Edited by: Bobbi Fleiss, RMIT University, Australia
Reviewed by: Sandra E. Juul, University of Washington, United States; Thalia Harmony, National Autonomous University of Mexico, Mexico
This article was submitted to Pediatric Neurology, a section of the journal Frontiers in Neurology
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Cerebral palsy (CP) is a group of syndromes caused by non-progressive brain injury in the fetus or infant and leads to lifelong disability (
Birth asphyxia is one of the important causes of neonatal morbidity and mortality (
Relevant studies were searched from the PubMed, Google Scholar, Embase, and Cochrane Library databases up to 31 December 2019. The search was performed using keywords and subject terms related to “birth asphyxia.” The keywords and subject terms related to “cerebral palsy” or “neurodevelopmental outcome” were used to acquire studies related to CP. We combined the two parts of the search terms using “AND” to retrieve the studies (
Eligible studies were limited to research focusing on the following: (1) newborn infants who were born at ≥35 weeks' gestation, (2) evidence of birth asphyxia based on a pH ≤ 7.0 and/or a base deficit ≥12 mmol/L in an umbilical cord blood sample during the first hour after birth, and (3) clinical hypoxic ischemic encephalopathy (HIE) manifestation as well as neurodevelopmental outcomes that included data on CP. Additionally, when multiple studies based on the same population were published, only the most complete one was included.
The following exclusion criteria were applied: (1) reviews, meta-analyses, or case reports, (2) studies not published in English, (3) studies using evidence for birth asphyxia that was inconsistent with our inclusion criteria described above, and (4) studies reporting overlapping data.
Information relating to data extraction was gathered individually from each identified article, including the name of the first author, study design, publication year, the size of sample, gestational age, asphyxiation criteria, follow-up period, and neurodevelopmental outcome regarding CP.
Of the included studies, eight were randomized controlled trials and two were observational studies. The Newcastle-Ottawa Scale was used to evaluate the quality of the observational studies (
Stata software version 12.0 (Stata Corporation, College Station, TX, US) was used for data analysis. The combined rate of CP and 95% confidence intervals (CIs) were calculated for all predetermined groups. A random effects model was used to give a pooled estimate of prevalence because of the small number of studies and the heterogeneity across studies in this meta-analysis. Heterogeneity was estimated by the Q statistic and the
The electronic database searches initially yielded 5,671 studies, and 5,616 studies were deleted due to either repetition or lack of relevance. A total of 55 full-text studies were retrieved and critically appraised. Of these articles, 45 did not satisfy the inclusion criteria (9 studies performed secondary analyses on the same study populations, 17 studies did not report the neurodevelopment outcomes, 4 studies did not have data for the pH of umbilical cord blood, and 15 studies were excluded due to unusable data such as articles that reported the prevalence of CP between those with birth asphyxia and those without birth asphyxia and articles for which the exact association between asphyxia and CP could not be determined). Of the remaining 10 acceptable studies, 8 studies were randomized controlled trials and 2 studies were observational studies (
Flow chart for study selection.
We compiled a dataset of 1,665 infants from the 10 studies. All of the neonates in the included studies meeting the asphyxia criteria were diagnosed as HIE. Of the eight randomized controlled trials (
Characteristics of the included studies.
Carli et al. ( |
2004 | Cohort study | 43 | ≥37 | pH < 7.00 or BD ≥ 12 mmol/L | 13 | 12–36 months |
Gluckman et al. ( |
2005 | RCT | 218 | ≥36 | pH < 7.00 or BD > 16 mmol/L | 52 | 18 months |
Shankaran et al. ( |
2005 | RCT | 205 | ≥36 | pH ≤ 7.00 or BD ≥ 16 mmol/L | 34 | 18–22 months |
Azzopardi et al. ( |
2009 | RCT | 323 | ≥36 | pH < 7.00 or BD ≥ 16 mmol/L | 81 | 18 months |
Simbruner et al. ( |
2010 | RCT | 111 | ≥36 | pH < 7.00 or BD > 16 mmol/L | 14 | 18–21 months |
Jacobs et al. ( |
2011 | RCT | 208 | ≥35 | pH < 7.00 or BD ≥ 12 mmol/L | 38 | 24 months |
Perez et al. ( |
2013 | Cohort study | 68 | ≥36 | pH < 7.1 and BD < −10 mmol/L | 11 | 8.2–15.7 years |
Filippi et al. ( |
2017 | RCT | 42 | ≥36 | pH < 7.00 and/or BD > 16 mmol/L | 13 | 18–24 months |
Malla et al. ( |
2017 | RCT | 100 | ≥37 | pH ≤ 7.00 and/or BD ≥ 16 mmol/L | 29 | 19 months |
Shankaran et al. ( |
2017 | RCT | 347 | ≥36 | pH ≤ 7.00 or BD ≥ 16 mmol/L | 47 | 18–22 months |
Sensitivity analysis was conducted on the eight randomized controlled trials, and none of them had a significant impact on the results of the meta-analysis, suggesting that this study had good stability (
In the eight randomized controlled trials, the number of infants with CP was 308 for a pooled rate of 20.3% (95% CI: 16.0–24.5,
Forest plot of the pooled rate of cerebral palsy. The solid diamonds and horizontal solid lines represent the proportions and 95% CIs of each included study. The size of the gray area indicates the study-specific statistical weight. The hollow diamonds show the pooled proportions and 95% CIs of each group and the overall population. The vertical red dotted line shows the combined effect estimate.
Forest plot of the pooled rate of cerebral palsy in the intervention and non-intervention groups in randomized controlled trials. The solid diamonds and horizontal solid lines represent the proportions and 95% CIs of each included study. The size of the gray area indicates the study-specific statistical weight. The hollow diamonds show the pooled proportions and 95% CIs of each subgroup and the overall population. The vertical red dotted line shows the combined effect estimate.
To our knowledge, this is the first evaluation of the link between birth asphyxia and CP using the pH value of umbilical cord blood as a diagnostic criterion for birth asphyxia in addition to clinical HIE manifestations. The results of this meta-analysis indicated that birth asphyxia is associated with CP in both term and near-term infants.
Birth asphyxia might affect the outcomes of neurodevelopment in infants through a variety of mechanisms. Prolonged or intense asphyxia will cause energy depletion in tissues that depend on aerobic metabolism, such as the central nervous system (
The accurate diagnosis of birth asphyxia is still a challenge worldwide, resulting in an unclear correlation between asphyxia and CP. Birth asphyxia is predicated by fetal metabolic acidosis, as measured by umbilical cord pH at birth (
The American Academy of Pediatrics and the Society of Obstetrics and Gynecology suggests that infants suffering from “asphyxiation” near delivery, which is severe enough to result in acute neurologic injury, should meet the following criteria: (1) severe metabolic or mixed acidemia (pH < 7.00) on an umbilical arterial blood sample, (2) an Apgar score of 0 to 3 for longer than 5 min, (3) neurologic manifestation such as seizure, coma, or hypotonia, and (4) evidence of multiorgan dysfunction (
The evidence reported in previous studies was unable to support a clear association between birth asphyxia and CP (
Previous analysis the association of birth asphyxia and CP showed a large variation from 3 to 50% (
Our meta-analysis has some other limitations. First, we only searched literature published in English. Second, publication bias and incomplete ascertainment of published literature might exist. Third, the number of studies in our analysis was small, and the selection of the diagnostic criteria of birth asphyxia might have caused a selection bias in our study. Therefore, the results of this study should be interpreted with caution. Furthermore, some of the included studies used interventions, so measurement bias existed and some heterogeneity was inevitable.
In conclusion, our meta-analysis provides evidence that birth asphyxia is associated with CP in children. Thus, the prevention and treatment of birth asphyxia is of great significance for reducing the prevalence of CP.
All datasets presented in this study are included in the article/
SZ and BL searched the databases, screened the articles, and collected the data. SZ wrote the first draft of the manuscript. BL and XZ were responsible for the statistical analysis and interpretation of the data. XW coordinated and supervised the data collection. SZ, CZ, and XW participated in study conception and design. XZ, CZ, and XW critically reviewed and revised the manuscript. All authors contributed to and approved the final version. All authors contributed to the article and approved the submitted version.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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