Neonatal Hypertension

Neonatal Hypertension

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Advances in the ability to identify, evaluate, and care for infants with hypertension, coupled with advances in the practice of neonatology in general, have led to an increased awareness of hypertension in modern neonatal intensive care units (NICUs). This article provides an overview of the differential diagnosis of hypertension in the neonate, the optimal diagnostic evaluation of the disease, and immediate and long-term antihypertensive therapy. (See Presentation, DDx, Workup, Treatment, and Medication.)

Blood pressure (BP) in newborns depends on various factors, including gestational age, postnatal age, and birth weight. Hypertension can be observed in various situations in the modern NICU and is especially common in infants who have undergone umbilical arterial catheterization. A careful diagnostic evaluation should lead to determination of the underlying cause of hypertension in most infants. (See Etiology, Presentation, and Workup.)

As in older infants and children, most cases of neonatal hypertension are of renal origin, with the 2 largest categories being renovascular and renal parenchymal diseases. Other predisposing factors include a history of umbilical catheterization and cardiac, endocrine, and pulmonary causes.

A 1992 study by Singh and colleagues clearly demonstrated that hypertension was considerably more common in infants with BPD, patent ductus arteriosus, or intraventricular hemorrhage or in those who had indwelling umbilical arterial catheters. Approximately 9% of the infants in their series who had indwelling umbilical arterial catheters developed hypertension. [1]

The complexity of the infant’s nursery course also appears to be important in the development of hypertension. Freidman et al studied hypertension in NICU graduates and reported that infants who developed hypertension tended to have lower initial Apgar scores and slightly longer NICU stays than did infants who remained normotensive, indicating that sicker babies have a somewhat greater likelihood of developing hypertension. [2]

A study by Blowey et al of 764 neonates diagnosed with hypertension indicated that the greatest hypertension risk was a high severity of illness as reflected in the APR-DRG (All Patient Refined Diagnosis Related Groups) scoring system. Extracorporeal membrane oxygenation, coexisting renal disease, and renal failure also posed high risks. (Infants with congenital cardiac disorders were excluded from the study.) [3]

With respect to renovascular disease, umbilical artery catheter–associated thromboembolism affecting the aorta, the renal arteries, or both probably is the most common cause of hypertension observed in the typical NICU. In 1972, Neal et al were the first investigators to demonstrate an association between the use of umbilical arterial catheters and development of arterial thrombi. Using aortography at the time of umbilical artery removal, as well as autopsy data, they demonstrated thrombus formation in 25 of 31 infants studied (81%). [4]

Following Neal’s report, the association between umbilical arterial catheter–associated thrombi and the development of hypertension was confirmed by several other groups of investigators. Although potential predisposing factors, such as duration of line placement and line position (low versus high), have been studied, these studies have not been conclusive, leading to the assumption that the cause of hypertension in such cases is related to thrombus formation at the time of line placement, which is probably related to disruption of the vascular endothelium of the umbilical artery. Such thrombi may then embolize into the kidneys, causing areas of infarction and increased renin release.

Other renovascular problems that may lead to neonatal hypertension include renal venous thrombosis (RVT) and renal artery stenosis secondary to fibromuscular dysplasia (FMD). Many infants with FMD may have main renal arteries that appear normal on angiography but demonstrate significant branch vessel disease that can cause severe hypertension.

Other vascular abnormalities may also lead to hypertension in the newborn, including idiopathic arterial calcification and renal artery stenosis secondary to congenital rubella infection.

Finally, mechanical compression of 1 or both renal arteries by tumors, hydronephrotic kidneys, or other abdominal masses may also lead to hypertension.

Numerous congenital renal parenchymal abnormalities can lead to hypertension in the newborn period. For example, patients with autosomal dominant or autosomal recessive polycystic kidney disease (PKD) may present in the newborn period with severe nephromegaly and hypertension. The most severely affected infants with PKD are at risk for development of congestive heart failure (CHF) due to severe, malignant hypertension.

Although much less common than in PKD, hypertension has also been reported in infants with unilateral multicystic dysplastic kidneys. Renal obstruction may be accompanied by hypertension, even in the absence of renal arterial compression. This has been observed, for example, in infants with congenital ureteropelvic junction obstruction and in infants with ureteral obstruction by other intra-abdominal masses. The mechanism of hypertension in such instances is unclear, although the renin-angiotensin-aldosterone system (RAAS) may be involved.

Additional renal parenchymal causes of hypertension in the newborn period include severe acute tubular necrosis, interstitial nephritis, and cortical necrosis. Hemolytic uremic syndrome, although rare in the newborn period, is usually accompanied by hypertension that can be quite difficult to control, frequently requiring multiple agents.

The most important nonrenal cause of neonatal hypertension is BPD. This association was first described in 1984, by Abman et al, who studied 65 infants discharged from a NICU. [5] Abman et al reported that the incidence of hypertension in infants with BPD was 43% versus an incidence of 4.5% in infants without BPD. More than half of the infants with BPD who developed hypertension did not manifest it until following discharge from the NICU, highlighting the need for measurement of BP in NICU graduates. Investigators were unable to identify a clear cause of hypertension but postulated that hypoxemia may be involved.

These findings have subsequently been reproduced by several other investigators. For example, Alagappan found that hypertension was twice as common in very low birth-weight infants with BPD compared with the incidence in all very low birth-weight infants. [6] As in Abman’s report, the development of hypertension appeared to be correlated with the severity of pulmonary disease because all of the hypertensive infants were receiving supplemental oxygen and aminophylline. These observations reinforced the impression that infants with severe lung disease are clearly at increased risk of developing hypertension and need close monitoring for this problem.

Numerous other causes of hypertension in newborns are recognized. Of these, hypertension associated with coarctation of the thoracic aorta deserves further comment. This is perhaps one of the most easily detected forms of hypertension in the newborn period and has been included in the differential diagnosis of this problem since the earliest reported case series of neonatal hypertension. Repair early in infancy seems to lead to an improved long-term outcome compared with delayed repair, which may be followed by persistent hypertension.

Endocrinologic disorders that may produce hypertension in the newborn period include congenital adrenal hyperplasia (CAH), hyperaldosteronism, and hyperthyroidism.

Iatrogenic hypertension can be the result of medications administered to infants for treatment of pulmonary disease, such as dexamethasone and aminophylline, high doses of adrenergic agents, prolonged use of pancuronium, or administration of phenylephrine ophthalmic drops. Hypertension in such cases typically resolves when the offending agent is discontinued or its dose is reduced.

For infants receiving prolonged total parenteral nutrition (TPN), hypertension may result from salt and water overload or from hypercalcemia. Patients with certain tumors, including neuroblastoma, Wilms tumor, and mesoblastic nephroma, may present in the neonatal period, and the tumors may produce hypertension either because of compression of the renal vessels or ureters or because of production of vasoactive substances, such as catecholamines.

Neurologic problems, such as seizures, intracranial hypertension, and pain, constitute fairly common causes of episodic hypertension. Finally, illicit substances ingested by the mother during pregnancy, most notably cocaine and heroin, may also lead to significant problems with hypertension in the newborn either because of direct effects on the developing kidney or because of drug withdrawal.

Although precise figures are difficult to obtain, available data suggest that the incidence of hypertension in newborns is low, with published figures ranging from 0.2-3%. In a recent study, hypertension requiring treatment was found in 1.3% of neonates admitted to a teaching hospital NICU. [7] Hypertension is so unusual in otherwise healthy term infants that routine blood pressure (BP) determination is not advocated for these patients.

Hypertension may also be detected following discharge from the NICU. Friedman and Hustead diagnosed hypertension (defined as a systolic BP >113 mm Hg on 3 consecutive visits over 6 wk) in 2.6% of infants discharged from a teaching hospital NICU. [2] The diagnosis of hypertension was made in these infants at a mean corrected age of approximately 2 months. Although the number of babies affected is likely to be relatively small, this study supports screening for hypertension in the follow-up for NICU graduates, especially those with more complicated NICU courses.

A study of approximately 2600 infants treated at a single center in Australia over a 4-year period demonstrated a prevalence of hypertension of 1.3%. [8] Antenatal steroids, maternal hypertension, umbilical arterial catheter placement, postnatal acute renal failure, patent ductus arteriosus, treatment with indomethacin, and chronic lung disease were associated with the development of hypertension.

The long-term prognosis for most infants with hypertension is quite good. For infants with hypertension related to an umbilical arterial catheter, the hypertension usually resolves over time. These infants may require increases in their antihypertensive medications in the first several months following discharge from the nursery as they undergo rapid growth. Following this, weaning the patient off antihypertensive therapy is usually possible by making no further dose increases as the infant continues to grow. Home blood pressure (BP) monitoring by the parents is a crucially important component of this process.

Provide proper equipment, either a Doppler or oscillometric device, for all infants discharged from the NICU on long-term antihypertensive medications. Such infants may benefit from referral to a comprehensive pediatric hypertension clinic if their primary care provider is inexperienced in managing hypertension.

Other forms of neonatal hypertension may persist beyond infancy. In particular, polycystic kidney disease (PKD) and other forms of renal parenchymal disease may continue to cause hypertension throughout childhood. Infants with renal venous thrombosis (RVT) may also remain hypertensive, and some of these children ultimately benefit from nephrectomy.

Persistent or recurrent hypertension may also be observed in children who have undergone repair of renal arterial stenosis or coarctation of the aorta. Reappearance of hypertension in these situations should prompt a search for restenosis using the appropriate imaging studies.

The long-term sequelae of neonatal hypertension on renal growth, renal function, and future BP are unknown at this time. Long-term effects related to certain antihypertensive medications (eg, angiotensin-converting enzyme [ACE] inhibitors, calcium channel blockers) are also unknown. Infants with neonatal hypertension may need to be monitored closely even after their hypertension has resolved, particularly with respect to renal growth and the redevelopment of hypertension in later childhood.

Educate the parents of infants who develop hypertension requiring drug therapy about the expected effects and side effects of their infant’s antihypertensive medications. In addition, arrange home blood pressure (BP) monitoring equipment and educate the parents in its use prior to the infant’s discharge from the NICU. Parents must monitor the BP of all infants discharged on antihypertensive medications on a regular basis (ie, usually daily); parents should call the prescribing clinician if the infant’s BP exceeds or falls below the target range.

Patient education information on childhood hypertension can be found at the International Pediatric Hypertension Association web site.

For patient education information, see High Blood Pressure (Hypertension).

Singh HP, Hurley RM, Myers TF. Neonatal hypertension. Incidence and risk factors. Am J Hypertens. 1992 Feb. 5(2):51-5. [Medline].

Friedman AL, Hustead VA. Hypertension in babies following discharge from a neonatal intensive care unit. A 3-year follow-up. Pediatr Nephrol. 1987 Jan. 1(1):30-4. [Medline].

Blowey DL, Duda PJ, Stokes P, Hall M. Incidence and treatment of hypertension in the neonatal intensive care unit. J Am Soc Hypertens. 2011 Sep 17. [Medline].

Neal WA, Reynolds JW, Jarvis CW, Williams HJ. Umbilical artery catheterization: demonstration of arterial thrombosis by aortography. Pediatrics. 1972 Jul. 50(1):6-13. [Medline].

Abman SH, Warady BA, Lum GM, Koops BL. Systemic hypertension in infants with bronchopulmonary dysplasia. J Pediatr. 1984 Jun. 104(6):928-31. [Medline].

Alagappan A, Malloy MH. Systemic hypertension in very low-birth weight infants with bronchopulmonary dysplasia: incidence and risk factors. Am J Perinatol. 1998 Jan. 15(1):3-8. [Medline].

Sahu R, Pannu H, Yu R, Shete S, Bricker JT, Gupta-Malhotra M. Systemic hypertension requiring treatment in the neonatal intensive care unit. J Pediatr. 2013 Jul. 163(1):84-8. [Medline].

Seliem WA, Falk MC, Shadbolt B, Kent AL. Antenatal and postnatal risk factors for neonatal hypertension and infant follow-up. Pediatr Nephrol. 2007 Dec. 22(12):2081-7. [Medline].

Zubrow AB, Hulman S, Kushner H, Falkner B. Determinants of blood pressure in infants admitted to neonatal intensive care units: a prospective multicenter study. Philadelphia Neonatal Blood Pressure Study Group. J Perinatol. 1995 Nov-Dec. 15(6):470-9. [Medline].

Pejovic B, Peco-Antic A, Marinkovic-Eric J. Blood pressure in non-critically ill preterm and full-term neonates. Pediatr Nephrol. 2007 Feb. 22(2):249-57. [Medline].

Kent AL, Kecskes Z, Shadbolt B, Falk MC. Normative blood pressure data in the early neonatal period. Pediatr Nephrol. 2007 Sep. 22(9):1335-41. [Medline].

Dionne JM, Abitbol CL, Flynn JT. Hypertension in infancy: diagnosis, management and outcome. Pediatr Nephrol. 2012 Jan. 27(1):17-32. [Medline].

Dionne JM, Abitbol CL, Flynn JT. Erratum to: Hypertension in infancy: diagnosis, management and outcome. Pediatr Nephrol. 2012 Jan. 27(1):159-60. [Medline].

Task Force on Blood Pressure Control in Children. Report of the Second Task Force on Blood Pressure Control in Children–1987. Task Force on Blood Pressure Control in Children. National Heart, Lung, and Blood Institute, Bethesda, Maryland. Pediatrics. 1987 Jan. 79(1):1-25. [Medline].

Crossland DS, Furness JC, Abu-Harb M, et al. Variability of four limb blood pressure in normal neonates. Arch Dis Child Fetal Neonatal Ed. 2004 Jul. 89(4):F325-7. [Medline].

Brierley J, Marks SD. Treating the causes of paediatric hypertension using non-invasive physiological parameters. Med Hypotheses. 2010 May 3. [Medline].

Batisky DL. Neonatal hypertension. Clin Perinatol. 2014 Sep. 41(3):529-42. [Medline].

Nickavar A, Assadi F. Managing hypertension in the newborn infants. Int J Prev Med. 2014 Mar. 5(Suppl 1):S39-43. [Medline].

Postconceptual Age

50th Percentile

95th Percentile

99th Percentile

44 weeks

 

 

 

SBP

88

105

110

DBP

50

68

73

MAP

63

80

85

42 weeks

 

 

 

SBP

85

98

102

DBP

50

65

70

MAP

62

76

81

40 weeks

 

 

 

SBP

80

95

100

DBP

50

65

70

MAP

60

75

80

38 weeks

 

 

 

SBP

77

92

97

DBP

50

65

70

MAP

59

74

79

36 weeks

 

 

 

SBP

72

87

92

DBP

50

65

70

MAP

57

72

77

34 weeks

 

 

 

SBP

70

85

90

DBP

40

55

60

MAP

50

65

70

32 weeks

 

 

 

SBP

68

83

88

DBP

40

55

60

MAP

49

64

69

30 weeks

 

 

 

SBP

65

80

85

DBP

40

55

60

MAP

48

63

68

28 weeks

 

 

 

SBP

60

75

80

DBP

38

50

54

MAP

45

58

63

26 weeks

 

 

 

SBP

55

72

77

DBP

30

50

56

MAP

38

57

63

Drug

Class

Intravenous (IV) Dosage

Comments

Esmolol

Beta blocker

100-300 mcg/kg/min IV infusion

Very short acting; constant IV infusion necessary

Hydralazine

Vasodilator (arteriolar)

0.15-0.6 mg/kg/dose IV bolus or 0.75-5mcg/kg/min IV constant infusion

Tachycardia is frequent adverse effect; must administer every 4 hours when administered as IV bolus

Labetalol

Alpha blocker and beta blocker

0.2-1 mg/kg/dose IV bolus or 0.25-3 mg/kg/h IV constant infusion

Heart failure, bronchopulmonary dysplasia (BPD), relative contraindications

Nicardipine

Calcium channel blocker

1-5 mcg/kg/min IV constant infusion

May cause reflex tachycardia

Sodium nitroprusside

Vasodilator (arteriolar and venous)

0.5-10 mcg/kg/min IV constant infusion

Thiocyanate toxicity can occur with prolonged use (>72 h) or in renal failure; usual maintenance dose is below 2 mcg/kg/min; may use 10 mcg/kg/min for short duration (ie, < 10-15 min)

Drug

Class

Oral Dosage

Comments

Captopril

Angiotensin-converting enzyme (ACE) inhibitor

Under age 3 months: 0.01-0.5 mg/kg/dose 3 times daily; not to exceed 2 mg/kg/day

At or above age 3 months: 0.15-0.3 mg/kg/dose 3 times daily; not to exceed 6 mg/kg/day

Monitor serum creatinine and potassium levels

Clonidine

Central agonist

0.05-0.1 mg/dose 2-3 times daily

Adverse effects include dry mouth and sedation; rebound hypertension with abrupt discontinuation

Enalapril

ACE inhibitor

0.08-0.6 mg/kg/day, given once or twice daily

Monitor serum creatinine and potassium levels

Hydralazine

Vasodilator (arteriolar)

0.25-1 mg/kg/dose 3-4 times daily; not to exceed 7.5 mg/kg/day

Suspension stable up to 1 wk; tachycardia and fluid retention are common adverse effects; lupuslike syndrome may develop in slow acetylators

Isradipine

Calcium channel blocker

0.05-0.15 mg/kg/dose 4 times daily; not to exceed 0.8 mg/kg/d or 20 mg/day

Suspension may be compounded; useful for both acute and chronic hypertension

Amlodipine

Calcium channel blocker

0.1-0.3 mg/kg/dose twice daily; not to exceed 0.6 mg/kg/d or 20 mg/d

Less likely to cause sudden hypotension than isradipine

Minoxidil

Vasodilator (arteriolar)

0.1-0.2 mg/kg/dose 2-3 times daily

Most potent oral vasodilator; excellent for refractory hypertension

Propranolol

Beta-blocker

0.5-1 mg/kg/dose 3 times daily

Maximal dose depends on heart rate; may administer as much as 8-10 mg/kg/d if no bradycardia; avoid in infants with BPD

Labetalol

Alpha and beta blocker

1 mg/kg/dose 2-3 times daily, up to 12 mg/kg/d

Monitor heart rate; avoid in infants with BPD

Spironolactone

Aldosterone antagonist

0.5-1.5 mg/kg/dose twice daily

Potassium-sparing diuretic; monitor electrolytes; several days necessary to observe maximum effectiveness

Hydrochlorothiazide

Thiazide diuretic

2-3 mg/kg/d orally every day or divided twice daily

Monitor electrolytes

Chlorothiazide

Thiazide diuretic

5-15 mg/kg/dose twice daily

Monitor electrolytes

Joseph Flynn, MD, MS Chief, Division of Nephrology, Seattle Children’s Hospital; Professor, Department of Pediatrics, University of Washington School of Medicine

Joseph Flynn, MD, MS is a member of the following medical societies: American Academy of Pediatrics, American Heart Association, American Society of Hypertension, American Society of Nephrology, American Society of Pediatric Nephrology, National Kidney Foundation, Phi Beta Kappa

Disclosure: Received consulting fee from Pfizer, Inc for review panel membership; Received royalty from UpToDate, Inc. for author; Received royalty from Spronger, Inc for authoring.

Ted Rosenkrantz, MD Professor, Departments of Pediatrics and Obstetrics/Gynecology, Division of Neonatal-Perinatal Medicine, University of Connecticut School of Medicine

Ted Rosenkrantz, MD is a member of the following medical societies: American Academy of Pediatrics, American Pediatric Society, Eastern Society for Pediatric Research, American Medical Association, Connecticut State Medical Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Arun K Pramanik, MD, MBBS Professor of Pediatrics, Director of Neonatal Fellowship, Louisiana State University Health Sciences Center

Arun K Pramanik, MD, MBBS is a member of the following medical societies: American Academy of Pediatrics, American Thoracic Society, National Perinatal Association, and Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine

Disclosure: Nothing to disclose.

Neonatal Hypertension

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