At last: evidence rather than emotion

Perinatal stroke is often a devastating and unexpected event for families that leads them to ask the question of “why?” The study by Curtis et al¹  in this issue of Blood suggests that the answers to this question are not to be found in standard thrombophilia testing.

Thrombophilia, a broad term inclusive of a variety of disorders, has variably been shown to be associated with venous thromboembolic diseases in adults, although the link to arterial disease is more tenuous. Currently, most guidelines support very limited clinical usefulness of thrombophilia testing in adult populations.² 

The data supporting thrombophilia testing in neonatal or perinatal stroke is far from convincing. One could reasonably extend that statement to childhood stroke and potentially childhood thrombosis in general.³  Previous studies of dubious quality have suggested a potential association with perinatal stroke, however, none have demonstrated any impact of testing on recurrence rates, clinical outcome, or future therapy.⁴  Although some studies have suggested a link to neurological outcome, most would argue the recommended follow-up and interventions are unchanged by the results of thrombophilia testing.⁴  Yet thrombophilia testing is frequently performed in this situation. Many clinicians, in an attempt to provide some answers for desperate parents, embark on testing knowing that the interpretation of any positive results is fraught with uncertainty. Testing is often driven by parents who have been scouring the internet for answers and come asking about thrombophilia. Childbirth is supposed to be a time of great joy. An unexplained perinatal stroke that will likely have lifelong significant consequences for the infant is incredibly challenging for parents. There are issues of their fears for their child, their unfounded feelings of guilt, as well as concerns about the risks for future children. Thus, the potential impact of performing tests of unknown significance for the child’s future, and, indeed, for future children in the family, is arguably more negative than positive because it may increase unfounded fears, leading to overtreatment and inhibitions or restrictions on the child. Until now, clinicians have not had quality data to support making an argument to parents against doing such testing.

Curtis et al performed a prospective, population-based, controlled, disease-specific study that suggests minimal association between perinatal stroke and thrombophilia (specifically, a broad range of thrombophilia markers). The authors make the relevant point that this does not exclude a role of disordered coagulation in the etiology of the event, but that such a role is unlikely to be found by testing standard thrombophilia assays. Such a view is entirely consistent with our knowledge of developmental hemostasis.⁵  The coagulation system changes rapidly in the first few days of life. In fact, the whole plasma milieu is fundamentally different when comparing neonates and adults.⁶  Placental-released glycosaminglycans probably contribute to the overall balance of coagulation, and yet these factors are no longer detectable after the first week of life.⁷  A much greater understanding the coagulation system in the placenta, fetus, and premature and term neonates is required. Such understanding must be an ongoing area of active research. The aim is to ultimately be able to provide families with evidence-based information to explain perinatal events, such as stroke.

The reported minimal association is consistent with epidemiological data as well. The large family cohorts that defined the original thrombophilias did not report neonatal events, but rather thrombotic complications in adult life, and the conclusion is that thrombophilias interact with patient age in correlating with the risk of thrombosis and rarely cause clinical events during childhood.⁸ 

So at last we have good quality evidence. As a result, clinicians who are faced with parents full of emotion and anxiety can now say that the available data does not support thrombophilia testing in their child who has suffered a perinatal stroke, because any abnormality found occurs with the same frequency as in the general population. We do not advocate testing the general population at birth, despite the relative frequency of thrombophilias, because there is no evidence that knowing if a thrombophilia is present improves the long-term outcome for the child, and such an approach is clearly not cost effective. Certainly, being labeled unnecessarily with a diagnosis of a coagulation abnormality early in life creates much anxiety and mismanagement. Without any evidence that results would change practice, it is impossible to argue that such testing is cost effective. Thus, there is no benefit in offering this testing in children who have suffered a perinatal stroke. No answer to the question of “why” remains better than the wrong answer. In the meantime, the search for the true answers must continue. At least in regard to thrombophilia, now that we have some evidence, we can help parents deal more constructively with their emotions after perinatal stroke.