Neonatal arterial ischaemic stroke: obstetric issues
Introduction
Perinatal arterial ischaemic stroke (PAIS) is estimated to occur in around 1/2500 to 1/5000 term neonates. It is an important cause of hemiplegic cerebral palsy and cognitive impairment in children.1, 2, 3, 4 Although many children appear to have good outcomes,5 especially those not affected by hemiplegia, problems with language, vision and specific behavioural difficulties and later epilepsy are increasingly recognised. With the availability of good quality early cranial ultrasound imaging6 and especially the introduction of magnetic resonance (MR) imaging and diffusion-weighted sequences,7, 8 diagnosis in the neonatal period has improved greatly. There is now increased awareness that PAIS is an important differential diagnosis in infants presenting with seizures and encephalopathy in the newborn period.9 Early imaging data have also enabled much-improved timing of the lesion and support the view that most PAIS in symptomatic term infants occurs in the immediate peripartum period.6, 7, 8
The pathophysiology is thought to be related to clot formation and there are risk factors unique to the pregnant woman and fetus that predispose the newborn to a hypercoagulable state. Pregnancy is a hypercoagulable state10, 11, 12, 13 and a period of high risk for maternal stroke. Newborns are also vulnerable in their own right having a high haemoglobin concentration, relatively slow blood velocity, and low serum activity levels of protein S and protein C. Antepartum and intrapartum risk factors have been identified in infants presenting with PAIS that are different between the term and preterm infants. The majority of studies are based on single centre tertiary hospital cohorts, with a potential bias towards more severe cases rather than having milder cases, where the diagnosis may have been overlooked or not pursued and where care may have been in non-tertiary centres without early imaging opportunities. One recent study from France, however, presents prospectively collected multicentre cohort data.14 The data on preterm infants are limited.3, 15, 16 The pathogenesis of PAIS remains ill-understood and much larger cohort studies will be required to help elucidate the multifactorial pathway leading to perinatal stroke.
The perinatal period lasts from 28 weeks of fetal life through to 7 days post delivery, during which time the fetus and infant are exposed to very different environments. In order to understand PAIS aetiology better, it will be important to separate cohorts into preterm and term infants, and to analyse separately: (i) infants who are symptomatic in the immediate postpartum period with evidence of PAIS of recent onset; (ii) infants who present with acute symptoms later in the neonatal period, often after some specific postnatal event; (iii) infants who present with hemiplegia or other neurological signs in the first months after birth and have a diagnosis of presumed perinatal infarction (PPERI); (iv) infants whose stroke has clearly occurred antenatally. The difficulty with the current literature is that in many series, infants with PAIS fitting into all these categories are analysed together. The purpose of this article is to review the current literature on the obstetric risk factors associated with PAIS with an emphasis on those PAIS presenting soon after birth.
Section snippets
Primiparity
Primiparity is a risk factor that has been identified in 30–75% of cases of PAIS in term infants, but not so in preterm infants.3, 14, 15, 17, 18 However, it may not be primiparity in itself, but its association with other factors such as prolonged second stage of labour and interventional delivery which predisposes a firstborn infant to PAIS. Indeed, the only published study to address this in a multivariate analysis demonstrated that primiparity was strongly related to prolonged second stage
Gender
Most, though not all, reports indicate that stroke occurs more frequently in males. In a recent study from the International Prognostic Scoring System (IPSS) registry data, 249 neonates aged <29 days with neonatal ischaemic stroke 57% were male, with a male:female ratio of 1.3:1 (not significantly different).31 In a French study of 100 acutely symptomatic term infants with PAIS males predominated (62:38, 1.6:1, P = 0.045).14 They noted an excess of large infants and one suggested reason for the
Antepartum risk factors
Several antepartum risk factors have been identified in case series of neonates with PAIS, although not always consistently recorded in all studies.2, 17, 18, 33, 34 Some of these risk factors are inter-related and not independent but part of the same causative pathway to PAIS. One study of multiple risk factors found that a history of infertility and pre-eclampsia were independent risk factors for PAIS, and the presence of more than one risk factor increases the probability of delivering a
Intrapartum risk factors
Intrapartum risk factors for PAIS are associated with proinflammatory states as well as a process of labour that is ‘complicated’ with a high likelihood of requiring an interventional delivery. However, it is not often that the infants are severely depressed after birth.5, 44 Some of the risk factors are similar to those for global hypoxia--ischaemia and it is likely that the pathogenesis whereby brain injury is sustained is not dissimilar.
Placental disorders
The placenta is a vascular organ that has areas of low flow that predispose to thrombosis.52 It is the most likely source of emboli to the fetal brain. Placental abnormalities reported in infants presenting with PAIS include placental thrombosis, infarction, chorioamnionitis, funisitis and placental chorioangiomas.3, 13, 15, 17, 53 It is difficult to determine their significance in PAIS as the reports are mostly based on isolated cases or a small proportion of case series. The practicalities of
Combination of risk factors increases likelihood of perinatal arterial infarction
Lee et al.3 using multivariate analyses on their cohort of cases of PAIS versus controls found that only 6% of controls had three or more risk factors compared with 60% of cases (odds ratio 25.3). From these data the probability of delivering a baby with PAIS in the presence of three or more risk factors would be 1 in 200. In that study of preterm and term PAIS and PPAIS the significant risk factors included primiparity, infertility, oligohydramnios, pre-eclampsia, chorioamnionitis, prolonged
Risk factors in preterm infants
Two recent case series have specifically looked at risk factors associated with PAIS in preterm infants.15, 16 The findings have been interesting in that the significant risk factors are mainly intrapartum, even though the stroke might not be apparent for some time after birth. In one study, 31 infants <36 weeks of gestation at birth with PAIS identified during their neonatal life had their birth characteristics compared with 93 matched controls.15 Univariate predictors of PAIS included
Limitations of studies
Although there are more data about the risk factors for PAIS, knowledge is still limited. Published studies, apart from the recent French study,14 have been small case series or retrospective case–control single tertiary hospital-based studies. It follows that the relative importance of the risk factors identified may not truly reflect PAIS as a whole group, but bias towards risk factors in the more severe cases. Indeed studies have shown that risk factors are different in those who present in
Conflict of interest
None declared.
Funding sources
None.
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