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a Department of Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg, Germany
b Robert Koch Institute, Berlin, Germany
c German Pediatric Surveillance Unit Office, University Children's Hospital, Düsseldorf, Germany
d Department of Biometry and Medical Statistics, University of Freiburg, Freiburg, Germany
e Perinatal Infectious Disease Epidemiology Unit, Departments of Obstetrics and Pediatrics, Hannover Medical School, Hannover, Germany
f Neuroepidemiology Unit, Department of Neurology, Children's Hospital and Harvard Medical School, Boston, Massachusetts
g Institute for Social Pediatrics and Adolescent Medicine, Ludwig Maxilimilians University, Munich, Germany
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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METHODS. A prospective active surveillance study involving all of the pediatric hospitals, which reported their cases to the German Pediatric Surveillance Unit, and all of the microbiological laboratories serving pediatric hospitals, which reported their cases to the Laboratory Sentinel Group at Robert Koch Institute Berlin, was conducted between 2001 and 2003. Capture-recapture analysis was used to evaluate the completeness of reported neonatal invasive group B Streptococcus infections.
RESULTS. We collected and analyzed data from 347 and 360 infants with invasive group B Streptococcus infection during the first 3 months of life, as reported by pediatricians to the German Pediatric Surveillance Unit and microbiologists to the Robert Koch Institute Berlin, respectively. Using capture-recapture analysis, we calculated an incidence of 0.47 per 1000 live births. Nearly 60% of the infants suffered from early-onset disease, and 16% of these presented with meningitis. In contrast, 61.8% of infants with late-onset disease presented with meningitis. Prematurity was present in 22.4% of early-onset disease and 39.7% of late-onset disease cases, respectively. A high proportion of infants suffered from sequelae because of group B Streptococcus infection at the time of discharge from the hospital. Most common sequelae were hydrocephalus and cerebral seizure. Case fatality rate was 4.3%.
CONCLUSIONS. This study, which is the first to provide information on the current national incidence and morbidity of invasive group B Streptococcus infection in Germany, demonstrates remarkable country-specific variation in comparison with other European countries, which gather data in a similar fashion. Therefore, the importance of country-specific prevention guidelines has to be stressed.
Key Words: Streptococcus agalactiae • incidence • invasive • neonatal • Germany
Abbreviations: GBS—group B Streptococcus • EOD—early-onset disease • LOD—late-onset disease • CRC—capture-recapture analysis • CSF—cerebrospinal fluid • ESPED—German Pediatric Surveillance Unit • RKI—Robert Koch Institute • IAP—intrapartum antibiotic prophylaxis
Group B Streptococcus (GBS) is the leading cause of sepsis and meningitis in newborns and infants.1 Neonatal infection with GBS presents as early-onset disease (EOD) (age 0–6 days) or late-onset disease (LOD) (age 7–90 days). Although EOD is typically related to the presence of GBS in the vagina of the mother and vertical transmission during birth, LOD is transmitted both vertically and horizontally from nosocomial and community sources.2 Although prevention guidelines have resulted in a decreased rate of EOD, the rate of LOD has not changed.3 After the implementation of the revised prevention guidelines recommended by the Centers for Disease Control and Prevention in 2002, the incidence of EOD was further reduced to 0.32 per 1000 live births in selected areas of the United States in 2003.4
Until now, neonatal GBS incidence data for Europe based on capture-recapture analysis (CRC) have been reported in a nationwide fashion only from the Netherlands (1.9 per 1000 live births)5 and England (0.72 per 1000 live births).6 The goal of our study was to assess the incidence, morbidity, and mortality of invasive neonatal GBS infections in Germany using CRC over a period of 2 years. Our comparison of English and German data derived from comparable reporting sources reveals country-specific differences in incidence, clinical course, and outcome.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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90 days of age. Surveillance was performed from April 1, 2001, through March 31, 2003. The level of completeness was determined by CRC. The German Pediatric Surveillance Unit (ESPED) detected 347 cases of invasive GBS infections, and 360 cases were reported to the Laboratory Sentinel Group at Robert Koch Institute (RKI). Parental consent was not considered necessary, because data were collected anonymously.
Case Finding
ESPED
Monthly reporting cards are sent to the head of department and responsible staff members of all of the pediatric departments nationwide. These cards ask for 12 pediatric conditions and include a null option to be ticked if neither of the 12 conditions has been observed.7 The return rate of the reporting cards in this active surveillance system were >95% during the entire study period. If the physician reported a case of invasive GBS infection, they were asked to fill out a standardized questionnaire, which included details about pregnancy, birth, clinical history of the infant, diagnosis, treatment, and outcome. Return rates for this questionnaire were 97%.
RKI
To assess and correct for reporting bias in the ESPED system, a second independent reporting system was used. Monthly questionnaires were mailed by the RKI to all of the microbiological laboratories serving pediatric hospitals throughout Germany. Laboratories were asked to report any blood or CSF culture-positive GBS infection in the pertinent age group. Again, a null option was included. The second initials of first name and surname, postal code, and month of birth were provided as additional information. The recall rate of the monthly questionnaires was 95%. Reports from these 2 independent active surveillance systems were the basis for CRC.
Risk Factors
Data collection included the previously known and analyzed risk factors, such as preterm delivery (<37weeks' gestational age), prolonged rupture of membranes (>18 hours), known genital GBS colonization, intrapartum fever, and urinary tract infection with GBS or previous child with GBS infection. Because this gynecological information is not easily obtainable by neonatologists, the information provided might be incomplete, which results in an underestimation of the number of maternal risk factors present.
Estimation of Incidences and CRC Technique
After completing the surveillance and elimination of false-positive and double reports, we used CRC methods to evaluate the completeness of reported neonatal invasive GBS infections in Germany. This methodology was designed to estimate population sizes on the basis of the proportion of subjects (re)captured by 
2 sources. It has to be taken into consideration that CRC cannot correct for failure to obtain cultures or for suppression of bacterial recovery by antibiotics administered to mothers during labor. CRC relies on the following assumptions: (1) sufficient information should allow for the matching of subjects from different sources; (2) the sources should be independent; and (3) each subject should have an equal likelihood of being captured. These assumptions are fulfilled by the 2 capture methods in our study. First, all of the pediatric departments were requested to report any case of GBS infection that met the criteria mentioned above and to complete a standardized questionnaire, which included details about pregnancy, birth, clinical history of the infant, diagnosis, treatment, and outcome. These questionnaires were sent to the ESPED office. Second, monthly questionnaires were mailed by RKI to all of the microbiological laboratories serving pediatric hospitals throughout Germany. Laboratories were asked to report any blood or CSF culture-positive GBS infections in the pertinent age group. The 2 independent data sources were linked, matching on the patients' diagnosis, month of birth, second initials of first name and surname, and postal code. The total number of invasive GBS infections was calculated using the formula n = a x b/c according to Hook and Regal,8 where a denotes the number of cases captured in data source A (here: ESPED), b denotes the number of cases captured in data source B (here: RKI), c denotes the number of cases captured in both sources, and n denotes the estimated total number of cases in a population.
Because the RKI did not provide information on age at onset of infection, CRC analysis could not be used to calculate incidence rates for EOD and LOD separately. Data on age at onset were only available for 245 of 360 cases; therefore, reliable CRC calculations of EOD or LOD incidence rates were impossible. For the estimation, the proportion of EOD and LOD cases identified in the ESPED database was multiplied by the overall estimate.
Sequelae
Pediatricians were asked to comment on the health status of the infants with regard to disability at the time of discharge from hospital. When verified or suspected sequelae because of the GBS infection were recorded, a specification of the neurodevelopmental disorders was added by the attending pediatricians in most cases.
Statistical Methods
Univariable analysis employed the 
2 test, t test, and Wilcoxon test. A P value <0.05 was considered statistically significant. We calculated 95% confidence intervals using the formula P ± 1.96 x 
[p x (1 – p)/n], where p denotes the sample proportion.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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3 months of age in Germany. On the basis of the data of the ESPED reports, an incidence of 0.28 per 1000 live births for EOD and 0.19 per 1000 live births for LOD was estimated.
Clinical Data
Clinical Data on EOD Cases
For the cases reported to ESPED during the 2 years, pediatric and gynecological clinical data were available. Of all of the ESPED cases recorded, 206 (59.6%) had EOD. In 5 cases, the onset of disease could not be determined. In the EOD cases, GBS were isolated from blood (182 cases [88.3%]), blood and CSF (20 cases [9.7%]), and CSF alone (4 cases [1.9%]). Male infants were more often affected than female infants (58.8% vs 41.2%; P < .01).
The most common presentation of EOD GBS infection was sepsis alone (165 cases [80.1%]) and sepsis and meningitis (28 cases [13.6%]). Five infants presented with meningitis alone (2.4%). Five infants had pneumonia without sepsis. Two infants were clinically healthy, but a blood culture was taken, because the mothers had a positive vaginal swab. For 1 infant no information was given about the clinical presentation. Four patients with EOD had recurrent episodes.
The clinical presentation sepsis was associated with EOD and LOD to the same extent (93.7% vs 90.4%, respectively). Pneumonia was more often found in EOD (30.6% in EOD vs 5.2% in LOD; P < .001). We found that 85% and 92% of the infants developed EOD within the first 24 and 48 hours of life, respectively. Eighteen percent of these children had symptoms at birth. Predominant initial symptoms in EOD were respiratory (86%), cardiovascular (67%), and neurologic (16%). Fever occurred in 12% of these infants.
Clinical Data on LOD Cases
In the 136 LOD cases recorded, GBS were isolated from blood (65 cases [47.8%]), blood and CSF (50 cases [36.8%]), CSF (20 cases [14.7%]), and pleural effusion (1 case [0.7%]). The most common presentation of LOD GBS infection was sepsis and meningitis (73 cases [53.7%]) and sepsis alone (50 cases [36.8%]). Eleven infants presented with meningitis alone (8.1%). Two infants suffered from cellulitis (1.5%). Four patients with LOD had recurrent episodes.
LOD was more likely than EOD to present with meningitis (61.8% vs 16.0%; P < .001) and neurologic symptoms (32.4% vs 15.4%; P < .001). LOD occurred more often in infants with lower birth weights: 31.7% of the infants with LOD were born with a birth weight <2500 g (compared with 6.9% of infants with EOD; P < .001). Furthermore, prematurity was found more often among LOD cases (LOD: 39.7% born preterm; EOD: 22.4% born preterm; P < .001). Predominant initial symptoms in LOD were cardiovascular (74%), respiratory (51%), and neurologic (32%). Fever occurred in 26% of the infants with LOD.
Gestational Age
Overall, 29.2% of the infants were born preterm (97 of 332 infants). The median birth weight was 3160 g (minimum: 580 g; maximum: 5230 g).
For EOD, duration of pregnancy was recorded for 201 of 206 cases. Of these infants, 22.4% were preterm. Median gestational age was 39 weeks (minimum: 24 weeks; maximum: 43 weeks). Median birth weight for infants with EOD was 3280 g (minimum: 680 g; maximum: 5230 g).
For LOD, duration of pregnancy was recorded for 131 of 136 cases. The percentage of infants born premature was higher (39.7%) than for EOD. Median gestational age was 38 weeks (minimum: 23 weeks: maximum: 42 weeks). Median birth weight for infants with EOD was 3015 g (minimum: 580 g; maximum: 4460 g).
Risk Factors
One or more previously described risk factors, such as preterm delivery <37 weeks' gestational age, prolonged rupture of membranes (>18 hours), known genital GBS colonization, maternal urinary tract infection with GBS, intrapartum fever, or previous child with GBS infection were present in 105 (51%) of 206 EOD cases. Only 2 cases of mothers with previous children with GBS infections (GBS detected only in superficial swabs, not as officially defined in invasive cultures) were recorded (Table 1). Data completeness was a problem for maternal information concerning GBS colonization status and GBS urinary tract infections, as shown in Table 1.
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1 risk factors and should, therefore, have received prophylaxis. Known risk factors were present in 61 (44.9%) of 136 LOD cases. Information about IAP was obtained in 104 of 136 LOD cases: 11 mothers received antibiotic prophylaxis. In most cases of mothers who did not receive prophylaxis, the clinical data about the set of known risk factors were mainly incomplete so that no valid statement about risk factors present at birth could be made.
Mortality
Overall mortality was 4.3% (n = 15) among the 347 ESPED cases. Although more deaths were observed when the analyzed risk factors were present, the difference was not significant (6.0% vs 2.9%, respectively). There was no difference between the EOD and LOD group with regard to mortality (4.9% vs 3.7%, respectively). Crude case fatality was significantly higher in preterm infants irrespective of time of onset (6 fatal courses of 235 term infants vs 9 fatal courses of 90 preterm infants; P < .01).
In all 10 fatal EOD cases, GBS were detected in the blood culture. Of these infants, 8 died within 48 hours after the initiation of antimicrobial treatment. In the case of these 8 infants, additional risk factors could be detected in 7 cases (prematurity or prolonged rupture of membranes >18 hours). Only 1 of 10 mothers of the infants with fatal courses received intrapartum prophylaxis.
Of the 5 fatal LOD cases, 2 infants died within 72 hours after admission and the others after weeks of treatment. In this group, only 1 infant had 1 additional risk factor (prematurity). In all of these cases, GBS were detected in CSF culture.
Sequelae
Of 347 infants, 50 (13.8%) suffered from sequelae because of GBS infection at the time of discharge from hospital. For 9 infants, the clinical outcome at discharge was not clarified. In 38 of 50 cases, the resulting sequelae were described in more detail. Hydrocephalus alone or in combination with cerebral seizures (14 and 11 cases, respectively), defective hearing (4 cases), microcephalus (3 cases), intracerebral abscess (3 cases), retinopathy (2 cases), muscular hypotension (2 cases), encephalomalacia, encephalopathy, porencephaly, apallic syndrome, cerebral palsy, osteolysis, and encephalocele (1 case each) were recorded.
Sixteen infants with EOD (7.8%) suffered from residual sequelae. Ten infants presented with meningitis, and 6 of these 10 infants were born premature. The percentage of LOD infants with sequelae was higher: For 33 (24.3%) of 136 infants, residual impairment was documented at discharge from hospital. Thirty LOD infants with sequelae were diagnosed with meningitis. Twelve of these 30 infants were preterm. For 1 infant born premature and released from hospital with sequelae, the onset of disease could not be determined.
Meningitis and preterm delivery could be identified in univariable analysis as significant risk factors for the development of residual impairment (P < .05). Infants with LOD suffered significantly more often from residual impairment than infants with EOD (24.3% vs 7.8%; P < .001). The initial clinical presentation and course differed between the children with residual impairment and the children discharged healthy. Infants with sequelae documented at discharge presented as critically ill infants from the beginning (see Table 2). It could be seen that infants with EOD were more often classified as being "healthy" at discharge from hospital than infants with LOD (87.2% vs 71.8%; P < .001).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Only 2 other European countries have calculated neonatal GBS incidence on the basis of CRC analysis and are, therefore, more suitable for a country-specific comparison than other countries. The Netherlands report an incidence of 1.9 per 1000 live births for GBS EOD.5 Although a comparable reporting system to our ESPED system was involved, and a large number of cases was collected by this source, we assume that the data from the Netherlands and Germany are only comparable to a certain extent. First, only a small number of cases was recruited by the second source used for CRC, which resulted in a small CRC denominator, and minor modifications of this number produce great fluctuations of the incidence calculated. Second, not only culture-proven, but also probable GBS EOD cases were included.
The study from the United Kingdom and Wales involved pediatric departments and microbiological laboratories as reporting sources and is, therefore, well comparable to our study.6 Interestingly, there seem to be substantial differences between the 2 countries. The incidence rate for England (0.72 per 1000 live births) reflects the number of culture-proven GBS infections per live births per year. The incidence calculated by CRC suggests that the total number of cases for selected areas in the United Kingdom might be 23% higher than estimated from reports alone.6 The incidence rate of 0.47 per 1000 live births reported for Germany already reflects the incidence rate after correction for underreporting. The overall incidence calculated from ESPED reports alone was 0.24 per 1000 live births.
Incidence rates for GBS EOD vary between 0.48 in England and 1.9 in the Netherlands,5,6 whereas the incidence of EOD in Germany was estimated to be 0.28 per 1000 live-births. Therefore, it can be assumed that the incidence of invasive GBS infections in Germany is substantially lower than in these 2 countries. The reason for this phenomenon remains unclear. A lower rate of rectovaginal GBS carriage of pregnant women might be an explanation. Current surveillance data from our hospital (data not published) do not suggest that this should be an important factor, but no national prevalence data are available. Second, there might be a higher rate of intrapartum prophylaxis in Germany than elsewhere. National recommendations are in place that combine the risk- and screening-based approach. However, data are lacking about the impact of the national guidelines on local policies of obstetricians. Third, differences in ethnic or specifically genetic factors between the populations in Germany, England and Wales, and the Netherlands might account for a different attack rate. Finally, the incidence of probable GBS infection presenting with clinical signs of sepsis in the absence of positive blood cultures was not assessed. Therefore, the true burden of neonatal GBS infections might be underestimated, as documented in a recent study from the United Kingdom.12
Not only the incidence rates, but also the proportion of LOD, disability, and mortality rates differs between European countries. In the Netherlands, only 7% of all GBS infections are LOD, which contrasts the United Kingdom and Germany, where LOD cases were found in 33.6% and 39.2%, respectively.5,6 In the present study, long-term visual, hearing, or cognitive impairment occurred in 13.8%. This number includes only infants with definite impairment because of GBS infection at discharge from hospital. No long-term follow-up of children with possible neurologic sequelae was performed, which definitely is the only way to include all of the cases with sequelae. Earlier studies have reported a high mortality rate of infants with GBS meningitis (17%–59%), but only very few infants with residual impairment after GBS meningitis at discharge from the hospital. In these studies, a long-term follow-up was conducted, and the presence of neurodevelopmental impairment was assessed a couple of years after discharge from the hospital. Major or moderate sequelae were detected in 4% to 29% and 0% to 21%, respectively.13–15 These data clearly underline that the percentage of 13.8% of infants with sequelae at discharge from the hospital in this study might be an underestimation. A significantly higher number would be expected if, in particular, children with GBS meningitis were reevaluated after some years. Nevertheless, the number of children with definite sequelae after GBS infection reported in the present study is twice as high as the rate reported from the United Kingdom (Fig 1). It can be shown that children who survived with residual sequelae were those with features indicative of severe infection, presenting as critically ill patients from the beginning or showing a severe clinical course. These infants presented more frequently with meningitis, seizure, and shock than those children who survived GBS infection without sequelae (P < .001; Table 2). Bearing this in mind, an understanding of risk factors for LOD would be of great value in the future.
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The current gold standard in GBS prophylaxis is the use of IAP. In 2002, the Centers for Disease Control and Prevention and the American College of Obstetricians and Gynecologists revised their guidelines for the prevention of early-onset GBS disease and recommended late prenatal screening of all pregnant women and intrapartum prophylaxis for GBS carriers.16,17 Nevertheless, the recognition of risk factors remains of major importance for prevention. In Germany, a combination of the screening- and risk factor-based approach is favored: IAP is offered at birth to all women carrying GBS in late pregnancy. Women for whom results are not available at the time of labor are offered IAP if they present with preterm labor, premature rupture of membranes >18 hours, or fever >38°C in labor. Women with symptomatic or asymptomatic GBS bacteriuria during pregnancy have to be treated immediately and are offered IAP in any case. Women with a previous infant affected with GBS generally receive IAP. The German prevention strategy is different from those of the United Kingdom or the Netherlands. In the Netherlands, the risk-factor-based guidelines are favored.18 In the United Kingdom, a general screening for GBS colonization is not recommended, and IAP is offered to women with risk factors only after in-depth discussion and consultation.19
Intrapartum fever, urinary tract infections with GBS, or previous children with GBS infections occurred only in single cases among our study population. With respect to maternal GBS colonization, the gynecologic data supplied by the pediatric hospitals were sometimes incomplete in our study and, therefore, might have resulted in underestimation. Although obstetric data were difficult to obtain, it was found that only 30 of 178 mothers of infants with EOD received IAP. In 148 cases, no antibiotics were given. Of these 148 cases, 68 women had 1 risk factors and should, therefore, have received prophylaxis but, in fact, did not. The other 80 infants could not have been identified using these risk factors, implying that screening for GBS colonization should be a more effective strategy, even in this population with a low incidence; failure to screen represents missed opportunities for ascertainment of risk. Future studies will have to address the issue of implementation of prevention guidelines for Germany.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address correspondence to Reinhard Berner, MD, Department of Pediatrics and Adolescent Medicine, University Hospital Freiburg, Mathildenstrasse 1, 79106 Freiburg, Germany. E-mail: berner{at}kikli.ukl.uni-freiburg.de
The authors have indicated they have no financial relationships relevant to this article to disclose.
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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), United Kingdom (
), and the Netherlands (
). The percentages for LOD, sequelae, and mortality are given on the left y-axis (%); the combined incidence rates for EOD and LOD for the United Kingdom and Germany and the EOD incidence rate for the Netherlands are shown on the right y-axis (cases per 1000 live births). a No data on sequelae were available from the Netherlands.