Abstract
OBJECTIVE:
Determine how blood pressure differs in premature infants born small for gestational age (SGA).
DESIGN:
A retrospective study was conducted on inborn infants 24–32 weeks gestation. Mean arterial blood pressure (MAP) was collected and averaged every 12 h for the first 96 h of life. For each time point, the difference MAP in SGA vs. AGA infants was evaluated with t-testing. Linear mixed-effects modeling was performed to model MAP over time accounting for GA, BW, gender, and SGA status.
RESULTS:
356 subjects were evaluated. 52 (14.6%) were SGA. SGA infants were smaller, more likely male, exposed to maternal hypertension, born via caesarian section, and have chronic lung disease and retinopathy of prematurity. MAP in the SGA group more closely matched the MAP of AGA babies of similar GA for the first 24 h of life. Subsequently, SGA infants had lower MAPs more closely resembling their weight-matched counterparts. Mixed modeling showed GA to be significant, p < 0.0001 while BW though still marginally significant had less of an effect, p = 0.049.
CONCLUSION:
SGA infants have blood pressure that is strongly associated with GA in the first 24 hours of life, but then fails to increase at the same rate as their AGA counterparts.
Introduction
Hypotension in the premature infant has been associated with the development of cerebral injury and subsequent neurodevelopmental delays [1–5]. Currently, there is no consensus as to what blood pressure defines hypotension in the preterm infant. The most widely used guideline for the lower limit of blood pressure is a mean arterial blood pressure (MAP) less than the gestational age (GA) in weeks [6–9]. Though it is known that generally blood pressure increases with gestational age and postnatal day, it is unknown how being small for gestation age (SGA) impacts these relationships.
There is vast variation in the definition and treatment practices for hypotension between neonatal intensive care units (NICUs) [10, 11]. Often, a combination blood pressure values with signs of hypoperfusion such as poor capillary refill, decreased urine output and metabolic acidosis are used to initiate therapy. It is important to establish consistent and accurate standardized blood pressures for premature infants as treatment also presents risks. Vasopressor therapy is not without risks, and has been associated impaired cerebral autoregulation, and an increase in the outcomes of intraventricular hemorrhage and death [12, 13].
Patient who are SGA often have already suffered tissue injury secondary to lack of adequate placental circulation in utero [14, 15]. These patients are known to be at higher risk of mortality and morbidities such as necrotizing enterocolitis, respiratory distress syndrome, intraventricular hemorrhage, and developmental delay [16, 17]. The combined effect of blood pressure therapy and SGA status is unknown, but raises concerns of additive injury.
The purpose of this study was to determine how blood pressure in SGA infants compares to their average for GA (AGA) counterparts accounting for GA and birth weight. A better understanding of this relationship will be important in further defining normal blood pressure in this population.
Methods
Study population and data collection
This was a 4-year single center retrospective cohort study conducted between 2008 and 2011 at the University of Maryland Medical Center. The study was approved by the University of Maryland Institutional Review Board. Inborn subjects 24 0/7 and 31 6/7 weeks GA were included. Patients were excluded if their medical records were incomplete, they expired before 24 hours of life or they had major congenital anomalies. Subjects were defined as SGA if birthweight was less than the 10th percentile. Perinatal and neonatal demographic and clinical data were collected from the medical records.
Blood pressure analysis
Blood pressure measurements were collected for the first 96 hours of life in 12 hour epochs. Blood pressures were measured by the oscillometric technique or by indwelling arterial lines. If both measurements were available, only arterial line data was collected. The frequency of blood pressure measurements varied but at a minimum was collected every 4 hours. For each 12 hour increment, the mean, minimum and maximum value for the MAP, systolic and diastolic blood pressures were calculated and recorded.
Although there was no defined blood pressure protocol to treat hypotension, management was initiated in infants with MAP < GA and signs of systemic hypoperfusion, this was likely more variable in SGA infants as there is no set protocol for how to address these patients. If pharmacologic treatment was started, the drug, maximum dose given and the duration of administration were evaluated and recorded. Pharmacologic therapy for hypotension included normal saline boluses, dopamine, and epinephrine, and less commonly dobutamine, vasopressin, and hydrocortisone.
Statistical analysis
SAS 9.3(Cary, NC) was used for all analysis. Differences between SGA and AGA infants were evaluated using T-test and Chi-square analysis for continuous and categorical data respectively. We compared the blood pressures of small for gestational age and appropriate for gestational age infants by both birth weight and gestational age at each epoch using T-test. MAP was modeled for time, GA, birth weight (BW), gender and SGA status using linear mixed-effect modeling to account for repeated measures and within subject clustering. Each 12 hour epoch was included as a categorical variable. A no intercept model was fitted using an unstructured covariance parameterization with maximum likelihood estimations. Any factor that did not show significance p < 0.05 or did not significantly improve the fit of the model using Akaiki’s Information Criterion (AIC) was removed from the model.
Results
Demographic data
A total of 393 neonates between 24 0/7 and 31 6/7 weeks of gestation were admitted the University of Maryland Medical Center NICU during the study period. Of those who were excluded, 18 expired before 24 hours, 10 had congenital anomalies and 9 had incomplete medical records leaving 356 patients for analysis. Fifty-two (14.6%) infants were SGA and 304 (85.4%) were AGA. Sixty-two percent of subjects had blood pressure measured by arterial line transduction. The demographic data for the subjects is shown in Table 1.
Demographic and clinical differences in SGA versus AGA subjects
Demographic and clinical differences in SGA versus AGA subjects
Chronic lung disease was defined as requiring oxygen at 26 weeks post menstrual age of discharge. Patent ductus arteriosus was defined by presence on echocardiogram.
The mean birthweight for SGA infants was significantly lower than the birthweight of AGA infants (p < 0.0001); however, there was no statistical difference in gestational age between SGA and AGA infants. SGA infants were more likely to be male (p < 0.01), be born by cesarean section (p < 0.0001) and had a higher incidence of retinopathy of prematurity (p = 0.03). Mothers of SGA infants were more likely to experience pregnancy induced hypertension (p < 0.0001) but mothers of AGA infants had a higher incidence of chorioamnionitis (p = 0.02).
Average mean arterial blood pressures in the first 96 hours of life by 12 hours epochs are graphically represented in Fig. 1 between SGA and AGA subjects by both gestational age and birthweight categories. We show that in the first 24 hours, there was no difference in blood pressure by gestational age, however, in subsequent time points, we note that SGA subjects are more likely to have lower blood pressure. When comparing the groups by birthweight, we note a difference only within the first 24 hours for subjects <1000 g with SGA subjects having a higher average MAP.
Mean arterial blood pressure over time by GA and BW. Black dashed line represents AGA while gray dotted line represents SGA subjects. Data is blood pressure expressed as means±standard deviation at each time point. a) N = 93 and 15 for AGA and SGA respectively, b) N = 39 and 31 for AGA and SGA respectively, c) N = 96 and 16 for AGA and SGA respectively, d) N = 77 and 12 for AGA and SGA respectively, e) N = 115 and 21 for AGA and SGA respectively, and f) N = 188 and 9 for AGA and SGA respectively* denotes p < 0.05.
We explored models using SGA status, BW, GA, gender, time in 12 hour epochs, and their interaction as factors. The most parsimonious model shown in Table 2 included, GA, BW, time in epochs, and the interaction of SGA and time in epochs. This yielded an AIC of 15819 and a likelihood ratio test with p < 0.0001. Figure 2 depicts blood pressure over time of a 28 week infant with a BW of 1000 g and a 28 week infant with a BW of 600 g using the predictive model.
Blood pressure over time predicted by the model for a 28 week infant with a BW of 1000 g (black solid line) versus a 28 week infant with a BW of 600 g (grey dashed line).
Linear mixed effects modeling of GA, BW, and SGA status over time
Literature reporting standardized blood pressures for infants born prematurely, and especially those born small for their gestational age, remains limited. Defining hypotension in preterm SGA neonates would better allow physicians to know when to initiate management for low blood pressure and avoid unnecessary interventions. In order to describe thresholds for hypotension, it is important to identify what determines blood pressure in this SGA population – size or maturity.
We found that in general, blood pressure increases over the first 96 hours of life in both SGA and AGA premature neonates. This is consistent with previous reports of blood pressure trends over time in premature infants [18–21]. More importantly, in our cohort, GA seems to be the more important determinant of blood pressure in these infants. Regardless of their size at birth, we found that SGA and AGA infants of the same gestational age had similar blood pressures in the first 24 hours of life. In addition, our model showed a more significant effect of GA as compared to birthweight. This finding is inconsistent with an early study showing blood pressure values for SGA infants to be similar to infants of the same birth weight rather than gestational age [22]. Physiologically, however, the hypothalamic-pituitary-adrenal (HPA) axis and myocardium mature with advancing GA [23, 24]. It follows, then, that a more mature infant would have a better ability to maintain and regulate blood pressure than their less mature counterpart regardless of size. This is supported in a more recent study by Aly et al. [25], showing no difference in in blood pressure on the first day of life between AGA and SGA late preterm infants.
Though it seems that maturity plays an important role in blood pressure regulation in the SGA neonate, we acknowledge that their physiology is far more complex. This complexity is underscored by studies of concordant and discordant twins showing that in discordant twins, the larger twin has a significantly higher blood pressure in the first 24 hours, however, they also note that the smaller twin has significantly high blood pressure than infants of a similar size, but younger gestation [26, 27]. These patients are often exposed to insufficient placental blood flow and intrauterine stress which also affects them physiologically. A blunted cortisol response to stress in growth restricted individuals [28, 29] may explain the lower blood pressure we note after the first 24 hours in our SGA cohort when compared to their AGA counterparts of similar gestation. This is likely secondary to down-regulation of the HPA axis due to chronic intrauterine stress exposure. It has also been shown that growth restricted neonates exhibit cardiovascular changes that may affect cardiac function contributing to blood pressure differences beyond simply size and maturity [30]. In addition, it has been shown that SGA infants have a higher total body water content at birth than their AGA counterparts [31, 32]. This may leave SGA patients at higher risk for decreasing circulating blood volume during the diuretic phase which may in part explain the inability of these patients to maintain the same blood pressure trajectory as their AGA counterparts.
It is clear that the growth restricted infant has complex physiology that we are just beginning to understand. Exposure to an adverse intrauterine environment triggers changes that are seen in later childhood and even into adulthood [33–35]. A better understanding of these changes and the natural course of blood pressure over time in this small subset of the population will allow us to tailor blood pressure therapy in a more knowledgeable way. Vasopressor therapy is not without risks which may be amplified in patients who have already been exposed to stress and hypoxia in utero. Here, we offer a model of blood pressure trajectory specifically for SGA infants. Mean arterial pressure in the AGA patient depicted in Fig. 2 follows a similar curve as what has been presented in previous literature which supports the validity of this model [18, 36].
This study, however, is not without limitations. As this study was single center and retrospective in nature, we could not control for practice variability in management of hypotension – management of hypotension especially in those who are SGA can vary from center to center limiting the generalizability of these results. Though we did not control for factors such as vasopressor therapy and PDA status, we did not find significant differences in the prevalence of either between the two groups. We also noted variable frequencies in blood pressure recording with intervals ranging from every 1 to 4 hours. Blood pressures were measured both by oscillometric technique and arterial lines, decreasing the consistency of BP measurements, though this was minimized by not including both measurements it they were available. The use of MAP measurements further minimize this variability as good correlation has been shown between oscillometry and arterial measurements of MAP [37, 38]. In addition, the cause of SGA status may be heterogeneous in nature and could not be controlled for with the current sample size.
In summary, this study identified that blood pressures in SGA neonates are more similar to blood pressures of their AGA counterparts of the same gestational age rather than the same birth weight in the first 24 hours suggesting that gestational age is an indicator of physical maturity and that the more mature an infant is at birth, the higher their blood pressure. Beyond the first 24 hours of life blood pressure becomes more variable with potentially multiple factors contributing to the trajectory, and we offer a model of prediction in the first 96 hours of life.