In newborn and premature infants, systemic hypertension is best defined as systolic and/or diastolic blood pressure that persistently exceeds the mean + 2 standard deviations for infants of similar postconceptual age (388). The graphs published by Zubrow et al. (Appendix G1c) are probably most useful in this regard (387). After one month of age, hypertension is defined as systolic and/or diastolic blood pressure >95th percentile for that infant’s age and gender (380). These normative values can be found in the curves published in the Second Task Force report (657) (Appendix G1d).

As with older children, the diagnosis of hypertension should not be made based on a single reading. If the infant is critically ill and continuous blood pressure monitoring reveals sustained blood pressure elevation over several hours, then hypertension should be diagnosed and appropriate investigation and intervention initiated. For less critically ill infants still in the NICU, a pattern of elevated readings over 1 to 2 days should be sufficient to make the diagnosis of hypertension. For older infants who are being followed as outpatients, then at least three elevated readings should be documented over 1 to 2 weeks before a diagnosis of hypertension is made (380).

Although one recent series found that 28% of infants with BWs less than 1,500 grams had at least one elevated blood pressure documented during their NICU stay (658), the actual incidence of hypertension in neonates is very low, ranging from 0.2% in healthy newborns to between 0.7% and 2.5% in high-risk newborns (659,660,661,662,663). Certain categories of infants are at significantly higher risk, however. For example, hypertension is relatively common in patients with a history of UA catheterization (3%) (664) and those with bronchopulmonary dysplasia (BPD) (as high as 43%) (660). In one series, it also was associated with PDA and intraventricular hemorrhage (663). On the other hand, hypertension is so uncommon in otherwise healthy term infants that routine blood pressure determination is not even recommended (665).

Although numerous conditions are known to cause hypertension in the neonate or older infant (Appendix G1e), a clear etiology can be determined in only approximately one-third of hypertensive newborn infants (661,666). The most important categories of causes of neonatal hypertension include renovascular hypertension, renal disease, and bronchopulmonary dysplasia (388,661).

The most common cause of neonatal renovascular hypertension is aortic or renal thromboembolism related to UA catheterization (664). This was first demonstrated in the 1970’s by Ford and associates (667) and Bauer and associates (668). Hypertension may develop either while the catheter is in place or long after its removal (669) and may be associated with a history of renal failure or hematuria. Associated signs may include ARF in patients with bilateral involvement, hematuria, and loss of femoral pulses and blood flow to the lower extremities in patients with extensive aortic thrombosis.

Although there have been several studies that have examined duration of line placement and line position (“low” vs. “high”) as factors involved in thrombus formation, these data have not been conclusive (670,671,672). Thus, the assumption has been made that the cause of hypertension in such cases is related to thrombus formation at the time of line placement, probably related to disruption of the vascular endothelium of the umbilical artery. Such thrombi may then embolize to the kidneys, causing areas of infarction and increased renin release. A similar phenomenon has been reported in infants with dilatation of the ductus arteriosus (673).

The Cochrane Group has recently attempted to resolve the controversy regarding UA catheter placement (674). They analyzed 11 randomized clinical trials and one study using alternate assignments to compare the incidence of morbidity and mortality for high vs. low catheter tip placement. The placement of a catheter tip was defined as high when located in the descending aorta above the diaphragm and low when placed in the descending aorta above the bifurcation but below the renal arteries. The reviewers concluded that high catheter position causes fewer clinically obvious ischemic complications and possibly decreases the frequency of aortic thrombosis. As far as hypertension was concerned, however, it was concluded that it seems to appear with equal frequency among infants with high or low placement.

Congenital vascular anomalies responsible for neonatal renovascular hypertension include stenosis or hypoplasia
of the renal artery (675,676) and segmental intimal hyperplasia (677). All these conditions may involve the aorta and the renal arteries. Unilateral renovascular stenosis may cause a reversible syndrome characterized by hypokalemic alkalosis, salt-losing syndrome, and hyperechogenicity of the contralateral kidney (678).

Hypertension may rarely result from two types of infiltration of the arterial wall. Idiopathic arterial calcification of infancy is characterized by calcium deposits in all layers of the arteries, including the aorta and the coronary arteries, and in the heart valves (679,680,681 and 682). Some of these deposits may be visible on a plain radiogram. Most cases have been diagnosed at autopsy. Hypertension typically fails to respond to standard antihypertensive medication and to nephrectomy; biphosphonate, calcium antagonists, or PGE1 may be successful (681,683). Galactosialidosis may result in intimal infiltration by sialyloligosaccharides and hyperreninemic hypertension (684).

Other causes of renovascular hypertension include neonatal renal arterial embolism in the absence of UA catheterization (673), intramural hematoma of the renal artery (685), renal venous thrombosis (686), external compression of the renal artery by a hydronephrotic kidney (687), adrenal hemorrhage (688), and urinoma (689). Finally, a neonate with hypertension as a result of an aneurysm of the abdominal aorta was recently reported (690); this fortunately rare condition may present with intractable congestive heart failure.

Many infants with BPD develop hypertension (653,691). This phenomenon was first described in the mid-1980s by Abman and colleagues (653). In a study of 65 infants discharged from a neonatal intensive care unit, the instance of hypertension in infants with BPD was 43%, vs. an incidence of 4.5% in infants without BPD. Investigators were unable to identify a clear cause of hypertension, but postulated that hypoxemia might be involved. Over half of the infants with BPD who developed hypertension did not display it until after discharge from the NICU, highlighting the need for measurement of blood pressure in NICU “graduates,” whether or not they have lung disease (666).

Abman’s findings have been reproduced by other investigators, most recently in 1998 by Alagappan (692), who found that hypertension was twice as common in VLBW infants with BPD compared to the incidence in all VLBW infants. Because all of the hypertensive infants required supplemental oxygen and aminophylline, development of hypertension appeared to be correlated with the severity of pulmonary disease. Anderson and colleagues have demonstrated that the more severe the bronchopulmonary dysplasia (defined as a greater need for diuretics and bronchodilators), the higher the likelihood of the development of increased blood pressure (693).

These observations reinforce the impression that infants with severe BPD are clearly at increased risk and need close monitoring for the development of hypertension. This is especially true in infants who require ongoing treatment with theophylline preparations and/or corticosteroids; as many as 30% of infants receiving dexamethasone for BPD manifest hypertension (694). If severe hypertension develops, the risk of intraventricular hemorrhage, CHF, and renal failure may outweigh the possible beneficial effects of steroids on the lung disease.

Hypertension is a common complication of renal anomalies and diseases such as polycystic kidney disease (PKD) (695), renal hypodysplasia (696), hydronephrosis (697), and interstitial nephritis (661). It is well known that both autosomal dominant and autosomal recessive polycystic kidney disease (PKD) may present in the newborn period with severe nephromegaly and hypertension (695,698,699). With recessive PKD, the median age of onset of hypertension was recently reported to be 16 days (700); the majority of affected infants will be discovered to be hypertensive during the first year of life (698). The most severely affected infants with recessive PKD are at risk for development of congestive heart failure as a result of severe, malignant hypertension. Bilateral nephrectomy may be life saving in such infants.

Although much less common than in PKD, hypertension has also been reported in infants with multicystic dysplastic kidneys (661,701,702). This is somewhat paradoxical, as such kidneys are usually thought to be nonfunctioning. In fact, the case has been made that hypertension in such patients is the result of another coexisting urologic abnormality such as parenchymal scarring (703). Another possible explanation is increased renin production by macrophages within the dysplastic kidney (704).

Renal obstruction may be accompanied by hypertension, even when there is no compression of the renal artery. This has been seen for example in infants with congenital ureteropelvic-junction obstruction (661,663), and sometimes may persist following surgical correction of the obstruction (705). Hypertension has also been described in infants with congenital primary megaureter (706). Ureteral obstruction by other intraabdominal masses may also be accompanied by hypertension. The mechanism of hypertension in such instances is unclear, although the RAS has been implicated (707,708). Finally, unilateral renal hypoplasia may also present with hypertension (696), although this is uncommon.

Hypertension as a result of acquired renal parenchymal disease is less common than that as a result of congenital renal abnormalities. However, severe ATN, interstitial nephritis, or cortical necrosis may be accompanied by significant hypertension (661,663), usually as a result of fluid and sodium overload or hyperreninemia. Hemolytic-uremic syndrome, which has been described in both term and preterm infants (709), is usually also accompanied by hypertension. Such hypertension may be
extremely difficult to control, requiring treatment with multiple agents (709).