Neonatal Hypertension

Etiology

Prematurity plays a significant role in the development of neonatal hypertension, with approximately 75% of affected infants born preterm. Neonates diagnosed with hypertension tend to exhibit greater illness severity, higher neonatal illness scores, and prolonged neonatal intensive care unit (NICU) stays. The most frequent causes of hypertension requiring pharmacologic intervention include respiratory illnesses, eg, bronchopulmonary dysplasia, medications like caffeine and dexamethasone, extracorporeal membrane oxygenation (ECMO), and renal conditions, including parenchymal or renovascular disease, acute tubular necrosis, and renal failure. Additional etiologic factors include neurologic issues (eg, seizures); endocrine or cardiac disorders, particularly coarctation of the aorta or, less commonly, a patent ductus arteriosus; and thromboembolic complications associated with umbilical artery catheterization.[10] 

Among nonrenal contributors, bronchopulmonary dysplasia represents the most significant cause of neonatal hypertension in very low birth weight (VLBW) infants and functions as an independent risk factor. Premature infants with intraventricular hemorrhage may also demonstrate an elevated risk.[11][12] Isolated case reports have described hypertension in term infants with ductal aneurysms. Additional anecdotal causes include adrenal hemorrhage, vitamin D toxicity with renal calcinosis, and exposure to total parenteral nutrition. Rare genetic causes, eg, biallelic loss-of-function mutations in the NPR1 gene, have been linked to isolated neonatal-onset systemic hypertension. Approximately 57% of cases remain without a clearly identifiable cause and are classified as idiopathic (see Image. Neonatal Hypertension Etiologies).[13][14]

Phthalates, particularly di-2-ethylhexyl phthalate (DEHP), are plasticizers used in medical equipment, eg, continuous positive airway pressure (CPAP) devices, endotracheal tubes, IV bags, and tubing. One study identified a possible association between phthalate exposure and idiopathic neonatal hypertension, typically emerging around 40 weeks postmenstrual age. This form presents with low plasma renin activity and responds favorably to spironolactone therapy.[15] The hypothesized mechanism involves the inhibition of 11-beta-hydroxysteroid dehydrogenase 2, leading to the activation of the mineralocorticoid receptor. Researchers at the same center observed a decrease in neonatal hypertension rates, from 7.7% to 1.4%, following the discontinuation of DEHP-containing IV fluids, with a subsequent rise to 10.1% when those fluids were reintroduced. These findings, however, have yet to be independently confirmed.[16]

Epidemiology

The incidence of neonatal hypertension has been reported at 0.2% among term newborns and up to 3% in infants admitted to NICUs.[3][17] This wide variation likely reflects differences in study populations and the definitions of neonatal hypertension applied across studies. Among preterm infants, 1.4% require antihypertensive treatment during their NICU stay, compared to 1% of term infants who receive similar therapy.[11]

In infants diagnosed with bronchopulmonary dysplasia, the incidence of neonatal hypertension ranges from 13% to 43%, underscoring the increased risk in this subgroup. However, the precise prevalence of neonatal hypertension within the broader preterm population has not yet been clearly established.

Pathophysiology

A renovascular mechanism is the most typical pathway and is operative in most conditions leading to neonatal hypertension. Systemic causes that might decrease renal perfusion vary. Catheterization of the umbilical artery causes endothelial cell injury and the formation of thrombi in the renal vessels. The resultant decrease in kidney perfusion activates the renin-angiotensin-aldosterone system (RAS), thus causing hypertension.[18] 

An inability to excrete free water and an increase in serum aldosterone levels have been reported in bronchopulmonary dysplasia, which might contribute to systemic hypertension. An increase in peripheral arterial wall thickness and abnormal vasomotor functions have recently been demonstrated as the etiopathogenesis for neonatal hypertension in infants with bronchopulmonary dysplasia.[12][19]

Infants of diabetic mothers or those with Factor V Leiden mutation may present with renal vein thrombosis and decreased renal perfusion. Neonatal asphyxia may result in renal tubular necrosis, which may be secondary to neonatal hypertension. Neonatal tumors, eg, pheochromocytoma, neuroblastoma, Wilms tumor, and mesoblastic nephroma, can cause neonatal hypertension by compressing the renal vessels or ureters or by producing vasoactive substances, eg, catecholamines. Coarctation of the aorta and patent ductus arteriosus lead to decreased forward blood flow, diminished renal perfusion, and the activation of RAS. Closing abdominal wall defects increases intra-abdominal pressure, which may compress the renal vessels. Hypertension in ECMO is thought to be secondary to the increased stroke volume caused by the increased aortic return from the ECMO pump blood and to be caused by abnormal sodium or water handling in response to the nonpulsatile arterial flow through the infants’ systems.

History and Physical

Clinical History

Neonates with hypertension typically remain asymptomatic, with diagnosis often occurring through routine continuous blood pressure monitoring in the NICU. When symptoms develop, they tend to be nonspecific and varied in nature. Affected infants may exhibit feeding intolerance, weak nipple efforts, irritability, hypotonia, hypertonia, vomiting, apnea, respiratory distress, and oxygen desaturation.

More severe presentations can include tachycardia, congestive heart failure, cardiogenic shock, and seizures. In term or older newborns, hypertension may also be identified during well-child visits or routine vital sign checks in the NICU. Newborns previously discharged from the nursery may return with signs (eg, irritability and failure to thrive).[20]

Physical Examination

A thorough, system-based physical examination plays a critical role in evaluation. A general inspection may reveal dysmorphic features suggestive of genetic syndromes associated with coarctation of the aorta, including Turner syndrome, Williams syndrome, or Noonan syndrome. Detection of a cardiac murmur, along with discrepancies in 4-limb blood pressures and diminished femoral pulses, raises suspicion for aortic coarctation. Signs of congestive heart failure, including tachycardia, murmur, mottling, and cyanosis, may also be present.

Abdominal palpation may uncover a mass associated with polycystic kidney disease, renal tumors, hydronephrosis, or renal vein thrombosis. Genitourinary examination could reveal congenital anomalies or ambiguous genitalia in cases of congenital adrenal hyperplasia. A prenatal history of oligohydramnios may suggest underlying congenital renal anomalies, often accompanied by characteristic physical features in severe cases.

Evaluation

A thorough maternal and perinatal history and physical examination guide in identifying the potential etiology. As renovascular or renal parenchymal disorders account for most cases of neonatal hypertension, the initial investigations focus on this system and include urine analysis, blood urea nitrogen level, and serum values of creatinine, electrolytes, and calcium. The urine should be tested for vanillyl mandelic acid and homovanillic acid. The initial evaluation should include aortic and renal ultrasonography with a Doppler study.[10]

Further investigation depends on the clinical history and the level of clinical suspicion. Recommended laboratory evaluations include:

• Thyroid function tests
• Cortisol levels
• Aldosterone and plasma renin activity
• Plasma and urine catecholamines and metanephrines
• Serum 11-deoxycortisol and 11-deoxycorticosterone
• Urinary 17-hydroxysteroid and 17-ketosteroid

Imaging studies provide additional diagnostic insights, including:

• Chest radiograph (eg, when assessing for bronchopulmonary dysplasia, congestive heart failure)
• Echocardiogram
• Voiding cystourethrogram
• Captopril renal scintigraphy
• Dimercaptosuccinic acid renal scan
• Computed tomographic angiography (to evaluate the renal artery and the aorta)
• Abdominal magnetic resonance imaging
• Head ultrasonography (to rule out intraventricular hemorrhage)

Treatment / Management

In most cases of neonatal hypertension, addressing the underlying correctable causes leads to resolution of the condition. Prompt removal of the umbilical catheter helps eliminate a common contributing factor to this condition. Correction of hypercalcemia or fluid overload can be achieved through fluid restriction or the use of diuretics. Adjusting doses or discontinuing medications, eg, inotropes, steroids, or caffeine, also contributes to blood pressure normalization.

Surgical conditions require timely intervention, and analgesia may be indicated to relieve pain that exacerbates hypertension. Endocrine disorders necessitate appropriate hormonal therapy. When systolic blood pressure remains above the 99th percentile despite these measures, initiation of antihypertensive treatment becomes necessary.

Mild Neonatal Hypertension Management

In cases of mild neonatal hypertension, defined as systolic blood pressure between the 95th and 99th percentile, careful monitoring often suffices for asymptomatic neonates. Antihypertensive therapy should be considered if blood pressure remains persistently elevated or if echocardiographic findings reveal end-organ effects, eg, left ventricular hypertrophy. 

Moderate Neonatal Hypertension Management

Moderate neonatal hypertension includes systolic pressure at or above the 99th percentile without evident end-organ damage. Although data remain limited, clinicians often prescribe calcium channel blockers, vasodilators, diuretics, or beta-blockers. Angiotensin-converting enzyme (ACE) inhibitors should be avoided in preterm infants younger than 40 to 42 weeks postmenstrual age due to their potential impact on nephron development (see Image. Oral Treatment for Neonatal Hypertension).[21]

Severe Neonatal Hypertension Management

Severe neonatal hypertension requires continuous intravenous infusion of antihypertensive agents. Rapid reductions in blood pressure must be avoided to prevent cerebral or renal complications. Intra-arterial monitoring provides the most accurate and continuous assessment of blood pressure in these critically ill patients. Specific intravenous agents, along with their recommended dosages, have been suggested (see Image. Intravenous Treatment for Neonatal Hypertension).

Surgical Management

Surgical management is indicated in cases involving structural or obstructive conditions, eg, coarctation of the aorta, renal artery or vein occlusion, ureteropelvic junction obstruction, polycystic kidney disease, neuroblastoma, or Wilms tumor.[22] Timely identification and correction of these abnormalities remain crucial for long-term blood pressure control and improved neonatal outcomes.

Differential Diagnosis

Neonatal hypertension is a manifestation of specific disorders of various organ systems. Appropriate investigations should differentiate the etiopathogenic disease entities leading to neonatal hypertension. As the clinical presentation of neonatal hypertension, with symptoms including respiratory distress, hypotonia, irritability, feeding intolerance, and tachycardia, among others, is nonspecific, all other neonatal causes for such symptoms should be ruled out.

Prognosis

The prognosis of neonatal hypertension is influenced by both the cause and the severity of the condition. Neonatal hypertension linked to renal venous thrombosis, umbilical catheterization, or acute renal tubular necrosis tends to be temporary and improves as the underlying issue is addressed. The presence of damage to end organs is linked to a poor prognosis. Typically, most newborns require medication for a brief period, with long-term treatment being rarely necessary. Xiao et al conducted a retrospective study on infants with idiopathic hypertension who were discharged from the NICU while receiving antihypertensive treatment. The study revealed that calcium channel blockers were the most commonly prescribed class of antihypertensives, accounting for 56% of prescriptions.

Following NICU discharge, 60% of the infants continued antihypertensive therapy, with 26% remaining on treatment after 1 year, and 7% after 2 years. This multicenter study indicates that the majority of infants diagnosed with idiopathic hypertension in the NICU will discontinue antihypertensive treatment within 2 years postdischarge.[23] Published data on the long-term outcomes of infants with hypertension as they progress into late childhood and adulthood are lacking. Consequently, monitoring patients with neonatal hypertension closely is crucial. Regular assessments of blood pressure and kidney function should be conducted, and an interprofessional team should oversee their management and treatment.

Complications

Infants with untreated severe, unrelenting hypertension may develop multiple end-organ damage and suffer from vascular injury, left ventricular hypertrophy, encephalopathy, and hypertensive retinopathy. Early, aggressive, and effective treatment should be provided in such conditions. Common complications of longstanding and severe hypertension are hypertensive nephropathy with variable renal dysfunction and hypertensive cardiomyopathy with left ventricular hypertrophy, dilation, or dysfunction. The long-term adverse effects and sequelae of untreated as compared to treated hypertension in infants are unknown. Recent epidemiological evidence suggests that childhood hypertension is associated with a higher risk for adulthood hypertension.