Cerebral palsy and multiple births in China
Jian-meng Liua,
Zhu Lia,
Qing Linb,
Ping Zhaoa,
Feng-lin Zhaoc,
Shi-xin Honga and
Song Lib
a National Center for Maternal and Infant Health, Beijing Medical University, 38 College Road, Beijing 100083, People's Republic of China. E-mail: Liujm{at}ncmih.bjmu.edu.cn
b The First Affiliated Hospital, Beijing Medical University, Beijing, PR. China.
c The Third Affiliated Hospital, Beijing Medical University, Beijing, PR. China.
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Abstract
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Background A population-based study on prevalence of cerebral palsy in multiple births has not been carried out in China. The purpose of this paper was to determine the prevalence of cerebral palsy in multiple births and to explore the influence of multiple pregnancy on cerebral palsy after controlling for birthweight.
Methods A cross-sectional study of cerebral palsy was carried out among 388 192 children aged <7 years in seven cities of Jiangsu province in China. Information about birthweight and plurality was obtained from routine health care records. Pediatricians at city level diagnosed all cases. All the doctors involved had taken part in a training programme held by Beijing Medical University. Stratified analysis by birthweight and its standard normal deviate was employed to compare the prevalence of cerebral palsy in multiples and singletons.
Results The prevalence of cerebral palsy for children aged <7 years in multiples was 9.7 per 1000 children (95% confidence interval [CI]: 6.514.0), which was 6.5 times that in singletons (95% CI : 4.49.3). The overall neonatal mortality rate was 60.9 per 1000 liveborn multiples, being highest (944.4 per 1000) in the 500999 g birthweight groups. Most liveborn multiples weighing <1500 g at birth probably died from diseases related to very low birthweight prior to this study. The prevalence of cerebral palsy in multiple births was likely to be higher than that reported in developed countries for children weighing 15002499 g even though our data were from a cross-sectional study. When stratified by birthweight, the prevalence of cerebral palsy in multiples weighing <2500 g had tended to be lower than that of singletons in the same birthweight group. In contrast, in normal birthweight categories multiple births had a higher prevalence of cerebral palsy than singletons. When stratified by birthweight normal deviate, the prevalence of cerebral palsy in multiple births was uniformly higher than that in singletons in all birthweight strata and the prevalence of cerebral palsy among multiples appeared to be augmented as birthweight increased.
Conclusion The prevalence of cerebral palsy in multiples, 9.7 per 1000 children, is 6.5 times that in singletons. Survival of low birthweight infants is lower in China than in developed countries and survival quality of Chinese children weighing 15002499 g needs to be further improved. In terms of birthweight multiples and singletons may be heterogeneous. It might be difficult to directly use actual birthweight specific prevalence to compare the prevalence of cerebral palsy in multiples and singletons. Birthweight normal deviate specific prevalence of cerebral palsy suggests that multiple pregnancy is an independent risk factor for cerebral palsy in all birthweight groups. Multiples are in adverse circumstances very early in gestation and as the foetus matures the risk of cerebral palsy increases.
Keywords Cerebral palsy, multiple births, low birthweight, prevalence, standard normal deviate, neonatal mortality
Accepted 20 September 1999
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Introduction
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Multiple births are not only vulnerable to early illness and death but are also at higher risk of developing cerebral palsy. The birth prevalence of cerebral palsy in twins, ranging from 6.712.6 per 1000 infant survivors, is approximately 58 times that in singletons in developed countries. Furthermore many
studies show that birthweight-specific prevalence in low birthweight groups is similar between twins and singletons and that in normal birthweight categories it is higher in twins than in singletons.15 Why does the risk of cerebral palsy in multiple pregnancies only become apparent in normal birthweight groups? In addition, until now there has been no population-based study on birthweight-specific prevalence of cerebral palsy in multiples in China. Here we mainly report overall and birthweight-specific prevalence of cerebral palsy in multiples and singletons and explore the adverse effect of multiple pregnancy on cerebral palsy after controlling for birthweight.
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Methods
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The data were from two sources: one was from a cross-sectional study carried out in seven cities and counties of Jiangsu Province from May to July 1997; another from computerized perinatal health care (PHC) surveillance data for births in 19931996 in the same areas. These have been described previously.6
Birthweight-specific prevalence of cerebral palsy was calculated by using data from the cross-sectional study, in which birthweight and plurality were obtained through checking related routine health care records. Information about gestational age was obtained from related medical records and interviewing mothers. Plurality was classified into two groups, multiples and singletons. The PHC surveillance data provided neonatal mortality rate in multiples and singletons and other information about loss probably due to death occurring before this study.
Prevalence and mortality rate estimates were provided with exact binomial 95% confidence intervals (CI). Fisher's exact test and t-test were used to test for the significance of the difference in proportions and in mean birthweight, respectively. Mantel-Haenszel
2 test was employed to test the overall degree of association between multiples and cerebral palsy after controlling for birthweight. All analysis was performed using SPSS 8.0 for Windows.
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Result
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Multiple pregnancy rate
According to PHC surveillance data, during 19931996 there were 205 895 pregnancies resulting in at least one livebirth, consisting of 204 771 singleton pregnancies (including 1800 pregnancies of unknown plurality), 1096 twin pregnancies and 28 triplet and higher order pregnancies. Twinning and triplet (including higher order) rate were 5.3 (95% CI : 5.05.6) and 0.1 (95% CI : 0.00.2) per 1000 total pregnancies.
Birthweight distribution in multiple births and singletons
During 19931996 there were 2297 multiple births and 204 771 singletons born alive. Multiple births made up 1.1% of all livebirths; 1038 twin pairs born alive were identified, of which there were 187 (18.0%) unlike-sexed pairs and 851 (82.0%) like-sexed pairs. The birthweight was known for 2236 (97.3%) newborns in multiple births and 196 170 (95.8%) in singletons. Figure 1
shows the birthweight distribution of liveborn multiple births and singletons. The mean and standard deviation (SD) birthweight in singletons was 3286 g (438 g) and in multiple births 2384 g (536 g). The difference in mean birthweight between multiple births and singletons was 902 g and was highly significant (P < 0.01). 0.81%, 5.5% and 53.2% of liveborn multiple births were of birthweight <1000 g, <1500 g and <2500 g compared with 0.1%, 0.2% and 2.6% of singletons, respectively. Multiple births were 20.5 (95% CI : 19.6 21.5) and 31.9 (95% CI : 26.139.0) times more likely than singletons to be born weighing <2500 g and 1500 g, respectively.
Neonatal mortality rate in multiple births and singletons
Among 2297 and 204 771 liveborn multiple births and singletons, there were 140 and 1261 neonatal deaths, giving a neonatal mortality rate of 60.9 (95% CI : 51.571.5) and 6.2 (95% CI : 5.86.5) per 1000 livebirths, respectively. Multiple births accounted for 10% of all neonatal deaths. The neonatal mortality rate in multiple births was 9.9 (95% CI : 8.411.7) times that in singletons. Table 1
shows the birthweight-specific neonatal mortality rates in multiple births and singletons. In multiple births, as birthweight increased from 1000 g to 2999 g the neonatal mortality rate decreased rapidly from 528.3 to 4.2 per 1000 livebirths and as birthweight went over 3000 g the neonatal mortality rate started to rise. The similar relationship between birthweight and neonatal mortality rate was also observed in singletons. But it was worth noting that neonatal mortality rate in multiples was significantly lower than that in singletons for those weighing 10002999 g (
MH = 27.457, P < 0.001) and that Mantel-Haenszel relative risk was 0.63 (95% CI : 0.530.75) for multiples compared with singletons after adjusting for birthweight, while the crude relative risk was 3.1 (95% CI : 2.53.7). The neonatal mortality rate in multiples with birthweight of
3000 g was higher than that in singletons of the same birthweight group, but the difference was not significant (P > 0.05) probably because the number of multiple births weighing
3000 g was not large enough to observe the occurrence of neonatal deaths.
Cross-sectional study
Prevalence
The cross-sectional study surveyed 388 192 children aged <7 years, among which there were 2875 multiples (twins and higher order), 385 185 singletons and 132 of unknown plurality; 28 multiples were diagnosed as cerebral palsy, giving a cerebral palsy prevalence of 9.7 per 1000 children (95% CI : 6.514.0). The prevalence in multiples was 6.5 (95% CI : 4.49.3) times that in singletons. Multiples accounted for 4.5% of all cases of cerebral palsy. Detailed information is listed in Table 2
.
Birthweight distribution
The birthweight was known for 2874 (100%) children in multiple births and 384 230 (99.8%) in singletons. Mean birthweight (SD) in multiples was 2508 g (477 g) and in singletons 3293 g (400 g). The former was about 785 g lighter than the latter and the difference was highly significant (P < 0.01). Of multiples 0.94% and 47.4% weighed 10001499 g and <2500 g compared with 0.02% and 1.63% of singletons, respectively. There were almost no children weighing <1000 g. The low birthweight group was predominantly composed of those weighing 15002499 g in multiples and singletons; 78.6% of cases of cerebral palsy in multiples and 21.8% in singletons were in children weighing <2500 g.
Birthweight-specific prevalence
Table 3
and Figure 2
show the birthweight-specific prevalence of cerebral palsy in multiples and singletons. The prevalence of cerebral palsy in multiples decreased from 44.0 to 4.9 per 1000 children as birthweight increased from 1500 g to 2499 g and appeared to rise as birthweight went over 2500 g. In contrast, the prevalence in singletons dropped from 1500 g and reached the lowest level in the group weighing 37503999 g. None of the low birthweight groups, compared individually, showed a significant difference in the prevalence of cerebral palsy between multiples and singletons. A comparison of all children of <2500 g as a single birthweight entity also showed no significant difference between multiples and singletons. But when the Mantel-Haenszel method was used the prevalence of cerebral palsy in multiples was significantly lower than that in singletons for those weighing 10002499 g (
M-H = 5.548, P = 0.019) and that Mantel-Haenszel relative risk was 0.59 (95% CI : 0.380.92) for multiples compared with singletons after adjusting for birthweight. The prevalence of cerebral palsy in multiples and singletons born weighing
2500 g were 4.0 (95% CI : 1.58.6) and 1.2 (95% CI : 1.11.3) per 1000 children, respectively. The difference was 2.8 per 1000 children and highly significant. The prevalence in multiples was 3.3 (95% CI : 1.57.4) times that in singletons for those children weighing
2500 g.
Birthweight normal deviate specific prevalence
Birthweight normal deviate for each child in multiples was calculated by using mean birthweight of multiples and its standard deviation and for singletons by the same method. Multiples and singletons were then regrouped according to the birthweight normal deviate. Table 4
shows the birthweight normal deviate specific prevalence of cerebral palsy in both multiples and singletons. Birthweight normal deviate specific prevalence of cerebral palsy in multiples was unanimously higher in all birthweight groups than that in singletons (
M-H = 173.931, P = 0.000). The risk of cerebral palsy in multiples, compared with that in singletons, appeared to be augmented as birthweight increased (Figure 3
).
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Table 4 Prevalence of cerebral palsy by birthweight normal deviate per 1000 children in multiple births and singletons
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Figure 3 Prevalence of cerebral palsy per 1000 children in multiples and singletons by birthweight normal deviate
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Gestational age-specific prevalence
The gestational age was known for 2495 (86.8%) children in multiples and 339 393 (88.1%) in singletons. 24.4% of multiples were of gestational age <37 weeks compared with 1.3% of singletons. 75% of cases of cerebral palsy in multiples and 21.4% in singletons were in children with gestational age <37 weeks.
Table 5
shows the gestational age-specific prevalence of cerebral palsy in multiples and singletons. The prevalence of cerebral palsy decreased in both multiples and singletons as the gestational age increased. None of the preterm (<37 weeks) groups, compared individually, showed a significant difference in the prevalence of cerebral palsy between multiples and singletons. A comparison of all children of <37 weeks as a single entity also showed no significant difference between multiples and singletons. But the difference in the prevalence of cerebral palsy between multiples and singletons was significant (P = 0.03) for those in the group 3741 weeks. The prevalence of cerebral palsy in multiples and singletons of 3741 weeks was 3.2 (95% CI : 1.27.0) and 1.2 (95% CI : 1.11.4) per 1000 children, respectively. The prevalence in multiples was 2.6 (95% CI : 1.25.9) times that in singletons for those in the group 3741 weeks.
Mean birthweight by gestational age
Table 6
shows mean birthweight by gestational age in multiples and singletons. The difference of mean birthweight between multiples and singletons was significant in all gestation groups except in the group 2830 weeks. It was noted that the larger the gestational age, the larger the difference.
Birthweight normal deviate specific prevalence for gestational age
Birthweight normal deviate for each child in multiples was calculated by using mean birthweight of multiples and its standard deviation for gestational age and in singletons by the same method. Then multiples and singletons were regrouped according to the birthweight normal deviate for gestational age. Table 7
shows the birthweight normal deviate specific prevalence of cerebral palsy for gestational age in both multiples and singletons. Birthweight normal deviate specific prevalence of cerebral palsy for gestational age in multiples was unanimously higher in all birthweight groups than that in singletons (
M-H = 101.74, P = 0.000). The risk of cerebral palsy in multiples, compared with that in singletons, appeared to be augmented as birthweight increased (Figure 4
).
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Table 7 Prevalence of cerebral palsy by birthweight normal deviate for gestational age per 1000 children in multiple births and singletons
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Figure 4 Prevalence of cerebral palsy per 1000 children in multiples and singletons by birthweight normal deviate for gestational age
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Discussion
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During 19931996, the multiple pregnancy rate was 5.5 per 1000 pregnancies resulting in at least one livebirth. Triplet and higher order only accounted for about 2.5% of all multiple pregnancies. The multiple pregnancy rate was much lower than that reported in developed countries, being around 13 per 1000 total pregnancies.78 Although the denominator used was different, it is unlikely that this could cause such a large difference. Higher multiple pregnancy rate in developed countries is partly attributable to the advancement and increasing use of infertility treatments in addition to ethnic differences which are perhaps a major contributor. Concern has been expressed about major short- and long-term health consequences of multiple birth such as cerebral palsy in western societies. It is certain that China will face the same problem with development of medical technology. This is the first large cross-sectional study to estimate the prevalence of cerebral palsy in multiples and to clarify the association between multiple birth and cerebral palsy in China. Relevant information about plurality and birthweight was taken from medical records. The details of plurality and gestational age of some children were not available in this cross-sectional study. Plurality was only classified into two groups, singletons and multiples.
The prevalence of cerebral palsy in twins is 6.712.6 per 1000 infant survivors or 3-year-old twin children.15 The crude prevalence of cerebral palsy in multiples was 9.7 per 1000 children in our study, which fell into the above range. Because our result was from a cross-sectional study, the most important factor to be taken into account was deaths related to low birthweight when making international comparisons.6 The neonatal mortality rate for birth years 19931996 in multiples in our study, 60.9 per 1000 livebirths, was more than three times that of birth years 19921994 in Australia (18.1 per 1000 total births8) and approximately twice that of birth years 19801989 in Western Australia (36.6 per 1000 livebirths5). Furthermore, In the UK Pharoah1 reported that infant mortality rates in five groups of 500999 g, 10001499 g, 15001999 g, 20002499 g and
2500 g were 666.7, 142.9, 26.4, 13.4 and 6.1 per 1000 livebirths in birth years 19821989. In contrast, neonatal mortality rates of multiples in our study for the same five groups were 944.4, 528.3, 123.2, 24.3 and 7.6 per 1000 livebirths and even higher than those infant mortality rates mentioned above. In addition, the results showed that 5.5% and 53.2% of liveborn multiple births were of birthweight <1500 g and <2500 g compared with 0.9% and 47.4% of multiple children in cross-sectional study. These results also indicated that most children born weighing <1500 g in multiples might die from some condition related to very low birthweight. Table 8
shows the difference in proportion of low birthweight children between China and Mersey.1 All these suggest that survival of multiples in China is lower than that in developed countries, particularly for those weighing <1500 g. So it is not appropriate to compare directly the crude prevalence of cerebral palsy with those reported in developed countries.
Table 9
compares birthweight-specific prevalence of cerebral palsy between our study and the Mersey data. Although the latter was a birth cohort study and used infant survivors as denominator, the prevalence of cerebral palsy in our data was still likely to be higher than that in the Mersey data for children weighing 15002499 g, particularly for those weighing 20002499 g. The prevalence of cerebral palsy for children born weighing <1500 g in our study was not available or was unstable because of scarce data probably caused by children's deaths. These findings suggest that the comparison of birthweight-specific prevalence is still meaningful in exploring the aetiology of cerebral palsy although our crude cerebral palsy prevalence is not comparable with those reported abroad. In summary, the survival quality of Chinese children born weighing 1500 2499 g needs to be improved further and that intrapartum and neonatal antecedents might play an important role in the aetiology of cerebral palsy compared to developed countries.
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Table 9 Comparison of prevalence of cerebral palsy per 1000 children or infant survivors between China and Mersey
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The prevalence in multiples was 6.5 times that in singletons. Multiples are at higher risk of cerebral palsy than singletons. Low birthweight is a strong risk factor for cerebral palsy and multiples are much more likely to be of low birthweight than singletons. Hence, is the higher risk of cerebral palsy in multiples caused by the confounding effect of low birthweight? Our results showed that the prevalence of cerebral palsy in multiples was higher than that in singletons in the group of normal birthweight (
2500 g), but did not differ from that in singletons in the low birthweight groups when compared individually. Although this was a cross-sectional study, the findings in comparison of birthweight-specific prevalence between multiples and singletons were consistent with those reported in developed countries.15,9 The higher crude prevalence of cerebral palsy in multiples is partly due to the lower birthweight distribution and partly due to the higher risk among children with normal birthweight. This explanation seems to be acceptable based on those findings above. But why is the cerebral palsy prevalence in the low birthweight groups in multiples not higher than that in singletons, and even tends to be lower? How do we explain the finding that adverse effect of multiple pregnancy as an independent risk factor only show up in the normal birthweight group, but not in those weighing <2500 g?
Results showed that multiples had much lower birthweight distribution and higher low birthweight proportion than singletons. The difference in mean birthweight between liveborn singletons and multiples was 902 g in our data set and in Western Australia 19801989 it was 946 g (3377 g versus 2431 g).5 Even after taking into account gestational age, the difference of mean birthweight of children for gestational age between multiples and singletons was still significant, being lowest (77 g) in the 2830 weeks group and highest (636 g) in the 3738 weeks group (Table 6
). In addition, multiples also showed a lower neonatal mortality rate than singletons in the low birthweight groups and the same findings had also been reported elsewhere.5 These findings suggest that multiples and singletons are two heterogeneous populations with respect to birthweight. The actual birthweight might not be comparable between multiples and singletons and hence it might be problematic to directly use actual birthweight-specific prevalence to make a comparison.
When multiples and singletons were regrouped according to the birthweight normal deviate, birthweight normal deviate specific prevalence of cerebral palsy in multiples was consistently higher than that in singletons in all birthweight groups and the risk of cerebral palsy in multiples seemed to become magnified as birthweight increased (Figure 3
). Furthermore, a similar result was obtained after controlling for both birthweight and gestational age at the same time (Table 7
and Figure 4
). These indicate that multiple pregnancy is an independent risk factor for cerebral palsy. Multiples are in adverse circumstances very early in gestation and the risk of cerebral palsy in multiples increases as the fetuses mature. The explanation for the increased risk of cerebral palsy in multiple pregnancy may be considered from two aspects: 1) multiples are at higher risk for many adverse outcomes such as intra-uterine growth retardation, placental vascular anastomoses, congenital anomalies and death of a co-twin; 2) as a fetus grows and matures, the uterus becomes more crowded, which may result in additional adverse effects such as reduced blood supply and severe retarded growth.
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Acknowledgments
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This study was a key project during the ninth 5-year plan for China and supported by China's government (969040603). We sincerely thank all Institutes for Maternal and Infant Health in seven cities for their co-operation in the field work.
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References
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