Risk factors of cerebral palsy in children: a systematic review and meta-analysis
Original Article

Risk factors of cerebral palsy in children: a systematic review and meta-analysis

Dandan Chen1#, Meiyuan Huang2#, Yangyan Yin1, Dongmei Gui1, Yuniao Gu2, Taiping Zhuang2, Caihua Chen2, Kaiming Huo3

1Department of Pediatrics, the First Affiliated Hospital of Hainan Medical University, Haikou, China; 2Department of Neonatology, Hainan Women and Children’s Medical Center, Haikou, China; 3Department of Pediatrics, The Second Affiliated Hospital of Hainan Medical College, Haikou, China

Contributions: (I) Conception and design: D Chen, C Chen; (II) Administrative support: Y Yin; (III) Provision of study materials or patients: D Chen, M Huang, C Chen; (IV) Collection and assembly of data: D Chen, C Chen; (V) Data analysis and interpretation: D Chen, M Huang, C Chen; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

#These authors contributed equally to this work.

Correspondence to: Caihua Chen. Department of Neonatology, Hainan Women and Children’s Medical Center, Haikou, China. Email: licaihua84649@163.com.

Background: This study aimed to explore the main risk factors for cerebral palsy in children by meta-analysis of the literature on the risk factors of cerebral palsy.

Methods: We performed a literature search of the PubMed, EMBASE, Medline, and CENTRAL databases using the following search terms: (“cerebrl plsy” or “cerebrl plsis” or “infantile cerebral palsy”) and (“risk factors”). Case-control or cohort studies of children with cerebral palsy and healthy children were included for meta-analysis. The Newcastle-Ottawa Scale (NOS) of case-control studies was used to evaluate the quality of the included studies. The Chi-square test was used to test the heterogeneity of the literature. This study used subgroup analysis and sensitivity analysis to identify sources of heterogeneity. If subgroup analyses and sensitivity analyses could not identify the source of heterogeneity, no pooling between study results was performed, and only individual study results were described. In this study, Egger’s test was used to test for publication bias. The random-effects model was used when heterogeneity existed, and the fixed-effect model was applied when heterogeneity did not exist.

Results: A total of 1,836 related articles were retrieved. After screening, 13 articles were included in the analysis, involving a total of 2,489 children with cerebral palsy and 4,782 children without cerebral palsy. None of the included articles achieved a NOS score of 9, four articles scored 8, eight articles scored 7, and one article scored 6. Meta-analysis showed that maternal hypertension during pregnancy, premature rupture of membranes, premature delivery and emergency cesarean section were risk factors for cerebral palsy in children, and there was no heterogeneity among the literatures and no publication bias.

Conclusions: This study identified gestational hypertension, preterm birth, premature rupture of membranes, and emergency cesarean section as risk factors for cerebral palsy in children through meta-analysis, providing a reference for risk monitoring and clinical intervention.

Keywords: Children; cerebral palsy; risk factors


Submitted Feb 15, 2022. Accepted for publication Apr 07, 2022.

doi: 10.21037/tp-22-78


Introduction

Pediatric cerebral palsy is a clinical syndrome caused by brain injury or lesions in children from before birth to 1 month after birth, and mainly manifests as non-progressive central dyskinesia and abnormal posture (1,2). Research has shown that the prevalence of cerebral palsy in children worldwide is about 3.16% (3), and results in heavy familial and social burdens as well as usage of medical resources (4,5). Despite considerable research, the complex etiology and pathogenesis of cerebral palsy remain unclear. The high-risk factors of cerebral palsy are complex and diverse (6,7), and the time span of these risk factors is long, which can occur at birth as well as before or after birth. Moreover, these risk factors affect each other and form an intertwined network, leading to the occurrence of diseases (8,9). Unfortunately, previous research on risk factors for cerebral palsy in children has been limited and inconsistent. For example, a study was limited to at-birth and fetal factors (5). Perinatal factors and maternal factors are usually ignored (5). Whether gestational hypertension increases the risk of cerebral palsy in children has long been controversial. A study has pointed out that preterm birth leads to a significant increase in the incidence of cerebral palsy (7). One study has also pointed to neurodevelopmental impairment, rather than preterm birth, as a risk factor for cerebral palsy (6). Emergency cesarean section and premature rupture of membranes are risk factors for cerebral palsy in term infants, but the relationship between the three is not close in preterm infants. In addition, due to the development of maternal and neonatal medical and nursing techniques, the risk factors for pediatric cerebral palsy have changed, such as premature birth and the incidence of brain injury caused by hyperbilirubinemia has dropped sharply. In today’s medical context, identifying or updating risk factors for pediatric cerebral palsy can inform preventive interventions. Aiming at the above-mentioned controversy, this study conducted a meta-analysis of the literature published over the past 20 years exploring the pregnancy risk factors of mothers with infantile cerebral palsy, in order to find the main risk factors of infantile cerebral palsy. Our study calculated the odds ratio (OR) and 95% confidence interval (CI) to provide a scientific basis for the prevention and decision-making of infantile cerebral palsy. We present the following article in accordance with the MOOSE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-22-78/rc).


Methods

Bibliography retrieval

We performed literature searches of the PubMed, EMBASE, MEDLINE, and CENTRAL databases using the following search terms: (“cerebrl plsy” or “cerebrl plsis” or “infantile cerebral palsy”) and (“risk factors”).

Literature screening

The inclusion criteria were as follows: (I) case-control or cohort study; (II) the subjects of the study were children with cerebral palsy and healthy control children; (III) the subject of literature research is the risk factors of cerebral palsy in children; (IV) exposure factors include gestational hypertension, premature birth, premature rupture of membranes, or emergency cesarean section; (IV) there are risk ratio (RR) values or odds ratio (OR) values and corresponding 95% confidence intervals (CI) in the results of literature studies or can be calculated based on data..

The exclusion criteria were as follows: (I) studies with no control group; (II) literature studies other exposure factors; (III) the diagnostic criteria of the subjects were lacking or unclear; and (IV) case reports and replicate studies.

Document data sorting

In this study, a researcher sorted the basic information and data of the literature that met the inclusion criteria, which included the literature title, publication year, author information, statistical methods, published journals, OR value or RR value, 95% CI, etc. Another researcher conducted information verification and data proofreading to ensure the accuracy of the information and data.

Literature quality evaluation

In this paper, three researchers used the Newcastle-Ottawa scale (NOS) of included studies to evaluate the quality of the included studies in terms of the selection of subjects (4 points), intergroup comparability (2 points), and exposure factor measurement (3 points), with a total of 9 points. Three researchers jointly completed the literature quality evaluation. Disagreements were resolved by discussion and consensus.

Heterogeneity test

The Chi-square test was used to assess the heterogeneity of the included studies. When the corrected I2 value by degrees of freedom was >50% and P<0.1, it was considered that there was heterogeneity among the published literatures. Subgroup analysis was used to explore the causes of heterogeneity; if the cause of heterogeneity was not found, the random effects model was employed. However, when I2≤50% and P≥0.1 after degrees of freedom correction, it was considered that there was no heterogeneity among the published literature, and the fixed effects model was applied.

Analysis of sources of heterogeneity and testing for publication bias

If there is heterogeneity among the literatures, this study used subgroup analysis and sensitivity analysis to determine the source of heterogeneity. If subgroup analyses and sensitivity analyses could not identify the source of heterogeneity, no pooling between study results was performed, and only individual study results were described. In this study, Egger’s test was used to test for publication bias.

Statistical analysis

The Cochrane RevMan5.3 software (The Nordic Cochrane, Copenhagen) was used to analyze the data. The observation factors were statistically described using the OR value and 95% CI. Two-sided P<0.05 was considered to indicate statistical significance.


Results

Retrieval results and literature quality evaluation

In this study, 1,836 literatures related to the risk factors of cerebral palsy in children were retrieved from the databases. After screening according to the inclusion and exclusion criteria, 13 articles were included in the analysis, 3 cohort studies, 10 case control studies. There were a total of 2,489 children with cerebral palsy and 4,782 children without cerebral palsy. In terms of the NOS scores of the 13 included studies, none of the articles scored 9, four scored 8, eight scored 7, and one scored 6. The literature screening flow chart was shown in Figure 1 and basic information of the included studies was shown in Table 1.

Figure 1 Literature screening flow chart.

Table 1

Basic characteristics and Newcastle-Ottawa Scale (NOS) scores of the included literature

Study Study design NOS
Drougia (4) 2007 Case control 8
Bufteac (8) 2021 Cohort 8
Gurbuz (9) 2006 Case control 7
Ichizuka (10) 2021 Case control 7
Kulak (11) 2010 Case control 7
Livinec (3) 2005 Cohort 7
Monokwane (12) 2017 Case control 8
Moster (13) 2010 Case control 7
Nielsen (14) 2008 Case control 6
Stelmach (15) 2005 Case control 7
Walstab (5) 2004 Case control 7
Yuan (1) 2019 Case control 7
Herbst (16) 2001 Cohort 8

Analysis of risk factors of cerebral palsy

Maternal pregnancy-induced hypertension

Six of the 12 included articles investigated the relationship between maternal pregnancy-induced hypertension and cerebral palsy. There was no heterogeneity among these six studies (χ2=7.69, P=0.17, I2=35%), and the fixed effects model was used. The combined OR value was 1.93, 95% CI was (1.48, 2.52), and the combined effect quantity was Z=4.80 (P<0.00001). Therefore, maternal gestational hypertension was identified as ana risk factor for cerebral palsy, as shown in Figure 2. Egger test showed no publication bias in the above six articles (P>0.05), as shown in Figure 3.

Figure 2 Forest map of maternal pregnancy-induced hypertension and cerebral palsy in children. CI, confidence interval; SE, standard error.
Figure 3 Funnel diagram of maternal pregnancy-induced hypertension and cerebral palsy in children. OR, odds ratio.

Premature rupture of membranes

Seven of the 12 included articles studied the relationship between premature rupture of membranes and cerebral palsy. There was no heterogeneity among the 7 studies (χ2=6.80, P=0.34, I2=12%), and the fixed effects model was us ed. The combined OR value was 2.82, 95% CI was (2.14, 3.72), and the combined effect quantity was Z=7.36 (P<0.00001). Thus, premature rupture of membranes was identified as a risk factor for cerebral palsy in children, as shown in Figure 4. Egger test showed no publication bias in these seven articles (P>0.05), as shown in Figure 5.

Figure 4 Forest map of premature rupture of membranes and cerebral palsy in children. CI, confidence interval; SE, standard error.
Figure 5 Funnel diagram of premature rupture of membranes and cerebral palsy in children. OR, odds ratio.

Premature delivery

Seven of the 12 included articles examined the relationship between preterm birth and cerebral palsy. There was no heterogeneity among the seven studies (χ2=2.98, P=0.81, I2=0%), and the fixed effects model was used. The combined OR value was 2.90, 95% CI was (2.13, 3.93), and the combined effect quantity was Z=6.83 (P<0.00001). Hence, preterm birth was identified as a risk factor for cerebral palsy in children, as shown in Figure 6. Egger test showed no publication bias in these seven articles (P>0.05), as shown in Figure 7.

Figure 6 Forest map of premature birth and cerebral palsy in children. CI, confidence interval; SE, standard error.
Figure 7 Funnel diagram of preterm birth and cerebral palsy in children. OR, odds ratio.

Emergency cesarean section

Six of the 12 included articles explored the relationship between emergency cesarean section and cerebral palsy. There was no heterogeneity among these six literatures (χ2=6.84, P=0.23, I2=27%), and the fixed effects model was used. The combined OR value was 1.99, 95% CI was (1.63, 2.43), and the combined effect amount was Z=6.75 (P<0.00001). Thus, emergency cesarean section was identified as a risk factor for cerebral palsy, as shown in Figure 8. Egger test showed no publication bias in these six articles (P>0.05), as shown in Figure 9.

Figure 8 Emergency cesarean section and forest map of cerebral palsy in children. CI, confidence interval; SE, standard error.
Figure 9 Funnel diagram of emergency cesarean section and cerebral palsy in children. OR, odds ratio.

Discussion

The pathogenic factors of cerebral palsy in children are complex. Comprehensive monitoring of various risk factors and timely intervention can significantly reduce the risk (17). Our study confirmed that maternal pregnancy-induced hypertension, premature rupture of membranes, premature delivery, and emergency cesarean section were risk factors for cerebral palsy in children.

Through meta-analysis, Himmelmann et al. (18) confirmed that maternal pregnancy-induced hypertension was a risk factor for cerebral palsy in children, which is consistent with our results. Research has pointed out that pregnancy-induced hypertension is primarily attributable a systemic arteriolar spasm, resulting in insufficient blood supply to the placenta and severe intrauterine hypoxia, fetal craniocerebral nerve injury, and even fetal neonatal death (19). In addition, a study has confirmed that the infants of pregnant mothers with pregnancy-induced hypertension have mental retardation, and the intelligence of these newborns is significantly lower than that of infants of normal pregnancy. In fact, there were still differences in intelligence between these two groups at adulthood (20). This study confirmed that gestational hypertension causes irreversible damage to the fetal nervous system. Timely symptomatic treatment and control of maternal blood pressure during pregnancy can effectively reduce the long-term disability risk of newborns (20).

A previous study has also shown a significant correlation between preterm birth and cerebral palsy in children (21). In recent 20 years, neonatal science has been continuously developing, resulting in increased survival rates among premature infants. The incidence rate of cerebral palsy has also increased (22,23). Epidemiological investigation has shown that preterm infants account for about 7% of all surviving newborns, but preterm cerebral palsy accounts for about 40% of cerebral palsy cases (21). Premature infants have immature development in all organs. Brain tissue is the most vulnerable to damage, and clinical manifestations are the most obvious (24,25). In addition, a study has indicated that the incidence rate of cerebral palsy is negatively correlated with gestational age; when the gestational week is less than 28 weeks, the risk of cerebral palsy increases about 70 times (17).

Through meta-analysis, O’Callaghan et al. (26) confirmed that emergency cesarean section was a risk factor of cerebral palsy, which is consistent with our results. The results of their study do not support that elective cesarean section, full-term cesarean section, premature cesarean section, and breech cesarean section were risk factors for cerebral palsy, although they are also not protective factors. Their study does not recommend emergency cesarean section to prevent cerebral palsy in children. Compared with emergency cesarean section, clinical monitoring should be strengthened and planned elective cesarean section should be selected. An additional study has pointed out that caesarean section can reduce the incidence and severity of ventricular hemorrhage in preterm infants (27). In the case of premature delivery, further research should be conducted.

Premature rupture of membranes is a risk factor for mother-infant infection and can eventually progress to preterm birth (28). Research has confirmed a correlation between the incidence of premature rupture of membranes and the incidence of cerebral palsy in children. In our research results, premature rupture of membranes was a risk factor for cerebral palsy, which is consistent with previous research findings. Our research clearly expounded on the relationship between premature rupture of membranes and cerebral palsy. Clinically, it is necessary to treat premature rupture of membranes according to a series of conditions, such as amniotic fluid pollution, gestational weeks, and fetal maturity. Appropriate treatment can reduce the incidence rate of cerebral palsy (29).

In addition to the risk factors of cerebral palsy in children determined in our study, other studies have identified low body weight, neonatal respiratory distress, maternal infection during pregnancy, neonatal infection, persistent jaundice, multiple births, and amniotic fluid pollution a risk factors of cerebral palsy (12,30). It should be noted that these factors do not exist independently but are intertwined. The emergence of a risk factor may result from the joint action of several other risk factors. For example, pregnancy-induced hypertension and premature rupture of membranes may cause preterm birth. Preterm infants can easily experience symptoms such as neonatal low weight and infection (31). This interactive role network dramatically increases the difficulty of disease monitoring and prevention.

This study identified the risk factors of cerebral palsy in children through meta-analysis, which provides a reference basis for risk monitoring and clinical intervention.


Acknowledgments

Funding: The project was supported by Hainan Province Clinical Medical Center.


Footnote

Reporting Checklist: The authors have completed the MOOSE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-22-78/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-22-78/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.


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Cite this article as: Chen D, Huang M, Yin Y, Gui D, Gu Y, Zhuang T, Chen C, Huo K. Risk factors of cerebral palsy in children: a systematic review and meta-analysis. Transl Pediatr 2022;11(4):556-564. doi: 10.21037/tp-22-78