OBJECTIVE. Preterm infants are at an increased risk of sudden infant death syndrome, which may result from immature autonomic control of heart rate and blood pressure. Previous studies have demonstrated that preterm infants have altered heart rate and blood pressure control at term-equivalent age; however, little information is available beyond this age. The aim of this study was to determine the effect of preterm birth on heart rate and blood pressure control over the first 6 months of life after reaching term-equivalent age, including the age at which sudden infant death syndrome risk is increased, to understand the pathogenesis of sudden infant death syndrome.
METHODS. Preterm (n = 25) and term (n = 20) infants were studied longitudinally at 2 to 4 weeks', 2 to 3 months', and 5 to 6 months' term-corrected age by using daytime polysomnography. A photoplethysmographic cuff (Finometer) around the infant's wrist measured blood pressure during quiet and active sleep.
RESULTS. Blood pressure was lower in the preterm group during both quiet and active sleep at all ages studied. In contrast, there were no differences between groups in heart rate. Within the infants in the preterm group, blood pressure averaged lower at 2 to 3 months' corrected age compared with both 2 to 4 weeks' and 5 to 6 months' corrected age and was lower in quiet sleep compared with active sleep at all ages studied. Heart rate decreased with increasing age and was lower in quiet sleep compared with active sleep at 5 to 6 months' corrected age.
CONCLUSIONS. Sleep state and age affect heart rate and blood pressure patterns in prematurely born infants over the first 6 months of term-corrected age. It is notable that preterm infants had persistently lower blood pressure compared with age-matched term infants, signifying long-term alterations in cardiovascular control in infants born prematurely.
Despite a reduction in the incidence of sudden infant death syndrome (SIDS) after worldwide publicity of the factors that increase infant risk, SIDS remains one of the leading causes of postnatal infant mortality in western countries. Prematurely born infants are at significantly increased risk for SIDS, with ∼20% of SIDS cases being born preterm compared with 8% to 10% in the general population.1 SIDS is presumed to occur during sleep, and it has been shown that >90% of SIDS deaths occur within the first 6 months of life, with a peak incidence between 2 and 4 months.2
It has been suggested that immature cardiovascular control leading to an uncompensated hypotension during sleep may be involved in the fatal SIDS event.3 In support of this hypothesis, studies have identified that future SIDS victims have lower heart rate (HR) variability,4 alterations in sympatho-vagal balance,5 and QT interval prolongation.6,7 Furthermore, SIDS victims have significant abnormalities in serotonergic brainstem pathways responsible for cardiorespiratory control.8
The postneonatal period sees dramatic changes in the maturation of sleep architecture and cardiovascular control, particularly in infants born preterm.9 Sleep state and age have significant effects on HR in both term and preterm infants10–13 and importantly, preterm birth has been demonstrated to result in alterations in autonomic control of HR at term-equivalent age.14–17 Previously, it was not possible to noninvasively and continuously record blood pressure (BP) during sleep in infants; however, new technology now allows this.18 Recently, we demonstrated in healthy term infants that BP was also significantly altered by sleep state and importantly, that there was a fall in BP at 2 to 3 months of age, the age when the SIDS risk is highest.13 To our knowledge, there have been no studies examining the maturation of both HR and BP during sleep in preterm infants after term-corrected age (CA), and this study aimed to address this current lack of knowledge. We hypothesized that prematurely born infants would exhibit altered BP and HR patterns during sleep when compared with age-matched term-born infants.
Ethical approval for this project was obtained from the Southern Health and Monash University Human Research Ethics Committees. Written parental consent was obtained before commencement of the study, and no monetary incentive was provided for participation.
Twenty-five preterm infants (14 girls, 11 boys) born at 28 to 32 weeks' gestational age (GA) with birth weights ranging from 600 to 2061 g (mean: 1268 ± 64 g, mean ± SEM), and Apgar scores of 5 to 9 (median 8) at 5 minutes were studied. Twenty-two preterm infants were of appropriate birth weight for GA, and 3 infants were small for GA. All preterm infants routinely slept supine at home and all were born to nonsmoking mothers. One infant had moderate bronchopulmonary dysplasia during hospitalization, as defined by clinical criteria.19 None of the infants had congenital abnormalities and on discharge, all infants had normal cranial ultrasounds and no significant cardiorespiratory or other medical problems.
Twenty term infants (12 girls, 8 boys) served as controls. These infants were born at 38 to 42 weeks' GA, with normal birth weights ranging from 2970 to 4250 g (mean: 3590 ± 100 g) and Apgar scores of 9 to 10 (median: 9) at 5 minutes. All infants routinely slept supine at home, and all were born to nonsmoking mothers. In addition, each infant was of appropriate birth weight for GA and had no congenital abnormalities.
Each infant was studied longitudinally by using daytime polysomnography at 2 to 4 weeks', 2 to 3 months', and 5 to 6 months' CA. In the preterm group, 3 of the 25 infants were studied only at 2 to 4 weeks' CA. The results of the effects of sleep state and postnatal age on cardiovascular variables in the term infants have been previously reported.13
Polysomnography and BP Measurement
During the routine morning feed, electrodes required for recording physiologic variables were attached. Electroencephalogram, electrooculogram, electrocardiogram, submental electromyogram, thoracic and abdominal breathing movements (Resp-ez Piezo-electric sensor [EPM Systems, Midlothian, VA]), arterial blood oxygen saturation (Spo2) (Biox 3700e Pulse Oximeter [Ohmeda, Louisville, CO]), and abdominal skin temperature (YSI 400 series thermistor [Yellow Springs Instruments, Yellow Springs, OH]) were recorded by using a polygraph (Grass Instrument Co, Quincy, MA). Sleep state was defined as quiet sleep (QS), active sleep (AS), or indeterminate sleep by using electroencephalogram, HR, breathing pattern, and behavioral criteria.20 Data obtained during indeterminate sleep were excluded from analysis.
BP was measured by using a noninvasive photoplethysmographic cuff (Finometer [Finapres Medical Systems, Amsterdam, Netherlands]) placed around the infant's wrist, a method previously validated in preterm infants18 and used in term-born infants by our group.13,21
Infants slept naturally in the supine position, under dim lighting and constant room temperature (22–23°C) and were closely monitored to ensure there were no changes in behavior, sleep state, or HR induced by BP cuff inflation. Once the infant was in stable sleep, BP measurements were made in 1- to 2-minute epochs for the duration of each sleep cycle, with 5 to 8 minutes being recorded in each infant for each sleep state.
Beat to beat mean (MAP), systolic (SAP), and diastolic (DAP) arterial pressure and HR values were obtained. Movement artifacts that disrupted the physiologic signals and BP values that lay 1.5 times the interquartile range outside of the first and third quartiles were removed from subsequent analyses.13 For each infant, mean BP and HR values were calculated for QS and AS, and data were pooled for each study for comparison. In the preterm group, data were analyzed both including and excluding the infant with moderate bronchopulmonary dysplasia and those infants born small for GA. As the statistical outcomes were similar in all aspects, these infants were retained in the final data set.
Statistical analysis was performed by using SigmaStat (Systat Software Inc, Richmond, CA). Within the preterm group, the effects of sleep state were compared by using a paired Student's t test at each of the 3 ages studied, and the effects of age were compared for the 22 infants studied at all 3 ages by using 2-way repeated measures analysis of variance with Student-Newman Keuls posthoc analysis. The effects of sleep state were compared between term and preterm infants at each age using a 2-way analysis of variance with Student–Newman-Keuls posthoc analysis. Regression analysis was performed to assess the relationship between weight and BP at each age in each sleep state. Results are presented as mean ± SEM, with significance taken at the P < .05 level.
Effects of Sleep State in Preterm Infants
The effects of sleep state on HR and BP in preterm infants are presented in Table 1. Sleep state had no effect on HR at either 2 to 4 weeks' or 2 to 3 months' CA. However, at 5 to 6 months' CA, HR was significantly lower in QS compared with AS (P < .001). Sleep state also had a significant effect on BP, with MAP, SAP, and DAP all being significantly lower in QS compared with AS, at all ages studied (P < .001).
Effects of Age in Preterm Infants
The effects of age on HR in preterm infants are presented in Fig 1. HR significantly decreased with age during both QS and AS, from 2 to 4 weeks' to 2 to 3 months' CA (P < .001); from 2 to 4 weeks' to 5 to 6 months' CA (P < .001); and in QS from 2 to 3 months' to 5 to 6 months' CA (P < .01). Overall, MAP (Fig 2A), SAP (Fig 2B), and DAP (Fig 2C) were consistently lower at 2 to 3 months' CA compared with both 2 to 4 weeks' and 5 to 6 months' CA, with a significant interaction between age and sleep state for each of the 3 pressure measurements (repeated measures analysis of variance; P < .05). Specific differences were identified by posthoc analysis; during AS, SAP averaged 11 mmHg lower at 2 to 3 months' compared with 2 to 4 weeks' CA (P < .05); during QS, DAP also averaged 9 mmHg lower at 2 to 3 months' compared with 5 to 6 months' CA (P < .05); and during AS, MAP averaged lower by 9 mmHg (P < .05) at 2 to 3 months' compared with 2 to 4 weeks' CA.
Effects of Preterm Birth
There were no differences in HR during either QS or AS between preterm and term groups, at any of the 3 ages studied (Fig 3). In contrast, average BP was lower in preterm infants compared with term infants as identified by analysis of variance (P < .05), with the exception of SAP at 2 to 4 weeks' and 5 to 6 months' CA (Fig 4). Posthoc analysis identified MAP to be significantly lower in the preterm compared with the term group during both QS and AS at 2 to 3 months' CA (P < .05; Fig 4A). SAP also averaged less in the preterm group compared with the term group at 2 to 3 months' CA (P < .05); however, the differences were too marginal to isolate the conditions that differed by using a posthoc multiple comparison procedure. Posthoc analysis identified DAP to be significantly lower in the preterm group during QS at 2 to 4 weeks' and 2 to 3 months' CA (P < .05). During AS, DAP was also significantly lower in the preterm group at 2 to 3 months' and 5 to 6 months' CA (P < .05).
Demographics and Sleep Characteristics
Preterm infants weighed significantly less than term infants (P < .05) at all ages studied: 2 to 4 weeks' (preterm: 3218 ± 107 g; term: 3847 ± 66 g), 2 to 3 months' (preterm: 4604 ± 178 g; term: 5223 ± 145 g), and 5 to 6 months' CA (preterm: 6295 ± 183 g; term: 7000 ± 191 g). At each age studied, linear regression analyses comparing weight and MAP, SAP, and DAP in each sleep state demonstrated low correlation coefficients for each of the comparisons made, and overall there was no relationship identified between BP and weight in either preterm or term infants.
The effects of sleep state and age on sleep epoch length for both preterm and term infants are presented in Table 2. There was no effect of sleep state on epoch length at 2 to 4 weeks' CA in either preterm or term infants. In contrast, epoch length was longer during QS compared with AS at both 2 to 3 months' and 5 to 6 months' CA in both preterm and term infants (P < .01). Age had a significant effect on epoch length only in preterm infants with epoch length significantly decreasing with increasing age during AS from 2 to 4 weeks' to 5 to 6 months' CA (P < .001) and from 2 to 3 months' to 5 to 6 months' CA (P < .05), and during QS from 2 to 4 weeks' to 2 to 3 months' CA (P < .05). There were no significant differences in epoch length in either sleep state between preterm and term groups.
The effects of sleep state and age for both preterm and term infants on the physiologic variables recorded are presented in Table 3. There were no significant effects of sleep state or age on abdominal skin temperature or Spo2 in the preterm group at any age studied. In the term group, Spo2 increased with age during both QS and AS (P < .05). Respiratory rate in the term group was significantly higher in AS compared with QS, and with increasing age respiratory rate fell in both preterm and term groups in both sleep states from 2 to 4 weeks' to 5 to 6 months' CA (P < .001) and from 2 to 3 months' to 5 to 6 months' CA (P < .01).
Comparison between groups identified significant differences in the physiologic variables recorded. Temperature at 2 to 3 months' CA was higher in AS in the preterm group compared with the term group (P < .05); however, this was only by 0.7°C. Spo2 was higher in the preterm group during QS at 2 to 4 weeks' and during AS at 2 to 3 months' CA (P < .05), but again the differences were small (1.7% and 0.7%, respectively). Respiratory rate during AS at both 2 to 4 weeks' and 2 to 3 months' CA was significantly lower in the preterm compared with the term group by 7 and 6 breaths/min, respectively (P < .05), because of the preterm group having a greater frequency of apneas and periodic breathing at these ages.
This is the first study to provide normative data on both HR and BP during sleep in preterm-born infants across the first 6 months of CA. We used new technology to measure BP continuously during sleep and found significant alterations related to both sleep state and age in preterm infants. As we have previously reported in term-born infants,13 BP was significantly higher in AS compared with QS across the first 6 months of CA. Notably, at 2 to 3 months' CA, BP was lower than at both 2 to 4 weeks' and 5 to 6 months' CA. Importantly, we also identified that although HR was similar, preterm-born infants have lower BP when compared with term-born infants at matched ages, and that this difference in BP persists until 6 months' CA.
Effects of Sleep State in Preterm Infants
As previously reported in both preterm22 and term infants,10,13,23 we found no significant effect of sleep state on HR at 2 to 4 weeks' and 2 to 3 months' CA. This is in contrast to other studies of term infants, which have identified sleep-state related differences in HR from as early as 2 to 4 weeks of age.12,24 In all studies these sleep state related differences were small and similar to those observed in the current study. Furthermore, as previously identified in term infants,10,12,13,23 we identified a significant sleep state related difference in HR at 5 to 6 months' CA, in which HR was lower in QS compared with AS, suggesting the mechanisms controlling HR during sleep are similar in both preterm and term infants.
In contrast to the HR findings, we found that sleep state had a marked effect on BP, which was significantly lower in QS compared with AS at all ages studied. To our knowledge, this is the first study of BP during sleep in preterm infants. We have previously reported a similar sleep state difference in term infants.13 In adult rapid eye movement sleep and in AS in term infants, HR and BP are higher than in QS (non–rapid eye movement sleep) because of a predominance of sympathetic activity in this sleep state13,25,26; thus it seems that the sympathetic nervous system also predominates during AS in preterm infants.
Effects of Age in Preterm Infants
As has previously been reported in both term and preterm infants,10,11,13,22 we found a significant effect of age on HR, with HR falling progressively from 2 to 4 weeks' until 5 to 6 months' CA. These results are consistent with the proposal that the decrease in HR with postnatal age is a result of an increase in parasympathetic dominance of autonomic HR control with maturation.10,11,13,22
Overall, average BP in preterm infants was lower at 2 to 3 months' CA compared with both 2 to 4 weeks' and 5 to 6 months' CA, with significant differences confirmed in MAP, SAP, and DAP. We recently reported a similar lowering of MAP and DAP at 2 to 3 months in term infants,13 a finding supported by a large study of term infants during quiet wakefulness.27 The mechanisms underlying the fall in BP at 2 to 3 months of age remain unknown; however, 2 to 3 months' postnatal age also signifies the period in which there is physiologic anemia in term infants.28,29 Therefore, in term infants at the age when SIDS risk is greatest, low BP in combination with a reduction in oxygen carrying capacity may place infants at greater risk of reduced oxygen delivery to critical organs. In preterm infants, low BP and low hemoglobin are also associated with the peak risk for SIDS. The peak incidence of SIDS in preterm infants occurs somewhat earlier than in term infants, at around 6 to 7 weeks' CA in infants born 28 to 32 weeks' GA,30 as does the exaggerated hemoglobin reduction.28,29 Thus, the window of coincidence with low BP is somewhat broader in preterm than in term infants, possibly because the relatively lower BP of the preterm infants across the first 6 months of CA may extend the period of heightened risk.
Effects of Preterm Birth
Preterm birth has previously been shown to result in alterations in autonomic control of HR, with these infants exhibiting higher HR,14 reduced HR variability,15,16 and immature baroreflex control of HR17 at term-equivalent age. This study adds to our knowledge of cardiovascular function during sleep in preterm infants and provides novel evidence that preterm birth has a marked effect on BP during sleep, which persists across the first 6 months after CA.
As has been previously identified at 2 to 3 weeks' and 2 to 3 months' CA,22 we found there were no differences in HR between preterm and term infants at any age studied; nor were there differences in abdominal skin temperature, which would have signified peripheral dilatation. Notwithstanding these similarities, preterm-born infants have lower BP when compared with term-born infants at matched ages. Our data are consistent with the single previous study comparing preterm and term infant BP, which demonstrated that SAP in preterm infants reaching term was 11 to 14 mmHg lower than term infants.31 In the same study, however, no significant differences were observed between infants at 4 months of age, possibly because of the study being conducted during wakefulness, when BP is known to be increased when compared with sleep.31 Our examination during sleep identified that on average, MAP in preterm infants was 6 to 10 mmHg lower than in term infants, with the greatest difference being in QS at 2 to 3 months' CA.
We also identified that preterm-born infants consistently weighed ∼600 g less than term-born infants at each age studied; however, we did not find any relationship between weight and BP in the preterm or term group. It has been well documented that children and adolescents born preterm exhibit deficits in weight and height when compared with term-born controls.32,33 Previous studies have demonstrated a positive correlation between weight and BP in term infants between 4 days to 12 months of age34 and 7 days to 4 months' CA in preterm and term infants.31 However, it should be noted that the reported correlation coefficients were very low, with the highest correlation coefficient (r = 0.28) identified for SAP at 4 months' CA.31 Although the relationship between weight and BP often forms the basis of clinical assessment of preterm infants undergoing intensive care, it is difficult to compare our study with those conducted previously, because these studies made no allowance for infant sleep state31,34 or preterm birth,31 each of which had a significant effect on BP in our study.
Because HR remained unaffected by preterm birth, altered vascular regulation rather than altered cardiac function may underpin the lower BP of preterm compared with term infants. Moreover, additional impairment of vascular regulation in preterm infants seems to be indicated by the nadir in BP at 2 to 3 months' CA. It has been suggested that the fatal SIDS event may involve an uncompensated hypotension, resulting from immature cardiovascular control.3,35 In support of this hypothesis, SIDS victims have been found to have alterations in sympatho-vagal balance already evident at 2 months of age5 and in medullary serotonin signaling pathways responsible for control of the cardiovascular system.8 These findings suggest that impaired BP control in preterm infants may play a role in the increased risk for SIDS observed in this group.
Several investigators have identified that preterm birth has persisting effects on the cardiovascular system, well beyond the 6-month period studied here. Highlighting the long-lasting effects that preterm birth can have on the cardiovascular system; children, adolescents, and adults born preterm have higher BP and increased vascular resistance when compared with term-born controls.36–39 Additional investigation is needed to identify the exact mechanisms that give rise to the low BP of preterm infants in infancy and the later expression of hypertension in children, adolescents, and adults.
We acknowledge that there are limitations to our study. First, although we had selected the age range of our preterm group (28–32 weeks' GA) to exclude infants born extremely preterm, a number of infants had a history of pathologies requiring cardiorespiratory treatments soon after birth. However, despite the heterogeneity of the group, all infants had normal cranial ultrasounds, and none had significant cardiorespiratory sequelae or other medical problems at discharge or at the time of study. Second, 3 of the 25 infants studied were born small for GA. Because several studies have reported no significant differences in autonomic control of HR or BP in infants and children born preterm and small for GA compared with those born preterm and appropriate for GA,39–41 and our statistical analyses also identified no differences, we elected to include these infants in our analyses. Third, in this study we matched term and preterm infants for conceptual age, and we acknowledge that in preterm infants the period of peak SIDS risk occurs at an earlier CA than the 2 to 3 months age studied here, thus future studies should account for this.
This study has provided normative data on BP and HR patterns during sleep in preterm-born infants. We identified significant differences in BP between preterm and term infants that may contribute to the increased risk of SIDS in preterm infants. Additional studies examining baroreflex responses and cardiovascular variability during sleep are required to further understand whether preterm infants have impaired cardiovascular control during the early postnatal period. These studies may further explain the mechanisms involved in the increased risk for SIDS associated with preterm birth and the impact that this may have on the cardiovascular system later in life.
This project was supported by the National Health and Medical Research Council of Australia project 284357.
We thank the parents and infants who participated in this study and the staff of the special care nurseries at Monash Medical Centre and Jessie McPherson Private Hospital.
- Accepted August 31, 2008.
- Address correspondence to Rosemary S.C. Horne, PhD, Ritchie Centre for Baby Health Research, Level 5, Monash Medical Centre, 246 Clayton Rd, Clayton, Victoria 3168, Australia. E-mail:
The authors have indicated they have no financial relationships relevant to this article to disclose.
What's Known on This Subject
BP and HR are altered by sleep state and postnatal age in healthy term infants. Preterm infants have altered control of HR at term-equivalent age.
What This Study Adds
We provide normative data on the effects of sleep state and age on BP and HR in preterm-born infants. Preterm infants have lower BP compared with term infants, which may contribute to the increased risk of sudden infant death syndrome in preterm infants.
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- ↵Paterson D, Trachtenberg F, Thompson E, et al. Multiple serotonergic brainstem abnormalities in Sudden Infant Death Syndrome. JAMA.2006;286 (17):2124– 2132
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- ↵Hack M, Schluchter M, Carter L, Rahman M, Cuttler L, Borawski E. Growth of very low birth weight infants to age 20 years. Pediatrics.2003;112 (1). Available at: www.pediatrics.org/cgi/content/full/112/1/e30
- ↵de Swiet M, Fayers P, Shinebourne E. Systolic blood pressure in a population of infants in the first year of life: the Brompton Study. Pediatrics.1980;65 (5):1028– 1035
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- Copyright © 2008 by the American Academy of Pediatrics