaturation.32_{Keene et al’s data as well} as ours are in support of the statement of the Task Force of the American Academy of Pediatrics on SIDS1 _{for preterm infants. The American Society of} Gastroenterology recently indicated that prone posi-tioning as a therapy for reflux in infants is no longer generally recommended because of the concern for an increase risk for SIDS.33_{There is simply no good} reason to place a healthy infant in the prone sleeping position despite the myths of improved sleep, re-duced choking, and increased cardiorespiratory sta-bility.34

ACKNOWLEDGMENT

This study was supported by a Lucile Packard Children’s Hos-pital, Children’s Health Initiative grant.

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DOI: 10.1542/peds.111.3.622

2003;111;622

Pediatrics

Dubin and Roger B. Baldwin

Ronald L. Ariagno, Majid Mirmiran, Marian M. Adams, Anna G. Saporito, Anne M.

Infants at 1 and 3 Months' Corrected Age

Effect of Position on Sleep, Heart Rate Variability, and QT Interval in Preterm

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