Unless you can time travel back to your birth and prevent your preterm birth this gives no preventative measures on preventing these early strokes.
Young Adult Survivors of Preterm Birth Are at Increased Risk of Stroke: The Missing Link
See related article, p 2609
Adult survivors of prematurity are at increased risk of hypertension, diabetes, lipid disorders, and ischemic heart disease.1–4 Crump et al5 used data from the Swedish Birth Register and Swedish Death Register to investigate stroke risk in premature infants. This national retrospective cohort study included 95% of all singleton births in Sweden from 1973 to 1994 who survived to 18 years of age, were still living in Sweden, and had gestational age information in the birth register for a total of 2 140 866 individuals. Participants were followed up for first-time stroke (identified via the International Classification of Disease codes) through 2015, allowing 28 million years of follow-up. People with stroke at <18 years of age were excluded, and thus ages at the time of stroke were 18 to 43 years for a total of 4861 strokes (0.2%). Cox regression was used to examine stroke risks associated with gestational age at birth. Participants were grouped as follows: early preterm (22–33 weeks), late preterm (34–36 weeks), early term (37–38 weeks), full term (39–41 weeks), which was the reference group, and post-term (42 weeks). In addition, the first 2 groups were combined to provide summary estimates for preterm birth (<37 weeks). Importantly, preterm infants were also compared with full-term siblings, in the 1.7 million with siblings, to reduce confounding familial, genetic, or environmental risk factors for stroke unrelated to preterm birth. Low gestational age (22–33 weeks) was the highest risk group for any stroke; adjusted hazard ratio (1.42 [95% CI, 1.11–1.81]) and estimates were similar for ischemic or hemorrhagic stroke. Of note, stroke risk increased by 3% for each week of lower gestation, that is, the greater the degree of prematurity, the greater the stroke risk. After comparison to full-term siblings, termed co-sibling analysis, the hazard ratios attenuated slightly but still suggested increased risk of stroke. The age of the study cohort ranged from 25 to 43 years at the time of the study. Thus, the current cohort reports on stroke risk in young adults rather than all adults. While this is a weakness in one sense, factors contributing to stroke risk in young adults are of high interest.The incidence of stroke is changing over time, but the changes vary by age. While the incidence is decreasing in people over 65 years of age, it is increasing in young adults.6 This increase in young adult stroke is occurring on the backdrop of improved outcomes and increased life expectancy in children with critical or chronic medical conditions such as prematurity.7 Crump et al highlighted the high incidence of known adult stroke risk factors and elevated stroke risk in adult survivors of preterm birth. However, the mechanisms that underpin these observations are not well understood. To date, multiple mechanisms have been proposed including arterial stiffness, impairment in arterial vasodilatation, and tissue developmental arrest. A plausible unifying process, and potentially the missing link that explains the association between prematurity and young adult stroke risk, is vascular endothelial dysfunction at the microcirculatory level of the tissue capillary bed. Acute and chronic disturbances in oxygenation, altered hemodynamics, inflammation, and infection activate signaling molecules such as bradykinin and vascular endothelial growth factor and the production of NO through numerous pathways. Sustained NO activation, reduced NO bioavailability, and overproduction of reactive oxygen signaling results in oxidative stress and the tipping of normal vascular endothelial function into that of dysfunction. This results in disrupted vascular homeostasis, abnormal vasomotor tone and vascular reactivity, vascular remodeling, and a prothrombotic state.8 Vascular endothelial dysfunction is shown to begin early in childhood and is recognized as an early pathophysiological process in atherogenesis—the subclinical precursor of arteriosclerosis or arterial stiffness.9 This may result in accelerated vascular aging, which then eventually contributes to increased ischemic risk.
The reported relationship between gestational age and stroke risk is also striking as it points to critical developmentally determined periods of vulnerability. This is in-keeping with theories of selective vulnerability whereby the brain injury mostly reflects the specific cell lines maturing at the time of injury.10 It is notable that collagen content within the vascular wall is known to increase between the 12th and 25th weeks of fetal life.11 From the 25th to 42nd week of gestation, there is an increase in elastin production triggered by the release of endothelial factors such as platelet-derived growth factor and insulin-like growth factors. This is a critical period of vascular remodeling in which the elastin/collagen ratio plays a major role in the development of arterial compliance. Much of this work has been in systemic arteries necessitating further studies within the blood vessels of the brain.11 However, these observations of a lower elastin/collagen ratio in preterm compared with term infants and arterial stiffness provide a likely pathological basis for the association between gestation and stroke risk.
A major strength of this work was the co-sibling analysis, which demonstrated that the increased risk in ischemic and hemorrhagic stroke was partially explained by familial (genetic or environmental) factors. Modifiable environmental and lifestyle factors such as smoking and exercise are known to be important for the maintenance of vascular health and are, therefore, tangible interventions that target many of the proposed mechanisms of ischemic injury in adults. Crump et al also highlight the importance and impact of maternal health on fetal health and future adult stroke risk. Many of these modifiable environmental and lifestyle factors relate to social determinants of health and are also associated with preterm birth.12
Noninvasive cranial ultrasound and novel applications of functional magnetic resonance imaging provide tools for future research in this field. Hemodynamic disturbance and abnormal oxygenation are known to cause microstructural alterations in white matter and the secretion of toxic factors that impair myelination.13 Of note, abnormalities commonly seen on brain magnetic resonance imaging of preterm infants are similar to those associated with vascular endothelial dysfunction in the brain. Magnetic resonance angiography assessment of vessel wall macrostructure that uses black-blood imaging techniques represents an area of major advancement in noncontrast-based vessel wall imaging in children and an additional modality for the measurement of macrostructural changes in the circulatory system.14,15 However, much more work must be done to understand the pathophysiology.
Weaknesses in this work are those inherent to large administrative data studies including lack of complete clinical records particularly those to assess later-in-life risk factors and reliance on the International Classification of Disease codes. Other weaknesses include that improvements in care over time may result in survivor bias for preterm infants surviving early in the study and that Sweden is a country with a fairly homogeneous population. Additional geographic, racial, and ethnic diversity is needed in future work.
We have made great strides in caring for premature infants such that survivors of prematurity from the 1970s may be different than those from the 1990s. Today our neonatal intensive care units save incredibly sick premature infants, thus it is not surprising that Crump et al found that associations between premature birth and stroke risk are slightly stronger in more recent births. Follow-up programs track these former premature infants throughout childhood, but this study suggests the need for attention to medical conditions and stroke and cardiovascular risk factors is lifelong. Overall, this work, in combination with additional discussed literature, suggests that illness early in life may lead to premature vascular aging, particularly if hemodynamics and oxygenation are altered.
Disclosures Dr Jordan has served as a consultant for bluebird bio and Global Blood Therapeutics. The other author reports no conflicts.
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