Article of the Month - Jun 2022

Cardiovascular Health Profile at Age 25 Years in Adults Born Extremely Preterm or Extremely Low Birthweight

Hypertension. 2020;76:1838-1846. doi:10.1161/HYPERTENSIONAHA.120.15786

Jeanie LY Cheong, Anjali Haikerwal, John D Wark, Louis Irving, Suzanne M Garland, George C Patton, Michael M Cheung, Lex W Doyle; for the Victorian Infant Collaborative Study Group.

Reviewed by: Dr. Thomas A Forbes, PhD. Paediatric Nephrologist at The Royal Children’s Hospital and Clinician Scientist Fellow at the Murdoch Children’s Research Institute, Melbourne Australia.

Background:

Improvements in the critical care of premature and extreme low birth weight (EBLW) babies have dramatically increased survival rates over the last 30-40 years. Ex-premature (EP) and ELBW infants are now routinely surviving well into adulthood. In cohorts of EP/ELBW babies born prior to the routine use of neonatal ventilation strategies and exogenous surfactant, there is a well-established risk of hypertension compared to term-born controls. This article aims to examine the cardiovascular health profile outcomes in a cohort of EP/ELBW young adults born during the era of these advances in neonatal intensive care. Additionally, they characterize the health outcome associations across the life course from birth to young adulthood.

Methods:

The Victorian Infant Collaborative Study is a prospective, longitudinal study of EP/ELBW survivors born across multiple hospitals in the state of Victoria, in the south-east of Australia. Their 1991-1992 cohort registered 297 EP/ELBW survivors and 253 contemporaneous term-born normal birthweight controls, all recruited at birth and followed at regular timepoints for health and neurodevelopmental status. Gestational age was determined by obstetric ultrasound before 20 weeks or by menstrual history. A 25-year-old, day-long assessment included height, weight and dual-energy X-ray absorptiometry. Fasting blood samples were taken for insulin, glucose, lipid profile and C reactive protein. After 5 minutes of semi-recumbent rest, the mean of 3 oscillometric blood pressures from the non-dominant arm was recorded. Pulse wave velocity was calculated between the right common carotid and femoral artery. Carotid intima-media thickness (CIMT), 6-minute walk distance and a Beep-endurance test were performed. All technicians were blinded to cohort. The group adapted a cardiovascular health profile based on their measurements and defined normal cutoffs using control group data. Statistical approaches were appropriate and are described in detail in the article.

Results

297 of 301(98.7%)  EP/ELBW infants and 251 of 253(99.2%) controls discharged from hospital have survived to 25 years of age. 165/297 EP/ELBW young adults (55%) and 127/251 term born controls (50.5%) were available for assessment. Factors associated with pre-term birth such as pre-eclampsia, multiple birth and caesarian section were more common in the EP/ELBW cohort, as were recognised outcomes such as cerebral palsy and intellectual impairment. Systolic and diastolic BP were higher in the EP/ELBW cohort compared to controls and was unaltered by adjustment for family history of hypertension (SBP 123.3 vs 117.7 mmHg; DBP 72.5 vs 68.2 mmHg; p<0.001). Compared to controls, the EP/ELBW cohort had lower non-bone lean mass (adj mean diff -4.7 kg; 95% CI -6.0 to -3.4, p<0.001), and high visceral fat volume (adj mean diff 46 cm3; 95%CI 19-74, p=0.001), as well as higher (albeit still normal) fasting glucose (0.14 mmol/L; 95%CI 0.02-0.26, p=0.02). EP/ELBW cohort had lower HDL cholesterol(-0.09 mmol/L; 95%CI -0/18 to -0.01, p=0.04) and higher triglycerides (0.17 mmol/L; 95%CI 0.003-0.33, p=0.05) but no difference was found in pulse wave velocity or CIMT. The EP/ELBW cohort demonstrated lower exercise capacity that term-birth controls, however, when EP/ELBW adults with physical disabilities were removed from the analysis, only the Beep-endurance test maintained a significant difference. Of interest, differences in Beep test endurance, lean body mass, visceral fat volume and triglycerides were greater between male EP/ELBW and control cohorts than for comparison between females cohort. A combined cardiovascular health profile was less favourable in the EP/ELBW cohort than for controls.

Incorporating matched participant data from earlier cohort visits, male sex and elevated BP at the 18-year visit were associated with elevated BP at 25 years. Higher weight Z score between 2-8 years and between 8-18 years was associated with lower exercise capacity and higher abdominal visceral fat at 25 years.

Conclusion

This prospective cohort study with an impressive 25-year follow up highlights the less favourable cardiovascular health profiles of EP and ELBW infants compared to term-born, healthy controls, particularly in males. Longer term follow up of these cohorts will determine whether these findings translate to higher risk of more significant cardiovascular disease.

Significance

Whilst this study doesn’t illustrate an association between hard cardiovascular disease outcomes such as atherosclerosis, diabetes, myocardial infarction or cerebrovascular disease, the modifiable risk factors identified are linked to these outcomes in the general adult literature and ongoing follow up of these cohorts will consider these risks.
That this study represents a single-system perspective on the developmental origins of health and disease in EP/ELBW survivors. It is of interest that pulse wave velocity and CIMT did not differ between the cohorts in spite of well-established differences in blood pressure profiles in both this and other studies. Normal kidney development continues in the human fetus until 36 weeks of gestation, a developmental process that is likely to be disturbed by premature ex-utero transition and/or in utero growth restriction. Reduced nephron endowment may well result, placing EP/ELBW survivors at risk of hypertension, proteinuria and chronic kidney disease. Early detection and treatment of these insidious phenomena is clinically very straightforward and effective in the general population, highlighting the importance of long-term follow up care and awareness of risk for survivors of prematurity and ELBW.