Narrative Review on Prenatal, Intrapartum and Neonatal Risk Factors for Cerebral Palsy in Children
Correspondence Address :
Dr. Pranali Saurabh Thakkar,
C-504, Shreepad Celebration, Opp. Nakshatra Embassy, Near Shavion Circle, Gauravpath Road, Pal, Surat-390009, Gujarat, India.
E-mail: dr.pranalithakkar27@gmail.com
Cerebral Palsy (CP) is not a disease, however a syndrome advanced characterised by associate aberrant management of movement or posture, that seems early in life and ends up in long motor incapacity. The underlying causes of CP are still poorly understood. Many individual risk factors of CP are known, however less is understood concerning their interaction and the way they could relate to completely different pathophysiological pathways. The risk factors may be prenatal, intrapartum, neonatal or combined. Articles were searched to identify risk factors for CP, published from 2001 to 2021. A total of 43 relevant articles including randomised and non randomised controlled trials, systematic reviews and comparative studies were included in this review. From selected analysis reports, most of the studies enclosed within the review showed sturdy strength of association as a causative factor responsible for CP. From this review, it had been ended that multiple risk factors overcome the defence mechanisms and lead to CP. Although any one factor, if severe, may be sufficient to cause CP so preventive strategies and early intervention for high-risk infants are needed.
Cognitive function, Early intervention, Motor disability
Cerebral Palsy (CP) may be a non progressive condition affecting approximately 3 in 1000 newborns and it is characterised by acquired brain damage which affects motor and cognitive functions (1),(2),(3). CP is the most common cause of physical disability in childhood, with limitations that persist throughout life (4),(5),(6). CP is not an illness but a syndrome complex, characterised by an aberrant control of movement or posture, that seems early in life and results to lifelong motor disability. CP is defined as “a cluster of permanent disorders of the event of movement and posture inflicting activity limitation(s) that are attributed to non progressive disturbances that occurred in the developing foetal or infant brain”.
The motor disorders are often accompanied by disturbances of sensation, perception, cognition, communication and/or behaviour, epilepsy and musculoskeletal problems (7),(8). Incidence of perinatal and neonatal mortality has decreased, also maternal and neonatal care have undergone major changes, but the overall prevalence of CP has remained stable over the years, at between 1-3 per 1000 live births (9),(10),(11). If a neuronic loss because of brain injuries, the cortical (pyramidal) region will have spasticity, the basal ganglia (extrapyramidal) region will experience dyskinetic movements, and the cerebellum will experience hypotonia and mixed CP. Spastic CP, which accounts for 75% of cases, is the most prevalent kind. A lesser percentage of children with CP exhibit dyskinetic behaviour (12).
The underlying causes of CP are still poorly understood. Many individual risk factors of CP are known. However, less is understood regarding their interaction and the way they could relate to completely different pathophysiological pathways. The risk factors that will be antenatal, perinatal or neonatal, or postneonatal are represented in (Table/Fig 1) (13). Different areas of research are of interest over the years to spot causes of CP, and it is modified due to the development of maternal and neonatal care: as an example, the occurrence of cerebral damage due to hyperbilirubinemia has decreased dramatically in higher resource countries (14).
The purpose of this study was to review the current research on risk factors of CP for children and how the new findings can affect the content of the CP registers across the world. The research question for this study was ‘What risk factors for CP have been identified in the literature for infants?’
LITERATURE SEARCH
All the peer-reviewed full-text articles published in the English language, between 2001 to 2021, with the primary aim of identification of risk factors for CP in all birth types, were searched from various online databases including Google scholar, PubMed, Elton B. Stephens Company (EBSCO), Medline, ScienceDirect, Cumulated Index to Nursing and Allied Health Literature (CINAHL) and 182 articles were found. A 136 relevant articles were found out of 182, out of which 93 articles were excluded (i.e., three were published in languages other than English, 1-a case report, 38-included risk factors not specific to CP, 29 were articles dedicated entirely to genetic risk factors, 14 were published before 2001 and 8 were only abstracts). As a result, 43 full-text articles were identified and reviewed in this manuscript. A narrative review of all 43 articles was conducted to identify risk factors for CP.
There are several heterogeneous risk factors at focus in current research regarding CP. Studies regarding one or a few prenatal risk factors are listed in (Table/Fig 2) (15),(16),(17),(18),(19),(20),(21),(22),(23),(24),(25),(26),(27),(28),(29),(30),(31),(32),(33),(34),(35),(36). Those regarding perinatal and neonatal risk factors are listed in (Table/Fig 3) (36),(37),(38),(39),(40),(41),(42),(43),(44),(45),(46),(47),(48),(49) and similar review articles are described in (Table/Fig 4) (50),(51),(52),(53),(54),(56). Preventive strategies for CP in high-risk infants by identifying risk factors for CP are necessary. For an individual infant, it is essential to establish a diagnosis of CP or motor development as early as possible to optimise the effectiveness of rehabilitative intervention.
PRENATAL RISK FACTORS
Foetoplacental and uterine infection or inflammation will cause the initiation of preterm labour, which might cause Central Nervous System (CNS) injury and CP. Underdeveloped foetal brains are more prone to inflammation and inflammatory cytokines. These cytokines are hypothesised to be accountable for the event of Periventricular Leuckomalacia (PVL) (26),(45).
Chorioamnionitis is an infection of the chorion and amnion, the two membranes encompassing the developing foetus. It’s the foremost frequently related to maternal infection in CP. Wu YW et al., concluded that chorioamnionitis will be thought about a reason for CP. In their study, they found that chorioamnionitis is severally related to a 4-fold exaggerated risk of CP in infants (16). Chorioamnionitis could cause CP by depriving the foetus of oxygen for a while which can cause brain injury. Researches show that maternal infection and Urinary Tract Infection (UTI) is one of the causes of CP (18),(24),(26),(45). The main finding of this study was that maternal infection was related to more or less two-fold exaggerated risk of CP in each term and preterm infants. The effect of maternal infection on CP risk appears to be greater in preterm than in term infants.
Few studies showed that GA and pre-eclampsia are the reason for CP. GA appears to modify the impact of risk factors for CP, significantly pre-eclampsia, and small for GA (17),(19),(20),(21); these seems protective before 33 weeks gestation, however it is associated with an exaggerated risk of CP in term babies. Many explanations have previously been put forward to explain this counterintuitive phenomenon. Firstly, babies with cerebral damage delivered preterm to mothers with pre-eclampsia are more vulnerable to mortality. With current management, however, most babies delivered preterm attributable to severe pre-eclampsia survive. Secondly, magnesium sulfate, used in many centers for the prevention or treatment of seizures is also neuroprotective (14). Maternal age, the exaggerated risk of CP among offspring of women over the age of 35 years in one study was vital compared with offspring of women aged from 18 years to 35 years. The exaggerated risk of CP in this group might be associated with changes in uterine function seen with advancing age and the state of high-risk pregnancy and its multiple co-variates (33). In the present study, one of the articles showed that multiple pregnancies, low birth weight, and GA are causes of CP (34). Meeraus WH et al., in their study, found no association between antibiotic prescribing in pregnancy and CP (28). The distribution of cases differs substantially between twins and singletons, and the higher rate of CP in twins cannot be exclusively attributed to their low birth weight and GA (20).
INTRAPARTUM AND NEONATAL RISK FACTORS
Intrapartum risk factors as well as asphyxia and intrapartum stroke, had attracted the more range of publications, followed by genetic studies [57-62]. In general, CP is associated with complicated perinatal events, but most cases may require delivery care as well. Toxoplasmosis, other infections (varicella zoster, adenovirus, enterovirus), rubella, cytomegalovirus, herpes simplex virus, and syphilis are associated with Toxoplasmosis, Others (syphilis, hepatitis B), Rubella, Cytomegalovirus, Herpes simplex (TORCH) [63,64]. About 5% of CP cases are caused by TORCH infections (62). There has been some evidence that birth asphyxia contributes to CP (27),(47),(36),(51),(53). Between 4 and 9 million infants in developing countries suffer from birth asphyxia annually (65). Neonatal asphyxia accounts for 20%-40% of all neonatal deaths every year (15). There was also a strong association between birth asphyxia and CP, which is supported by recent reports identifying birth asphyxia in clinical chorioamnionitis (16).
Although CP is associated with preterm deliveries, the majority of infants with CP (75%) are born after 36 weeks. It is hypothesised that delivering a foetus with cerebral abnormalities is also associated with physiological changes that trigger labour as foetuses with cerebral abnormalities tend to be delivered either preterm or post-term (66). Gurbuz A et al., in their study concluded that low birth weight is one in every common causes of CP. The only significant perinatal risk factor was the neonatal weight of <2500 grams (39).
Few articles showed that low APGAR score, placental abruption, and vaginal breech delivery can be one of the causes of CP (15),(19). Low APGAR scores were highly associated with CP, and although low scores may reflect a compromise of different origins [15,19]. Five-minute APGAR scores below 4 at term in no malformed neonates are often associated with acidemia at birth, indicating intrapartum hypoxia, and with neonatal encephalopathy (19). Instrumental delivery and emergency caesarean delivery were both associated with CP (40).
A few causes supported by different articles are Meningitis, PDA, and PVL, IUGR; which is one of the causes of CP. PVL is considered the result of different causal pathways leading to CP in preterm neonates and is better interpreted as a proxy measure of CP rather than a risk factor, although a minority of children with PVL do not develop CP (41). The most common cause of CP in preterm newborns is PVL, a disorder in which the white matter around the ventricles of the brain is undeveloped. Intraventricular Haemorrhage (IVH), which is mostly linked to prematurity, is brought on by the infant’s developing blood vessels’ susceptibility to rupture. Other areas of the brain may experience ischaemia or PVL due to IVH (67). One study demonstrates that hypoxia and the neck cord are two causes of CP. Most cases of suffocation were caused by cord and placental problems. In one study, the chord around the neck was significantly associated with an increased risk of spastic CP, while placental infarction was more strongly connected with an increased risk of spastic quadriplegia (42).
Collins MP et al., showed that there was a strong relationship between exposure to a modest degree of hypocapnia and the risk of developing CP (37). One study showed that meningitis and encephalitis are also the cause of CP and they also found that mature babies had prenatal brain atrophy or hypoxic-ischaemic cerebral lesions. Immature babies ≥33 week showed prenatal porencephaly or encephalomalacia after asphyxia. Premature babies ≤32 week had cystic periventricular leucomalacia or cerebral haemorrhage (38).
A sizable number of CP cases are due to acquired factors such meningoencephalitis, seizure disorders, and newborn jaundice (51). One of the risk factors for CP is also epilepsy. A dyskinetic or bilateral spastic kind of CP, as well as other associated deficits, was more common in children with epilepsy, according to one of the studies, the author discovered (47).
All studies that have examined these risk factors for babies have found them to exist, and targeted prevention efforts should be made to address them; limiting the number of IVF embryo transfers, quitting smoking while pregnant, screening for and treating asymptomatic bacteriuria during pregnancy, and antiplatelet medications to prevent pre-eclampsia are some specific methods to lower the likelihood of premature birth (68).
Reducing the risk of premature delivery and other preventative measures by being aware of the risk factors are interventions that show promise for lowering the prevalence of CP. Since infancy and early childhood are times of maximum neuronal plasticity and when therapeutic interventions have the best chance of long-term effectiveness, it is important to diagnose CP or developmental delay in infants as early as possible to optimise the effect of the intervention. Therefore, the earlier we begin the intervention, the greater the impact on motor and cognitive outcomes (69),(70),(71),(72).
Preventive measures and early intervention for infants who are at high risk for CP are necessary because the condition includes a variety of aetiologies and risk factors, including prenatal, perinatal, and neonatal causes. Although the existence of many risk factors that override the body’s defence mechanisms may exacerbate CP, although any one risk factor, if significant, may be sufficient to cause CP. Patients with brain malformations are a unique population that requires additional research to determine the risk factors that may contribute to it, including environmental variables, genetic predisposition, and other prenatal or perinatal events. To discover the best preventative measures to use with these patients, more research is required.
Author, Dr. Pranali Saurabh Thakkar expresses immense pleasure and satisfaction in presenting this review. Author would like to express sincere gratitude to the advisor, Dr. Madhavan Iyengar for the guidance during the review. Author would wish to avail herself of this opportunity and, express a sense of gratitude and to author’s husband, parents and family for providing with all kinds of support. Author expresses heartily thanks to all the colleagues and friends.
DOI: 10.7860/JCDR/2023/56550.17671
Date of Submission: Mar 24, 2022
Date of Peer Review: Jun 18, 2022
Date of Acceptance: Oct 20, 2022
Date of Publishing: Mar 01, 2023
AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was Ethics Committee Approval obtained for this study? No
• Was informed consent obtained from the subjects involved in the study? No
• For any images presented appropriate consent has been obtained from the subjects. No
PLAGIARISM CHECKING METHODS:
• Plagiarism X-checker: Apr 02, 2022
• Manual Googling: Sep 23, 2022
• iThenticate Software: Oct 18, 2022 (22%)
ETYMOLOGY: Author Origin
- Emerging Sources Citation Index (Web of Science, thomsonreuters)
- Index Copernicus ICV 2017: 134.54
- Academic Search Complete Database
- Directory of Open Access Journals (DOAJ)
- Embase
- EBSCOhost
- Google Scholar
- HINARI Access to Research in Health Programme
- Indian Science Abstracts (ISA)
- Journal seek Database
- Popline (reproductive health literature)
- www.omnimedicalsearch.com