Neonatal Hypertension

Etiology

Prematurity is a risk factor, and 75% of all infants with NH are born preterm.[7] Newborns suffering from NH are generally sicker and have higher neonatal illness scores and extended NICU stays. The most common causes of significant hypertension requiring medication in neonates are respiratory illnesses (BPD), drugs (caffeine, dexamethasone), ECMO, and renal disorders (parenchymal,  reno-vascular, acute renal tubular necrosis, renal failure). Other etiological factors may be neurological (seizures), endocrinal, cardiac- mainly coarctation of the aorta or infrequently PDA, and umbilical artery catheter-related thromboembolism.[8] 

BPD is an independent risk factor for NH and the most significant non-renal cause of hypertension in VLBW infants.[9][10] Premature infants with intraventricular hemorrhage may be at risk for NH. Case reports of a term infant with ductal aneurysm have been recently published. Other anecdotally reported rare causes are adrenal hemorrhage, vitamin D toxicity with renal calcinosis, and total parenteral nutrition.  Almost 57 % of the cases of NH do not have identifiable causes and are categorized as idiopathic (See Table. Causes of Neonatal Hypertension).[8][11]

Epidemiology

The incidence of neonatal hypertension is reported to be 0.2% in term newborn infants and up to 3% in the infants admitted to the NICU.[3] The variation in the incidence may be attributed to the differences in the study population and the definition of NH used for the study. It is reported that 1.4% of preterm infants require antihypertensive therapy during their NICU stay compared to 1% in term infants.[9]

The incidence of NH is demonstrated to be 13% to 43% in infants with BPD. The exact prevalence of NH in the preterm population has not been determined.

Pathophysiology

A reno-vascular mechanism is the commonest pathway and is operative in most conditions leading to NH. 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.[12] 

An inability to excrete free water and an increase in serum aldosterone levels have been reported in BPD, 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 NH in infants with BPD.[10][13]

Infants of diabetic mothers or those with Factor V Leiden mutation may present with renal vein thrombosis (RVT) and decreased renal perfusion. Neonatal asphyxia may result in renal tubular necrosis (ATN) and secondary to that in NH. Neonatal tumors, such as pheochromocytoma, neuroblastoma, Wilms tumor, and mesoblastic nephroma, can cause NH by compressing the renal vessels or ureters or by producing vasoactive substances, such as catecholamines. COA and PDA lead to decreased forward blood flow, diminished renal perfusion, and the activation of RAS. Closing abdominal wall defects increases intraabdominal pressure that may compress renal vessels. Hypertension in ECMO is thought to be secondary to the increased stroke volume caused by the increased aortic return from ECMO pump blood and to be caused by abnormal sodium or water handling in response to the non-pulsatile arterial flow through the infants’ systems.

History and Physical

The neonates suffering from NH are usually asymptomatic, and the hypertension is detected via routine continuous BP monitoring in the NICU. Those who are symptomatic may present with feeding intolerance, poor nipple efforts, irritability, hypotonia, hypertonia, vomiting, apnea, respiratory distress, oxygen desaturations, and in severe cases, tachycardia, congestive heart failure, cardiogenic shock, and seizures.  The symptoms are non-specific and varied. In older and term newborns, it is either detected by routine monitoring in the NICU or by checking vital signs during well-child visits. The newborns who are discharged from the nursery may return with symptoms of irritability and failure to thrive.[14]

A detailed system-wise physical examination is important. The general appearance may reveal dysmorphism, consistent with Turner, William’s, or Noonan syndromes, the diseases associated with coarctation of the aorta. The presence of a cardiac murmur with a discrepancy in the 4 limb blood pressures and femoral pulses suggests COA. Physical features of congestive heart failure like tachycardia, murmur, mottling, and cyanosis may be present. Palpation of the abdomen may reveal a mass in conditions of polycystic kidney disease, renal tumors, hydronephrosis, and renal vein thrombosis. The genitourinary examination may reveal congenital anomalies or ambiguous genitalia in congenital adrenal hyperplasia. The history of oligohydramnios may suggest congenital renal anomalies, and the infant may be born with typical features in severe cases.

Evaluation

A thorough maternal and perinatal history and physical examination guide in identifying the potential etiology. As the reno-vascular or renal parenchymal disorders account for most cases of NH, the initial investigations pertain to 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 workup should include aortic and renal ultrasonography with a Doppler study.[8]

Further investigation is guided by history and clinical suspicion and should include the following:

• Thyroid function tests, cortisol levels, aldosterone and plasma renin activity, plasma and urine catecholamines and metanephrines, serum 11 dexoycortisol, and 11 deoxycorticosterone. Urinary 17-hydroxysteroid and 17-ketosteroid
• Additional studies include a chest radiograph (BPD, congestive heart failure), an echocardiogram, a voiding cystourethrogram, captopril renal scintigraphy, a dimercaptosuccinic acid renal scan, computed tomographic angiography to evaluate the renal artery and the aorta, abdominal MRI, and head ultrasonography to rule out intraventricular hemorrhage.

Treatment / Management

In most infants with NH, treating the correctable causes usually resolves the condition. The umbilical catheter should be removed as soon as possible. Hypercalcemia or excessive fluid intake should be corrected with fluid restriction or diuretics. Doses of medications like inotropes, steroids, or caffeine should be adjusted or the drug discontinued. Surgical conditions should be addressed as needed. Analgesia may be considered for the relief of pain. Appropriate hormonal therapy should be administered for endocrinal disorders. If hypertension persists above the 99th percentile of the normative data despite these measures, antihypertensive therapy should be initiated.[15](A1)

Mild hypertension: These infants can be regularly monitored and closely observed. If hypertension does not resolve spontaneously, then it can be treated with a thiazide (preferred) or a loop diuretic agent.

Moderate hypertension: These infants have blood pressure readings between the 95th and 99th percentiles for their age without signs of end-organ involvement. They can be treated with diuretics (first line), hydralazine, or propranolol. There is a paucity of information regarding the indications and benefits of oral antihypertensive agents for mild to moderate hypertension in neonates. The details of the commonly used oral agents are presented in the table. See Table. Oral Treatment Options for Hypertension in the Neonatal Age Group.

Severe hypertension: If the blood pressure is greater than the 99 percentile, treatment with continuous intravenous drug infusion is warranted. A rapid reduction in blood pressure should be avoided. Close blood pressure monitoring with an intra-arterial catheter is preferred in these patients. The recommended IV antihypertensive agents and their doses and side effects are presented in the table (see Table. Intravenous Treatment Options for Hypertension in the Neonatal Age Group).

Surgical intervention in the management of neonatal HT is indicated under conditions such as coarctation of the aorta, renal artery or vein occlusion, urinary tract or ureteropelvic junction obstruction, polycystic kidney disease, neuroblastoma, or Wilms tumor, among others.[16]

Differential Diagnosis

NH is a manifestation of specific disorders of various organ systems. The etiopathogenic disease entities leading to NH should be differentiated by appropriate investigations. As the clinical presentation of NH, with symptoms like 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 outcome of NH depends on the etiology and severity of the condition. NH associated with renal venous thrombosis, umbilical catheterization, or acute renal tubular necrosis are transient and resolve as the underlying disorder ameliorates. The presence of end-organ damage is associated with poor prognosis. Most newborns generally require drug therapy for a short period, and long-term therapy is infrequently needed. A retrospective study reported that only 15 percent of the 40 percent of infants discharged from the hospital on antihypertensive medication required treatment by 3 to 6 months.[2] 

The natural history of NH is different from that of hypertension in older children. A study that included 700 infants reported that the median duration of therapy with antihypertensive drugs in infants in the NICU was 10 days. Infants suffering from hypertension due to BPD are usually found to have their BP normalized on follow-up examinations.[17] NH, due to underlying renal parenchymal diseases, may have persisting hypertension into childhood and require prolonged therapy.

Complications

Infants with untreated severe unrelenting hypertension may develop multiple end-organ damages 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.