Hypertension in neonates is increasingly recognized as a result of advances in our ability to identify, evaluate, and care for premature infants. Normative data on normal blood pressure (BP) in term and preterm infants remain limited, although a variety of factors are clearly important, including birth weight, gestational age, and postmenstrual age. A focused evaluation will usually lead to identification of the cause of hypertension in an affected neonate; thromboembolism, kidney diseases, and chronic lung disease will account for most cases. Individual clinical judgment must be relied upon to decide on the most appropriate approach to treatment, with some infants needing either intravenous or oral antihypertensive medications. Outcome is usually good, although few long-term data are available. Areas for further research include development of large-scale normative data, generation of evidence-based treatment recommendations, and better information on long-term outcome.
Keywordsinfant, prematurity, kidney disease, chronic lung disease, thromboembolism, renovascular hypertension, congestive heart failure, calcium channel blockers, angiotensin converting enzyme inhibitors
Normative Values for Neonatal Blood Pressure
First described in the 1970s, awareness of neonatal hypertension has increased over the past several decades. However, there is still uncertainty over which neonates require treatment for hypertension primarily because of conflicting data on normative blood pressure values in neonates. This chapter reviews the existing data on normal neonatal blood pressure and presents a reasonable approach to evaluation and management based upon likely causes and pathophysiology. Finally, research needs, especially those related to late-onset hypertension and long-term outcome, are reviewed.
Normative Values for Neonatal Blood Pressure
Factors Affecting Blood Pressure at Birth
There are many complexities to the changing patterns of blood pressure (BP) in the newborn period. Infant characteristics such as gestational age at birth, postnatal and postmenstrual (formerly termed postconceptual [AAP 2004]) age, as well as appropriateness of size for gestational age all influence BP. Maternal illnesses such as diabetes and other prenatal factors may also affect BP levels following delivery. As in older children, BP values in neonates may vary according to the method of BP assessment (e.g., intraarterial, Doppler, oscillometric) and according to the infant’s state (e.g., sleeping, crying, feeding). All these factors need to be taken into account when reviewing the literature on BP standards as well as in clinical practice. Despite the fact that neonatal BPs have been measured for decades, we are still in the early phase of identifying the normal patterns of infant BPs, and there are still many physiologic changes that need further investigation.
Data on BP on the first day of life was published in 1995 by Zubrow and coworkers. From data on 329 infants on day 1 of life, they were able to define the mean plus upper and lower 95% confidence limits for BP; their data clearly demonstrated increases in BP with increasing gestational age and birth weight ( Fig. 16.1A and B ). A more recent study by Pejovic and coworkers, limiting their analysis to hemodynamically stable premature and term infants admitted to the neonatal intensive care unit (NICU), also showed that BPs on day 1 of life correlated with gestational age and birth weight. Healthy term infants do not seem to demonstrate this same pattern.
After the first day of life, it appears that BPs in premature newborns increase more rapidly over the first week or two of life followed by a slowing of the rate of increase. The previously mentioned Philadelphia study categorized over 600 infants in the NICU into gestational age groups and showed a similar rate of BP increase over the first 5 days of life, regardless of gestational age. The more recent study by Pejovic and colleagues on stable NICU infants showed a similar pattern with BPs in each gestational age category of premature infants increasing at a faster rate over the first week of life with subsequent slowing. In these infants, they determined that the rate of rise was more rapid in the preterm than full-term infants ( Fig. 16.2 ). As premature neonates mature, the strongest predictor of BP is postmenstrual age. Fig. 16.3 from Zubrow and coworkers shows the regression lines between postmenstrual age and systolic and diastolic BP along with the upper and lower 95th confidence limits for systolic and diastolic BP for each week of postmenstrual age.
In term infants, appropriateness for gestational age seems to be an important influence on BP. In an Australian study of healthy term infants, BPs were higher on day 2 of life compared to day 1 but not thereafter. In addition, a correlation between birth weight and BP on day 3 of life was recently demonstrated in a large Japanese study of term infants ; this study also showed an increase in BP from days 2 through 4 of life, which is consistent with studies mentioned previously. A Spanish study demonstrated that small for gestational age infants had the lowest BP at birth but subsequently had the fastest rate of rise, so by 1 month of age, all term infants had similar BPs. Genetic factors likely also play a role in determining BP, although only limited studies have been completed to date. One study identified the cytochrome P450 (CYP2D6) CC genotype as being associated with higher BPs in preterm infants during hospitalization and at neonatal follow-up. It is likely that additional genetic mutations with an effect on neonatal BP will be identified in the future.
Maternal factors, including medications, underlying illnesses, and adequacy of nutrition during pregnancy, can also influence a neonate’s BP. Higher infant BPs have correlated with maternal body mass index greater than 30 kg/m 2 and low socioeconomic status in Nigerian infants and in an Australian study to premature infants born to mothers with diabetes or neonates with abnormal uteroplacental perfusion by placental pathology. There is some suggestion in the literature that chorioamnionitis and HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome may be related to lower infant BPs. While these factors may not have caused hypotension or hypertension by definition in all infants, it is clear that many antenatal and postnatal processes combine to influence BP values in the newborn period.
Normal BPs in infants older than 1 month have not been extensively studied recently. The percentile curves reported by the Second Task Force of the National High Blood Pressure Education Program (NHBPEP) ( Fig. 16.4 ) remain the most widely available reference values. These curves allow BP to be characterized as normal or elevated not only by age and gender, but also by length (provided in the legend below the curves). Unfortunately, these BP values were determined by a single measurement on awake infants by the Doppler method, which reduced the number of diastolic BP readings by more than half. Comparison with the more recently published values for 1-year-olds in the Fourth Report from the NHBPEP reveals significant differences that further question the validity of the 1987 curves. Additionally, a recent study of 406 healthy term infants with BPs measured by the oscillometric method on day 2 of life and then at 6 and 12 months of age demonstrated BPs that are slightly higher than the Task Force values. These issues highlight that there is clearly a pressing need for new normative BP data on infants during the first year of life.
What Level of BP Should Be Considered Hypertensive?
In older children, the definition of hypertension is persistent systolic and/or diastolic BP equal to or greater than the 95th percentile for age, gender, and height. As can be deduced from the preceding discussion, there is considerable variation in neonatal BP, and no generally agreed upon reference values are available. For term infants and infants between 1 and 12 months of age, the best available reference data would be those from the Second Task Force Report (see Fig. 16.4 ). In this age group, the diagnosis of hypertension is made if the infant’s BP is repeatedly greater than or equal to the 95th percentile for an infant of comparable age (also note that weight and length are given below the curves, and could also be used to help determine if an infant’s BP is normal or elevated).
The major unresolved question is what BP values to use in diagnosing hypertension in preterm infants. From the limited published data, it is possible to derive systolic and diastolic BP percentiles, as well as mean arterial pressure percentiles according to postmenstrual age ( Table 16.1 ). Although not derived from a large-scale study (which is sorely needed), these values may be useful clinically. Specifically, infants with BP values persistently at or above the 95th percentile may warrant closer monitoring, and those with BP values above the 99th percentile would clearly merit investigation, and possibly initiation of antihypertensive drug therapy. Although it is tempting to use these values to diagnose hypertension in a similar manner as in older infants and children, such decisions need to be tempered by clinical circumstances and personal experience.
|Postconceptual Age||50th Percentile||95th Percentile||99th Percentile|
Hypertension is so unusual in otherwise healthy term infants that routine BP determination is not advocated for this group. For preterm and otherwise high-risk newborns admitted to modern NICUs, reported incidences of hypertension range from 0.2% to 3%. In an Australian study of approximately 2500 infants followed for over 4 years, the prevalence of hypertension was 1.3%. Antenatal steroids, maternal hypertension, umbilical arterial catheter placement, postnatal acute renal failure, and chronic lung disease were among the most common concurrent conditions in babies with elevated BP. A more recent single-center case series from Texas demonstrated a nearly identical incidence of hypertension, although the focus was on treated patients. Prenatal factors such as antenatal steroid administration, maternal hypertension, and maternal substance abuse were associated with the diagnosis of hypertension in that study.
Larger, multicenter studies examining neonatal hypertension have been rare. An incidence of around 1% was found in a study using administrative data from a consortium of pediatric hospitals. The most common factors associated with hypertension in that study were extracorporeal membrane oxygenation (ECMO) treatment and either congenital or acquired renal disease.
Hypertension may also be detected long after discharge from the NICU. In a retrospective review of over 650 infants seen in follow-up after discharge from a tertiary level NICU, Friedman and Hustead found an incidence of hypertension (defined as a systolic BP of greater than 113 mm Hg on three consecutive visits over 6 weeks) of 2.6%. Hypertension in this study was detected at a mean age of approximately 2 months postterm when corrected for prematurity. Infants in this study who developed hypertension tended to have lower initial Apgar scores and slightly longer NICU stays than infants who remained normotensive, indicating a somewhat greater likelihood of developing hypertension in sicker babies. Unfortunately, this study has not been replicated, so the current prevalence of hypertension in high-risk infants remains unclear. However, these data do support routine BP monitoring following NICU discharge, as advocated by the NHBPEP.
In older infants and children, the potential causes of hypertension in neonates are numerous ( Table 16.2 ), with the largest number of cases probably accounted for by umbilical artery catheter-associated thromboembolism affecting either the aorta and/or the renal arteries. This was first demonstrated in the early 1970s by Neal and colleagues and later confirmed by other investigators. Hypertension was reported to develop in infants who had undergone umbilical arterial catheterization even when thrombi were unable to be demonstrated in the renal arteries. Reported rates of thrombus formation have generally been about 25%.
Renal Parenchymal Disease