Obstetrics & Gynecology:
Cerebral Palsy and Perinatal Infection in Children Born at Term
Ahlin, Kristina MD; Himmelmann, Kate MD, PhD; Hagberg, Gudrun; Kacerovsky, Marian MD, PhD; Cobo, Teresa MD, PhD; Wennerholm, Ulla-Britt MD, PhD; Jacobsson, Bo MD, PhD
Perinatal Center, Department of Obstetrics and Gynaecology, Institute for Clinical Sciences, Sahlgrenska Academy, Sahlgrenska University Hospital/Östra, and the Department of Paediatrics, Institute for Clinical Sciences, Sahlgrenska Academy, Gothenburg, Sweden; the Department of Obstetrics and Gynaecology, Charles University in Prague, Medical Faculty Hradec Kralove, Prague, Czech Republic; the Maternal Fetal Medicine Department, Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain; and the Department of Genes and Environment, Division of Epidemiology, Institute of Public Health, Oslo, Norway.
Corresponding author: Bo Jacobsson, MD, PhD, Department of Obstetrics and Gynaecology, Perinatal Centre, Sahlgrenska University Hospital/East, SE-416 85 Gothenburg, Sweden; e-mail: email@example.com.
Supported by The Göteborg Medical Society, FOU-Unit in Södra Älvsborg, Swedish government grants (ALFGBG-136431), and the Swedish Medical Society (2008-21198).
Financial Disclosure The authors did not report any potential conflicts of interest.
The authors thank Mattias Molin at Statistiska Konsultgruppen, Göteborg, for assistance with statistics and Dr. Elisabet Hentz for expert advice on neonatal issues.
OBJECTIVE: To investigate the link between infection-related risk factors for cerebral palsy subtypes in children born at term.
METHODS: A case–control study was performed in a population-based series of children with cerebral palsy born at term (n=309) matched with a control group (n=618). The cases were divided into cerebral palsy subtypes: spastic hemiplegia, spastic diplegia, spastic tetraplegia, and dyskinetic cerebral palsy. All forms of spastic cerebral palsy were also analyzed together. All records were examined for maternal and neonatal signs of infection. Univariate and adjusted analyses were performed.
RESULTS: Infection-related risk factors were shown to be independent risk factors for spastic cerebral palsy in the adjusted analyses. This was especially pronounced in the subgroup with spastic hemiplegia in which bacterial growth in urine during pregnancy (n=11 [7.5%], odds ratio [OR] 4.7, 95% confidence interval [CI] 1.5–15.2), any infectious disease during pregnancy (n=57 [39.0%], OR 2.9, 95% CI 1.7–4.8), severe infection during pregnancy (n=12 [8.2%], OR 15.4, 95% CI 3.0–78.1), antibiotic therapy once during pregnancy (n=33 [22.6%], OR 6.3, 95% CI 3.0–15.2) as well as several times during pregnancy (n=9 [6.2%], OR 15.6, 95% CI 1.8–134.2) constituted strong independent risk factors. However, only neonatal infection (n=11 [9.1%], OR 14.7, 95% CI 1.7–126.5) was independently significantly associated with an increased risk of spastic diplegia and tetraplegia.
CONCLUSIONS: Infection-related factors are strong independent risk factors for the subgroup with spastic hemiplegia in children with cerebral palsy born at term. The finding is less pronounced in the subgroups with spastic diplegia or tetraplegia.
LEVEL OF EVIDENCE: II
Cerebral palsy is a lifelong neurologic motor disorder with first symptoms early in life that is common worldwide. The prevalence is 2 per 1,000 live births and more than half of the children with cerebral palsy were born at term.1–3 Cerebral palsy is an umbrella term for a group of disorders affecting body movement, balance, and posture caused by a brain maldevelopment or a lesion that occurred prenatally, perinatally, or neonatally, or during the first years of life.
Despite a longstanding theory that events during labor are entirely responsible for cerebral palsy, based on multiple epidemiologic studies, up to 80% of cases result from some sort of antepartum event4–7 and much of the etiology of cerebral palsy remains elusive. Infectious and inflammatory mechanisms have been suggested to be involved.8–11 If the child had shown signs of inflammation already during the fetal period, this is strongly associated with serious short- and long-term morbidity.12 The existing literature supports a relationship between chorioamnionitis and cerebral palsy. Increased cytokine levels in amniotic fluid have been shown to cause white matter damage.13 White matter lesions are observed in many cases of cerebral palsy.2,14 Neurotropic virus infection, cytomegalovirus infection, chorioamnionitis, and maternal urinary tract infection have all been shown to be associated with a higher risk of cerebral palsy for children born at term.10,11,15,16
Few large and population-based studies investigating the link between infection and cerebral palsy (including subtypes) are available in children born at term. The aim of this large case–control study was to analyze infection-related risk factors during pregnancy, delivery, and the neonatal period for cerebral palsy subtypes in children born at term.
MATERIAL AND METHODS
This case–control study was conducted in the Western Health Care Region of Sweden and is part of the population-based “Panorama of Cerebral Palsy in the Western Sweden Study.”4,17,18 The study included all children born at term with cerebral palsy (n=356) between 1983 and 1994. Inclusion criteria were children born at term (37 or more weeks of gestation) in Sweden, age at least 4 years at the time of diagnosis, and had lived in the study area on a specific census date. All cases with a postneonatal cause of cerebral palsy (n=21) and one case with a spinal malformation were excluded from this study because the etiology of those cases is considered different from what the study intended to examine. Ataxic cerebral palsy (n=25), a small group, difficult to distinguish from other noncerebral palsy syndromes,19 was therefore also excluded for the purpose of this study. Information about total population and case selection is shown in Figure 1. The final case group consisted of 309 cases of which 307 children were born singletons and two children were from twin pregnancies. Hospital records of all cases were found.
The recruited cohort...Image Tools
Cerebral palsy was defined as a group of nonprogressive but often changing motor impairment syndromes secondary to lesions or abnormalities of the brain arising in the early stages of development20 using the definition by Mutch et al. Cerebral palsy type was classified as spastic hemiplegia, spastic diplegia or spastic tetraplegia, and dyskinetic cerebral palsy using the internationally accepted Swedish classification by Hagberg.18,19 All spastic cerebral palsy was also analyzed together. Spastic diplegia and tetraplegia were analyzed together, representing bilateral spastic cerebral palsy.
Every case was matched with two control participants. The control participants were matched for gestational age, sex, multiple birth, delivery ward, and date of delivery. The closest births occurring before and after the case birth were chosen. Matching for gestational age, multiple birth, and sex was complete in all cases, and matching with regard to delivery ward was complete in 93%, because control participants could not always be recruited from small units. In these instances, control participants were recruited from another unit of similar level and size. The matched control participants were analyzed together with the cases in the subtype analyses. The same case–controls have previously been analyzed for noninfectious risk factors for cerebral palsy (in press).21
Records were scrutinized in detail for maternal and neonatal signs of infection. Two investigators (K.A. and B.J.), unaware of the pediatric outcome, reviewed all the 927 standardized original paper obstetric records recording a total of 26 infectious variables of a total of 75 variables collected. An independent researcher randomly chose 20 obstetric original records to ensure consistency in gathering of the data and to validate the database. There were very little missing data on variables, less than 4%, except for the variables antibiotic therapy during delivery (5.4%) and foul-smelling amniotic fluid (12.7%).
Severe infectious disease was defined as pyelonephritis or clinical chorioamnionitis. Clinical chorioamnionitis and pyelonephritis were grouped together, because previous studies implied that severe infection in close relation to the genital tract might be associated with brain injury.22 Clinical chorioamnionitis was defined as an intrapartum temperature of 37.8°C or higher recorded at two occasions 4 or more hours apart and either uterine tenderness or fetal tachycardia or foul-smelling discharge in the absence of other focus of infection with at least two of these criteria met.23 Fever before onset of delivery was defined as fever (38°C or higher) before the occurrence of regular contractions, rupture of membranes, or cervical dilation. Postpartum endometritis was defined as fever (38°C or higher recorded at two occasions 4 or more hours apart) and uterine tenderness or foul-smelling cervicovaginal discharge. Neonatal infection was defined as proven infection during admission to the neonatal intensive care unit and any of the following: congenital infection (toxoplasmosis, intrauterine cytomegalovirus infection, or varicella), pneumonia, septicemia, infection, meningitis, encephalitis, neonatal urinary tract infection (UTI), or ventriculitis. The term sexually transmitted disease was applied if the mother had a history of chlamydia, gonorrhoea, syphilis, human immunodeficiency virus, herpes, Trichomonas vaginalis, or condyloma infection. Between 1983 and 1994 when the births of the children in this study were performed, group B streptococci prophylaxis was not routine in Sweden. As such, antibiotics used in this cohort were primarily to treat infections, not to prevent neonatal group B streptococci disease.
Small for gestational age was defined as below 24% weight deviation from the mean birth weight for a given gestational age and sex corresponding to below −2 standard deviations from the mean, the latter a more common definition in pediatric contexts. Standardization of birth weight according to gestational age and sex was performed using a recent study of ultrasonography-estimated fetal weights.24 Calculation of gestational age was based on ultrasonography in most pregnancies (97%) that was performed between 16 weeks and 19 weeks of gestation. The remaining 3% of pregnancies were dated by last menstrual period. Instrumental delivery was delivery by cesarean or by vacuum extraction. Smoking was defined as positive if occasional or more frequent smoking was reported when the woman registered at the prenatal clinic.
For power calculations, we chose chorioamnionitis as our main outcome variable and calculated with an event rate of 6% chorioamnionitis in the cerebral palsy group and 2% in the control group, a power of 80% at a significance level of 5%. For comparison between groups and P value in univariate analyses, Fisher’s exact test was used and Mann-Whitney U test was used for continuous variables. Binary logistic regression was performed to assess the independent role of antepartum, intrapartum, and postpartum infection-related factors to predict the occurrence of cerebral palsy and its subtypes. In addition, adjusted analyses were performed using multiple logistic regression adjusting for confounders (maternal age, maternal body mass index*, parity, smoking*, noncohabitation with the father of the child*, small for gestational age*, and instrumental delivery*). Variables were selected as confounders if they reached significance, less than 0.05 (*variables), had been added as standard covariates in some of previous similar studies (maternal age, parity), or both. All significance tests were two-tailed, and P<.05 was considered to be statistically significant. Using a threshold of .05 and given the amount of variables tested, we have calculated the risk of false positive significances and found this to be between 1.2 and 2.5 variables per subgroup. In cases in which there was a zero in either case or control variable, only P and not odds ratio (OR) and 95% confidence intervals (CIs) are presented. All statistical analyses were performed using IBM SPSS Statistics 20.
Approval was obtained from the Regional Ethics Committee in Gothenburg (Ö 173-01).
The distribution of cerebral palsy types according to different subgroups is shown in Figure 1. The cerebral palsy cases were divided into spastic cerebral palsy and dyskinetic cerebral palsy. In the spastic cerebral palsy group, there were several significantly associated infectious factors such as bacterial growth in urine during pregnancy (n=18 [6.7%], OR 2.1, 95% CI 1.1–4.1), Escherichia coli bacteriuria during pregnancy (n=9 [3.4%], OR 4.6, 95% CI 1.4–15.2), any infectious disease during pregnancy (n=100 [37.4%], OR 1.7, 95% CI 1.2–2.3), severe infectious disease during pregnancy (n=19 [7.1%], OR 2.0, 95% CI 1.0–3.8), antibiotic therapy once during pregnancy (n=54 [20.2%], OR 2.1, 95% CI 1.4–3.1), antibiotic therapy several times during pregnancy (n=16 [6.0%], OR 2.6, 95% CI 1.2–5.4), antibiotic therapy several times before delivery (n=4 [1.5%], P=0.012), antibiotics during delivery (n=8 [3.1%], OR 8.2, 95% CI 1.7–38.9), and antibiotics postpartum (n=23 [8.7%], OR 3.1, 95% CI 1.6–5.9) as well as temperature 38°C or greater postpartum (n=17 [6.4%], OR 2.3, 95% CI 1.1–4.7), temperature 38°C or greater twice postpartum (n=12 [4.5%], OR 5.0, 95% CI 1.7–14.2), and neonatal infection (n=15 [5.6%], OR 15.8, 95% CI 3.6–69.8) (Table 1).
In the dyskinetic cerebral palsy group, only antibiotic therapy postpartum (n=7 [17.1%], OR 5.5, 95% CI 1.3–22.5) and neonatal infection (n=4 [9.5%], P=.011) were shown to be significantly associated (Table 2).
The spastic cerebral palsy group was then further divided according to distribution of symptoms into spastic hemiplegia, spastic diplegia, and tetraplegia. Our results showed that in the bilateral spastic cerebral palsy group, only antibiotic therapy postpartum (n=14 [11.7%], OR 2.8, 95% CI 1.2–6.3) and neonatal infection (n=11 [9.1%], OR 24.1, 95% CI 3.1–189.0) were associated with a significantly higher risk of cerebral palsy (Table 3). However, in the spastic hemiplegia group, several infectious-related factors were highly significantly associate such as E coli bacteriuria during pregnancy (n=6 [4.1%], OR 4.1, 95% CI 1.0–16.8), any infectious disease during pregnancy (n=57 [39.0%], OR 2.1, 95% CI 1.4–3.2, severe infection during pregnancy (n=12 [8.2%], OR 4.3, 95% CI 1.6–11.6), antibiotic therapy once during pregnancy (n=33 [22.6%], OR 3.4, 95% CI 1.9–6.1), antibiotic therapy several times during pregnancy (n=9 [6.2%], OR 3.8, 95% CI 1.2–11.5), antibiotics during delivery (n=5 [3.6%], OR 10.1, 95% CI 1.2–87.5), and antibiotics postpartum (n=9 [6.3%], OR 3.8, 95% CI 1.3–11.6) as well as temperature 38°C or greater postpartum (n=10 [6.9%], OR 3.5, 95% CI 1.2–9.7) and temperature 38°C or greater twice postpartum (n=8 [5.6%], OR 17.1, 95% CI 2.1–137.8) (Table 4).
Only one case fulfilled the full diagnosis of clinical chorioamnionitis in the maternal records (Table 3). Sexually transmitted disease, hepatitis, group B streptococci bacteriuria during pregnancy, bacterial growth of unknown etiology, long time from rupture of the membranes until delivery, foul-smelling amniotic fluid, and endometritis were not related to cerebral palsy in any of the subtypes.
In the spastic hemiplegia group, bacterial growth in the urine during pregnancy (n=11 [7.5%], OR 4.7, 95% CI 1.5–15.2), any infectious disease during pregnancy (n=57 [39.0%], OR 2.9, 95% CI 1.7–4.8), severe infection during pregnancy (n=12 [8.2%], OR 15.4, 95% CI 3.0–78.1), antibiotic therapy during pregnancy (n=33 [22.6%], OR 6.3, 95% CI 3.0–15.2) as well as antibiotic therapy several times during pregnancy (n=9 [6.2%], OR 15.6, 95% CI 1.8–134.2) remained significant risk factors after adjustment for confounders (Table 4).
Only neonatal infection (n=11 [9.1%], OR 14.7, 95% CI 1.7–126.5) was associated with spastic diplegia or tetraplegia in adjusted analysis (Table 3). No infectious factors were associated with dyskinetic cerebral palsy after adjusting for confounders (Table 2). However, there was evidence of an association with neonatal infection in the univariate analysis, but as a result of no events in the control group, adjusted analysis could not be performed.
Maternal infection-related factors are strong risk factors for the cerebral palsy subtype spastic hemiplegia in children born at term, but not for spastic diplegia, tetraplegia, or dyskinetic cerebral palsy. Our findings add new and important knowledge of the etiology in the different subtypes of cerebral palsy. A new finding is that maternal infection-related risk factors are associated with spastic cerebral palsy but not dyskinetic cerebral palsy. In addition, maternal infections only seem to be involved in causing unilateral spastic cerebral palsy and not bilateral spastic cerebral palsy. Neonatal infections, however, are associated with the latter. We also confirmed the association between UTI and cerebral palsy reported previously.9,16 Our results differ from prior studies in the overall rate of chorioamnionitis, only 0.1% in our term born cohort compared with 1–4% in a recent review.25 This was even lower than we could anticipate from the knowledge that perinatal infections are less frequent in a Scandinavian population26.
We hypothesize that maternal infection activates an inflammatory response in the fetus, termed fetal inflammatory response syndrome,12,27 mediated by cytokines.28 Fetal inflammatory response syndrome has been implicated as a cause of fetal or neonatal injury that leads to cerebral palsy in preterm-born children.12,29 Pang reported in 2005 that maternal E coli, one of the most common bacteria in UTI, induced neonatal white matter injury in rodents.30 Periventricular white matter lesion is an important cause of motor impairment in cerebral palsy,31,32 occurring during the late second trimester or early third trimester when these areas of the brain are the most vulnerable. More than one-third of the children born at term with spastic hemiplegia have these findings on neuroimaging.2,33 Thus, the cerebral palsy is of antenatal origin in these cases. Experimental data suggest that infectious, inflammatory, or both insults can play a dual role in their effect on the brain either can a subdamaging insult increase the vulnerability to further subdamaging insults (sensitization)34 or that under certain circumstances instead establish a situation that protects the brain from a second event (tolerance or precondition).35 Both of these aspects can be relevant for the interpretation of the results in this study. Reduced brain damage resulting from preconditioning might also be an explanation for our results that maternal infection gives rise only to unilateral spastic cerebral palsy and not bilateral.
Another one-third of children with spastic hemiplegia have cortical or subcortical changes on neuroimaging,3 most often the result of perinatal stroke. Ischemic perinatal stroke is the most common variety of stroke in late preterm and term neonates.36 Previous studies have shown that infection is a risk factor for cerebrovascular ischemia.37,38 The mechanisms linking infection and cerebral ischemia are still largely undetermined, but inflammatory mechanisms are thought to exacerbate the natural prothrombotic state present during a normal pregnancy and stimulate coagulation by several pathways.39
In the present study, severe maternal infection during pregnancy was associated with a 15-fold increased risk of spastic hemiplegia. This finding is in accordance with the reports by Grether and Nelson40 and Neufeld.9 Mild maternal infection such as UTI and report of antibiotic treatment resulted in three to five times higher risk of spastic hemiplegia, whereas severe maternal infection resulted in 15 times higher risk of cerebral palsy. Neonatal infection was associated with a very high risk (15 times higher risk) of spastic diplegia and the more severe form tetraplegia. Thus, according to our results, the severity of infection is related to the motor severity of spastic cerebral palsy.
Maternal infection did not increase the risk of the dyskinetic subtype of cerebral palsy in the present study. This is in line with findings reported by Gilbert et al41 about noninfectious mechanisms and the occurrence of adverse obstetric events as responsible for this outcome in 30% of children with cerebral palsy. However, neonatal infection appears to be significantly associated with this cerebral palsy type. These findings are clinically relevant because it clarifies the different pathophysiology of the subtypes of cerebral palsy.
This was a large, population-based case–control study, resulting in wide coverage of cerebral palsy including mild cerebral palsy cases. There were less than 4% missing data. Another strength is the matching of the control group to the same environmental conditions. The main weakness of the article is some absence of consistent and reliable information on maternal infection treated outside the antenatal unit before admission for delivery and the age of the data. Furthermore, our information on neonatal infection is only gathered from their diagnosis from the neonatal intensive care unit. They receive this diagnosis only if there is a proven infection but we lack specific information on bacterial growth and therefore better classifications on infections. Universal screening for group B streptococcus is not performed in Sweden.42 Future studies are needed to verify the results found in the dyskinetic and bilateral cerebral palsy groups. These limitations notwithstanding, this study provides valuable insight because it supports the hypothesis that infection and inflammation are associated with an increased risk of cerebral palsy.
Infection-related factors are associated with cerebral palsy in children born at term. These results indicate that infections are to be taken seriously and should be treated and reported accurately. Furthermore, an important finding is that maternal infection only seems to be important as a risk factor in spastic hemiplegia, whereas neonatal infections seem to play a role in bilateral spastic and in dyskinetic cerebral palsy.
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