Introduction

Preterm birth (those born before 37 weeks gestational age) affects ∼11% of births worldwide, similar with an annual prevalence of prematurity in Argentina between 8 and 9%. Infants born at 22 or 23 weeks weighing close to 500g survive thanks to the new therapeutics and the increasing complexity of neonatal intensive care units^1-3.

Preterm newborns and small for gestational age (SGA) (birth weight of less than 10th percentile for gestational age) are particularly vulnerable to the development of hypertension (HTN) and chronic kidney disease (CKD). In preterm newborns, there is premature exposure to the conditions of extrauterine life in organs that are not yet prepared for it. In these organs, the premature arrest of the development of the vascular tree results in stiffer and narrower arteries, which predisposes to glomerular and endothelial damage, structural alterations due to glomerular hyperfiltration, and increased systolic blood pressure (SBP) in children and adults^3;4. SGA infants may be at increased risk of higher BP later in life, which may be in part due to a decreased nephron development as well as other factors, such as exposure to intrauterine stress that generates an altered fetal programming, placental insufficiency, or altered vascular system.

Although the morbidity and the complications of the appearance of arterial HTN in the neonatal period has not been completely established, it could be a predisposing factor for the appearance of cardiovascular and renal disease in the long term. Hence, this is an important disease that needs to be recognized and addressed prior to discharge.

We consider that we are facing a “silent epidemic” of CKD and HTN in these patients, so preventive strategies should be implemented early to avoid the progression of these and CVD.

Methods

This review was conducted to synthesize current evidence on the epidemiology, pathophysiology, diagnostic evaluation, and long-term outcomes of hypertension in preterm and small-for-gestational-age (SGA) infants. A comprehensive literature search was performed across major biomedical databases, including PubMed, Scopus, Web of Science, and Google Scholar, for studies published between January 2000 and August 2025. The search combined controlled vocabulary and free-text terms such as “neonatal hypertension,” “preterm neonate,” “small for gestational age,” “blood pressure,” “chronic kidney disease,” “fetal programming,” and “cardiovascular outcomes.”

All original research articles, systematic reviews, meta-analyses, and relevant case series reporting data on neonatal, pediatric, or adult hypertension following preterm birth or intrauterine growth restriction were considered. Publications not available in English, those without accessible full text, or studies lacking neonatal data were excluded. Reference lists of selected papers were also hand-searched to identify additional relevant studies.

Data extracted from each eligible article included study design, sample size, gestational age and birth-weight categories, blood-pressure measurement methods, diagnostic criteria used, comorbidities, and follow-up outcomes. Emphasis was placed on clinical correlations between gestational maturity, renal function, and cardiovascular remodeling in later life.

Given the heterogeneity of study designs and populations, findings were analyzed descriptively. Quantitative synthesis (meta-analysis) was not performed; instead, trends and consistent associations were highlighted. The review follows standard ethical principles for literature-based research and does not involve human or animal experimentation.

Pathophysiology

There are few mechanisms linking impaired fetal growth and the increased risk of CVD and HTN in adulthood. Fetal programming of HTN occurs in response to an insult during intrauterine life, which leads to adaptations by the fetus to allow fetal survival. But it also results in permanent structural and physiological changes with long-term consequences such as an increased risk for CVD and HTN^5;6. The intensity, timing and nature of the fetal insult are critical to the phenotypic outcome.

The renal alterations that have been reported in fetal programming of HTN include small kidney size at birth (reduced nephron number), kidney disfunction, and alterations in sodium transport, renin-angiotensin aldosterone system (RAAS), and sympathetic renal nerves.

It has been demonstrated that subjects preterm or low birth weight have a lower nephron number with a smaller glomerular filtration area, causing compensatory glomerular hyperfiltration and hypertrophy, and eventually glomerulosclerosis with kidney injury favoring the development of HTN^3;5;7. Alterations in the RAS appear to contribute to hypertension programmed in response to certain fetal insults, with different impact and with tissue-specific effects⁶. For example, in an animal model, late gestational exposure to glucocorticoids leads to an increase in fetal pulmonary angiotensin converting enzyme (ACE), an expression associated with an increase in blood pressure⁸. Conversely, another experimental study in sheep shows that placental insufficiency leads to suppression of the fetal renal RAS. This could alter the activity of the intrarenal RAS and so affect growth and development of the kidney⁹.

Another mechanism involved in the fetal programming of hypertension is vascular dysfunction. Fetal stress may affect vasculogenesis and cause vascular remodeling. This process is characterized by changes such as an alteration in wall thickness and lumen diameter, which may develop or be precursors of HTN later in life. In the case of intrauterine growth restriction, elastin synthesis is altered during the fetal stage, reducing arterial elasticity^10;11. Preterm birth results in a restricted vascular bed, impaired endothelial function, narrowed and stiffer arteries, predisposing to endothelial dysfunction and arterial hypertension⁶.

On the other hand, it has been proposed that oxidative stress produced by vascular, immune, and enzyme systems may account for several organ system alterations such as endothelial dysfunction with increased vascular tone. Maternal deprivation, sodium overload during pregnancy, and placental dysfunction are associated with higher oxygen radicals being one of the plausible mediators between adverse fetal growth and higher risk for CVD and HTN^6;12-13.

In addition, studies suggest that epigenetic changes are one of the mechanisms responsible for fetal programming that may explain both organ system alterations and vascular dysfunction and HTN in the offspring. These epigenetic changes consist in modifications in genes related to the RAAS, angiotensin type 1 receptor, vascular tone, ion channels, epithelial sodium channels, Na+-K+-2Cl- cotransporter, an increased expression of micro-RNA that regulates the translation of angiotensin converting enzyme-1, micro-RNA associated with cardiac injury, angiogenesis and cell changes, modifications in endothelial nitric oxide synthase (eNOS), and DNA modifications in important genes in endocrine hypertension.^5;14

Neonatal hypertension

Diagnosis and treatment of neonatal HTN remain challenging due to the scarcity of normative data on neonatal blood pressure values, the relative rarity of the condition, and exclusion of neonates from clinical trials of antihypertensive medications¹⁵. The global incidence ranges from 0.2%-3%, but these values may change according to population studies, being higher in preterm newborns who were in critical condition¹⁶.

The gold standard for blood pressure measurement remains to be the invasive intra-arterial measurement; this is most commonly done in a NICU and measured with an umbilical artery catheter. However, the majority of umbilical arterial catheters are not placed to monitor for hypertension. In this population the method of choice is oscillometric devices, which have a good correlation between oscillometric and umbilical or radial artery BP, are easy to use and provide the ability to follow BP trends over time^17;18.

HTN is defined as systolic and/or diastolic BPs persistently equal to or greater than the 95th percentile according to the tables for gestational age and postmenstrual or postconceptional age^15;16;19. Dionne et al. created tables which provide derived systolic and diastolic BP percentiles based on post-menstrual age¹⁸. (Table 1)

Table 1. Blood Pressure Percentiles by Post-Menstrual Age