**3.2 Infection, inflammation and CP**

There is a consensus in the literature that infections/inflammation via cytokinemediated injury to the immature brain are causally associated with CP (see **Figure 2**). Infection, inflammation and cytokines play a fundamental role in CP causation through their link with preterm labour (prematurity), placental pathology (chorioamnionitis, funisitis), congenital malformation, FGR, cerebral white matter injury (WMI) and perinatal asphyxia [29, 33–37]. Studies including recent meta-analyses have shown compelling evidence that maternal infections in pregnancy, intra-amniotic infection (chorioamnionitis), evidence of FIRS and neonatal infections are causally associated with CP [25, 29, 35–37]. Both transplacental TORCH infections (Toxoplasmosis, Others [syphilis, Epstein Barr virus, HIV, Zika virus], Rubella, Cytomegalovirus [CMV], Herpes virus), genitourinary infections (bacterial vaginosis, chlamydia, trichomonas, UTI) and neonatal infections (GBS-early onset sepsis, neonatal pneumonia, meningitis) have all been implicated in CP [37]. Many studies [22–25] in the twentieth and twenty-first centuries have suggested that inflammatory phenomena/infections play a more critical role in the aetiology of brain lesions common in CP. Additionally, placental histology should be requested for in babies compromised at birth since

*Aetiology and Pathophysiology of Cerebral Palsy DOI: http://dx.doi.org/10.5772/intechopen.106685*

chorioamnionitis, funisitis (umbilical cord inflammation) (placental pathology) are evidence of infection predating labour [17].

In the setting of infection/inflammation, one neuropathological substrate for CP is a cytokine-mediated cerebral white matter injury (PVL) in the preterm infant, though minimal evidence exists for such a process in term newborns [37]. Other mechanisms include: brain damage/cerebral dysgenesis by TORCH infections especially CMV, direct cytokine toxicity to premyelinating oligodendrocytes (pre-OLs), hypoxic brain damage by neonatal pneumonia with PPHN, ischaemic cerebral damage from microvascular thrombosis and hypoperfusion in neonatal meningitis et cetera [31, 33, 37].

#### **3.3 Cerebral dysgenesis and CP**

Disruption of the development of motor pathways that control movement and posture is the underlying pathogenesis of CP attributed to cerebral malformations. Cerebral dysgenesis has a firm causal link with CP and both cerebral and non-cerebral malformations increase the likelihood of CP [17, 19]. Some brain malformations have genetic causes like LIS1 and doublecortin (DCX), TUBA1A mutations in lissencephaly while acquired intrauterine infections such as CMV and Zika virus also cause cerebral malformations. A wide range of cerebral malformations especially cortical migration defects are seen in children with CP and include: lissencephaly, polymicrogyria, schizencephaly, cortical dysplasia, agenesis of the corpus callosum, holoprosencephaly, and posterior fossa malformations such as Dandy-Walker malformation and Joubert syndrome [19, 38].

Neuroimaging reliably detects cerebral malformations which mainly occur in early gestation thereby implicating antenatal aetiological factors [4]. The detection of cerebral malformation is useful in establishing that the aetiology of CP is unrelated to perinatal events and this may protect the attending Obstetrician from "maternity negligence" claims that are rife in HICs [4, 17].

#### **3.4 Genetic mutations and CP**

Genetic aetiology for CP is predictable since CP occurs more frequently in some families/consanguineous families (familial clustering), monozygotic twins and congenital malformations and should be suspected even in those without traditional risk factors [39]. Rare genetic mutations (inherited or de novo) or CP-associated genes are implicated in CP [40, 41]. Indeed, current studies employing new genetic testing techniques called Next Generation Sequencing (NGS) such as whole exome sequencing (WES), whole genome sequencing (WGS) and copy number variant analysis continue to identify pathogenetic variants (copy number variants and single nucleotide variants) and likely pathogenic variants in some cases of CP [40]. For instance, some implicated gene mutations (pathogenic variants) involve KANK1, AP4MI, GAD1, ZC4H2 genes [17, 41]. CP genomics is currently evolving and the discovery of more CP-associated genes or genetic mutations underlying CP is expected to add to the presently known panel of pathogenic variants [41].

The neuropathology of genetic mutations in CP stems directly from disrupting early brain development (specifically motor development) (cerebral malformation) and indirectly through genetic susceptibility to different pathways that cause different neuropathologies [41]. These different pathways include infection/inflammatory cytokine responses, foetal growth restriction/IUGR, prematurity or perinatal stroke since genetic susceptibility has been reported to underlie these other risk factors [41].

### **3.5 Foetal growth restriction (FGR) and CP**

Birth weights below the tenth percentile (10th centile) for gestational age (GA) (small-for-gestational age; SGA) remains a major aetiological/risk factor for CP in both term and preterm babies as shown by multiple studies [42–44]. The risk of CP has been reported to increase with increasing severity of foetal growth restriction (FGR) with babies below the 3rd centile having the greatest risk [44]. However, it has been shown that the large for gestational age (LGA) baby also has increased risk of CP [44]. Recall that macrosomic babies have higher risks related to maternal diabetes and obstructed labour [27] FGR acts indirectly to damage the developing brain through chronic hypoxia-ischaemia resulting from impaired placental function (utero-placental insufficiency) and increased occurrence of perinatal asphyxia and hypoglycaemia [27, 32, 33] (see **Figures 3** and **4**). Thus the neuropathology includes grey matter and WMI (PVL).

#### **3.6 Multiple pregnancy/births and CP**

Twinning and higher-order births (triplets, quadruplets, quintuplets, sextuplets, septuplets) from natural or spontaneous conception and Assisted Reproductive Technology (ART) are well-known risks factors for both cerebral dysgenesis and CP [45, 46]. Indeed, the risk of CP increases with increasing number of infants [46]. Peterson et al. [46] in a study of multiple births in Western Australia reported prevalence of CP of 1.6, 7.3 and 28 per 1000 live births in singletons, twins and triplets respectively. The increased risk of CP in multiple births is a consequence of the increased odds of congenital malformations, placental vascular anomalies, FGR, low birth weight (LBW), preterm birth, co-twin death and birth complications/asphyxia (see **Figure 3**) [19, 27, 46]. More so, the increased risk of CP among co-twins has been attributed partly to monochorionic placentation and in-utero death of the co-twin. The "dissolving" or "disappearing twin" is said to release thromboplastin and emboli that can damage the brain of the surviving twin (disappearing twin syndrome) [19, 27, 46]. But a more common setting for brain injury in monochorionic twins by ischaemia and infarctions is the twin-twin transfusion syndrome (TTTS) that results from abnormal placental vascular anastomoses (A-V connections) in which placental tissue supplied by an artery from a donor twin is drained by a vein from the recipient twin [19, 27, 46].

The increasing rate of multiple births reported in HICs suggests an increasing contribution of multiple births to CP pathogenesis [46]. However, a recent large population-cohort study based on Surveillance for Cerebral Palsy in Europe (SCPE) registers found a decreasing risk of CP among the multiples despite the increased prevalence since the 1990s [47]. This study [47] further reported that multiples displayed similar severity of motor impairment as singletons and concluded that advances in obstetric care accounted for these changes in CP risk among preterm low birth weight multiples.

Patently, the neuropathologies of multiple births are the indirect effects on the brain of prematurity, FGR, congenital malformations and hypoxic-ischaemic injury and cerebral infarctions (intrauterine stroke) to which multiples are predisposed (see **Figure 3**).
