OBJECTIVE: Group B Streptococcus (GBS) is the leading cause of meningitis in young infants. We evaluated long-term outcomes among GBS meningitis survivors. We hypothesized that despite reduced mortality, GBS meningitis would remain a significant cause of morbidity among GBS survivors.
METHODS: Ninety term and near-term infants diagnosed with GBS meningitis from 1998 through 2006 were identified from 2 children’s hospitals. Five died acutely, and 5 died at 6 months to 3 years of age. Forty-three survivors (54%; mean age 6.8, range 3–12 years) were consented for evaluation and underwent physical and neurologic examinations, hearing and vision screening, and standardized developmental assessments. Associations among presenting features, laboratory parameters, neurologic status at hospital discharge, and later developmental outcomes were explored by using descriptive statistics and logistic regression.
RESULTS: Twenty-four of 43 (56%) children evaluated demonstrated age-appropriate development, 11 (25%) had mild-to-moderate impairment, and 8 (19%) had severe impairment. Admission features associated with death after hospital discharge or severe impairment included lethargy (P = .003), respiratory distress (P = .022), coma or semicoma (P = .022), seizures (P = .015), bulging fontanel (P = .034), leukopenia (P = .026), acidosis (P = .024), cerebrospinal fluid protein >300 mg/dL (P = .006), cerebrospinal fluid glucose <20 mg/dL (P = .026), and need for ventilator (P = .002) or pressor support (P < .001). Features at discharge associated with late death or severe impairment included failed hearing screen (P = .004), abnormal neurologic examination (P < .001), and abnormal end of therapy brain imaging (P = .038).
CONCLUSIONS: Survivors of GBS meningitis continue to have substantial long-term morbidity, highlighting the need for ongoing developmental follow-up and prevention strategies such as maternal immunization.
- CDI —
- Child Developmental Inventory
- CSF —
- cerebrospinal fluid
- GBS —
- group B Streptococcus
- PEDS —
- Parents’ Evaluation of Developmental Status
- WBC —
- white blood cell count
- WIAT-II —
- Wechsler Individual Achievement Test, Second Edition
What’s Known on This Subject:
Group B Streptococcus (GBS) is a common cause of meningitis in young infants. Studies from the 1980s revealed that GBS meningitis resulted in substantial mortality and reported that survivors of the infection had a high likelihood of adverse neurodevelopmental outcome.
What This Study Adds:
Contemporary long-term outcomes for children surviving GBS meningitis reveal that 56% are functioning normally. The remainder sustained mild-to-moderate (25%) or severe (19%) neurodevelopmental impairment, highlighting the need for GBS prevention and for ongoing developmental follow-up for GBS meningitis survivors.
Group B Streptococcus (GBS) is a major pathogen in young infants.1–4 Intrapartum antibiotic prophylaxis has been associated with a decrease in the incidence of early-onset, but not late-onset, GBS disease.3,5–7 Meningitis is a particularly serious manifestation of GBS infection. Active population-based surveillance conducted from 1999 through 2005 found that 7% of 1232 infants with early-onset and 27% of 1036 infants with late-onset GBS infection had meningitis.1
In early reports, mortality due to GBS meningitis ranged from 20% to 30%, and survivors were at risk for long-term sequelae.8–10 We recently reported that, despite advances in neonatal care, one-fourth of term or near-term infants with GBS meningitis die acutely or have neurologic abnormalities evident at hospital discharge.11 Contemporary data are needed to define long-term outcomes among infants surviving GBS meningitis. We hypothesized that GBS meningitis continues to pose a high risk for long-term impairment and that features at hospital admission or discharge could predict infants at risk for sequelae.
Term and near-term infants admitted to Texas Children’s Hospital or Monroe Carell Jr Children’s Hospital from January 1998 through December 2006 with the diagnosis of GBS meningitis were identified through review of consultation records of the Pediatric Infectious Diseases Services at each hospital and by an International Classification of Diseases, Ninth Revision code–based medical record search. The codes reviewed were 320.2 (streptococcal meningitis), 041.02 (bacterial infection due to Streptococcus, group B), 322.9 (meningitis, unspecified), 320.89 (meningitis due to other specified bacteria), and 038.0 (streptococcal septicemia). Medical records, laboratory studies, and diagnostic imaging in identified patients were reviewed.
Children born at or near term (≥36 weeks) gestation who were at least 3 years of age at evaluation were eligible for inclusion. Those born at <36 weeks’ gestation, for whom issues related to prematurity could confound interpretation of outcomes, were excluded.12 Meningitis was defined as a cerebrospinal fluid (CSF) that grew GBS or CSF pleocytosis (white blood cell count [WBC] >30/mm3 in CSF) in an infant with a blood culture that yielded GBS.
The institutional review boards for human research of the Baylor College of Medicine Affiliated Hospitals and Vanderbilt University approved the protocol and informed consent. Parents were contacted by letter with telephone follow-up to explain the study. Those agreeing to participate provided written consent on the day of study. The on-site evaluation consisted of physical and neurologic examinations, hearing screening by using a Beltone audiometer (Glenview, IL) with testing from 15 to 50 dB, and visual acuity screening by using the kindergarten picture chart for children <5 years of age and Snellen eye chart for older children. Children with corrective eyeglasses were tested while wearing them.13
Developmental testing was conducted by a diplomate subspecialist in developmental and behavioral pediatrics (PES, Baylor) or licensed psychologist (TC, Vanderbilt). Children <6 years of age or at a developmental level of <6 years of age were assessed with the Mullen Scales of Early Learning. Children ≥6 years of age were assessed with the Wechsler Individual Achievement Test, Second Edition (WIAT-II). When Spanish was a child’s first language, testing was conducted in Spanish. The Mullen Scales of Early Learning assess cognitive skills in domains of visual reception, fine motor, receptive language, and expressive language. Subtest scores are reported as T scores (mean = 50, SD = 10), with an Early Learning Composite standard score derived from the 4 cognitive scales (mean = 100 and SD = 15).14 The WIAT-II is a standardized assessment of academic achievement evaluating skills in reading, mathematics, and spelling with mean standard scores = 100 (SD = 15).15 We administered the word reading, reading comprehension, numerical operations, math reasoning, and spelling subtests of the WIAT-II.
To assess parents’ perceptions of their children’s development, parents of children <6 years of age completed the Child Developmental Inventory (CDI), and parents of children ≤8 years of age completed the Parents’ Evaluation of Developmental Status (PEDS). The CDI is a 270-item questionnaire providing a profile of social, self-help, gross and fine motor, expressive language and language comprehension, and letter and number skills development for children aged 15 months to 6 years. The General Development scale of the CDI provides an overall index of development. Results are interpreted as “normal,” “borderline” (25% below age cutoff or equivalent to −1.5 SD), or “delayed” (30% below age cutoff or equivalent to −2 SD below the mean for age).16 The PEDS is a 10-item parent questionnaire which assesses the parent’s level of concern about behavior, learning or development. Two or more predictive concerns or abnormal domains constitute a positive screen. Parental responses on the PEDS were interpreted as “normal” or “at risk.”17
Medical records of patients were reviewed for the presence of select clinical and laboratory features. GBS isolates from Texas Children’s Hospital were typed by the Lancefield capillary precipitin method.18 Several authors, who were not blinded as to clinical outcome, reviewed diagnoses made by radiologists during the patients’ admissions for evidence of abnormal neuroimaging.
Statistical analysis was performed by using Stata 8 software (StataCorp LP, College Station, TX). Means, medians, and ranges were calculated for descriptive data. Analyses of clinical features were performed by using the Fisher exact or χ2 tests for categorical variables and Wilcoxon test for numerical variables. Univariate analyses of features predicting an adverse outcome were performed by using logistic regression. A P value < .05 was considered significant. Multivariate logistic regression was performed on risk factors that were associated with adverse outcome at a P ≤ .20.
Outcomes were defined as normal level of function for age, mild-to-moderate impairment, or severe impairment by using the following definitions:
Normal functioning was characterized by cognitive testing scores within 1 SD of the mean on all cognitive subtests, on the Mullen Scales of Early Learning (≤6 years old), or WIAT-II (>6 years old) and no evidence of neurologic or functional impairment.
Mild-to-moderate impairment was characterized by cognitive testing scores within 1 to 2 SD below the mean in any domain of the Mullen Scales of Early Learning or WIAT-II, or academic underachievement characterized by a >15-point split between subtest categories with evidence of concomitant school difficulties,19 or history of grade retention, or receipt of special education services, or evidence of mild neurologic or functional impairment (eg, hydrocephalus requiring ventriculoperitoneal shunt, loss of a digit, seizure disorder well controlled by medication, or mildly delayed development and learning).
Severe impairment was characterized by cognitive skills >2 SD below the mean in ≥1 domains of the Mullen Scales of Early Learning or WIAT-II or evidence of severe neurologic or functional impairment such as blindness, bilateral sensorineural hearing loss, cerebral palsy, motor deficits, or significantly delayed development and learning.
Chart review identified 90 infants with GBS meningitis. The group included 1 infant, reported previously, later found to have interleukin-1 receptor-associated kinase-4 deficiency.20 Five infants (6%) died during the hospital admission. Five additional children, each with an abnormal neurologic examination and abnormal brain imaging at hospital discharge, died at 6 months to 3 years after discharge from complications attributable to GBS meningitis. Terminal illnesses included aspiration pneumonia after a seizure in 1 neurologically devastated child and severe electrolyte imbalance from pan-hypopituitarism secondary to GBS meningitis in another. Three of the 5 children died at home. Families of 43 of the remaining 80 children (54%), aged 3 through 12 years, consented to their child’s participation. By physician report, 7 of 37 children not evaluated were reportedly functioning normally and 7 were impaired; 23 (29%) were lost to follow-up (Fig 1). Features at admission were comparable (except for irritability at presentation) for evaluated and unevaluated children (Table 1).
The general characteristics of the evaluated cohort are shown in Table 1. Thirty-seven of these children (86%) had late-onset meningitis diagnosed at a mean of 48 (median 32; range 8–202) days of life. Forty-seven percent were white, 28% Hispanic, 23% African American, and 1% Asian. Seven were born at 36 weeks’ gestation, and the remainder at term. Among 29 infants for whom GBS typing was performed, type III accounted for 76% of isolates and type Ia for the remainder.
At a mean age of 6.8 (range 3–12) years, 24 (56%) of the 43 survivors had no detectable sequelae and were functioning normally, 11 (25%) had mild-to-moderate impairment, and 8 (19%) had severe impairment (Tables 2 and 3). Regarding early childhood outcomes of GBS meningitis survivors, 16 children aged <6 years and 2 children who were at a developmental age of <6 years were assessed with the Mullen Scales of Early Learning (Table 2). Of these 18 children, 9 (50%) were functioning within the normal range, characterized by all Mullen scores within 1 SD of the mean, and no evidence of functional or medical impairment. Four children (22%) demonstrated mild-to-moderate impairment, characterized by Mullen Scores 1 to 2 SD below the mean on any cognitive domain (ie, visual reception, fine motor, receptive language, expressive language) or had evidence of mild functional or medical sequelae. Five children (28%) demonstrated severe impairment characterized by Mullen scores >2 SD below the mean in any cognitive domain or evidence of severe functional or medical sequelae (Table 2). Regarding school-age childhood outcomes of GBS meningitis survivors, 24 children aged 6 through 12 years were assessed with the WIAT-II (Table 3). Of these, 15 (63%) were functioning within the normal range, 7 (29%) demonstrated mild-to-moderate impairment, and 2 (8%) demonstrated severe disabilities.
Among the 11 children classified as having mild-to-moderate impairment, 3 had repeated ≥1 grade levels in school. One child was functioning at age level but required a ventriculoperitoneal shunt for hydrocephalus. One 5-year-old child sustained loss of terminal digits of his right thumb and forefinger due to purpura fulminans during hospitalization and demonstrated delayed fine motor skills (Table 4). Severely impaired children included a 9-year-old with profound global developmental delay functioning at a 2- to 6-month age equivalent with cerebral palsy, cortical vision impairment, hydrocephalus requiring a ventriculoperitoneal shunt, and seizure disorder and a legally blind 4-year-old with severe-to-profound sensorineural hearing loss functioning at a 10- to 16-month age equivalent.
Twenty-five parents completed the PEDS. Parental responses on the PEDS accurately identified children who were functioning normally (sensitivity = 93%) or who demonstrated severe delays (sensitivity = 100%). For parents of children with mild-to-moderate impairment, parental responses on the PEDS did not identify these children as having developmental concerns (sensitivity = 16%). Parents of 16 children completed the CDI. Parental responses on the CDI accurately identified children functioning normally (sensitivity 100%) or who were severely delayed (sensitivity = 100%). Parental responses on the CDI often failed to identify children with mild-to-moderate delays as being developmentally at risk (sensitivity = 25%).
Predictive Features at Admission
At presentation, three-fourths (76%) of the evaluated survivors were lethargic, 20% were in coma or semicoma, and 32% had seizures. Neutropenia (WBC <5000 per mm3) was common (49%) with 11 infants having an absolute neutrophil count <1000 per mm3. Thirty-four percent had a CSF WBC exceeding 1000/mm3 and 11 (28%) had a CSF protein exceeding 300 mg/dL.
Analysis of features during initial hospitalization and at hospital discharge that revealed a significant risk of death after discharge or of severe impairment are shown in Table 5. These features less reliably predicted mild-to-moderate impairment (Table 6). Analysis was performed to evaluate the magnitude of associations between the selected risk factors and poor mild-to-moderate or severe outcomes. None of the features was significant by multivariate analysis, likely due to small sample size.
Thirty of 43 subjects had cranial imaging performed within 72 hours of hospital admission, usually an unenhanced (63%) or enhanced (23%) computed tomographic (CT) scan. Infants sustaining mild-to-moderate or severe long-term impairment more often underwent early imaging than did those with normal outcome (95% vs 50%, P = .002). Abnormal imaging findings, including extra-axial fluid collections (23%) and ischemia or infarct (30%), were detected in 70% of studies but were not predictive of outcome. Five of 9 infants with normal early imaging results had long-term impairment.
Thirty-two of 43 subjects had later (mean 15.6 days, range 7–63 days) cranial imaging during hospitalization, including enhanced CT scan (59%) or MRI (28%). Infants sustaining mild-to-moderate or severe impairment more often underwent late cranial imaging than those with a normal outcome (89% vs 63%, P = not significant). Imaging abnormalities were noted in most CT and MRI studies (72%), including 82% from children with impairment and 60% from those with a normal outcome (P = .243). Imaging findings of infarction, encephalomalacia, or hydrocephalus, were present in 11 of 18 children with impairment versus 3 of 15 normal children (P = .016).
GBS meningitis remains a substantial cause of mortality and morbidity in young infants. Active population-based surveillance by the Centers for Disease Control and Prevention Emerging Infections Program Network reported that GBS accounts for 86.1% of meningitis cases among US children <2 months of age.6 In a contemporary French survey, GBS was the most common cause of neonatal bacterial meningitis, accounting for 66% of cases in term infants.21 When GBS emerged in the 1970s, acute mortality was 20% to 30% with survivors at high risk for lifelong impairment.8–10 In 1985, we reported that among 61 infants with GBS meningitis, 21% died acutely and of 38 survivors evaluated at a mean age of 6 years, 29% had severe sequelae, 21% had mild-to-moderate deficits, and 50% were functioning normally.8 In the current study, acute mortality was 5.5%, comparable to that reported by Thigpen et al4 (11.1%) among infants with GBS meningitis in the United States and by Georget-Bouquinet et al22 (14%) among infants in France.
Contemporary data are sparse regarding long-term sequelae and factors associated with poor outcomes.23–26 Our contemporary outcomes are remarkably similar to those in our 1985 report8 and others from that era, including Chin et al10 in 1984 and a case-control study from England and Wales in 1985–1987.24 Among 49 survivors of GBS meningitis evaluated at 9 to 10 years of age in the latter report, 14.3% had severe neurodisability, 22.4% had mild or moderate impairment, and 67% had no impairment. De Louvois et al26 evaluated a cohort of 5-year-old children who had GBS meningitis in 1996–1997; 5% had severe, 29% moderate and 27% mild disability, and 39% had normal outcomes.
That more than one-half of our children were functioning normally is encouraging. However, morbidity as a consequence of GBS meningitis remains substantial. The parent report questionnaires highlight 2 features; parents were accurate informants regarding developmental status if their children were functioning in the normal or severely delayed ranges. If their children demonstrated mild-to-moderate impairment, parental responses on developmental screening questionnaires did not consistently identify children with developmental delays. Thus, parent developmental questionnaires may not be sufficient to identify children with mild-to-moderate delays, and more follow-up for GBS meningitis survivors is indicated. In the school-age period, 4 of 7 children (57%) classified as having mild-to-moderate impairment demonstrated evidence of a learning disability, school failure, or developmental delay, requiring additional school services. Our study provided the opportunity to counsel families to seek additional testing or school-based resources to assist their child to function optimally.
An often voiced question is, “Will my child be normal?” We identified a number of features associated with death or severe long-term impairment. Previous investigators have associated admission features of coma, seizures, leukopenia, inotrope use, assisted ventilation, high CSF protein, and low CSF glucose with death or early severe sequelae.8,11,27,28 In addition, we found that failed hearing screen, abnormal neurologic examination at hospital discharge, and specific end-of-therapy cranial imaging findings were associated with long-term impairments.
Imaging features have not been widely used to predict outcomes for infants surviving GBS meningitis, although recently Hernández et al29 described 8 newborns with focal infarction by MRI; 6 died or had severe disability 2 years later. We found that early cranial imaging abnormalities were not predictive of outcome. End-of-therapy cranial imaging findings of infarction, encephalomalacia, or hydrocephalus were significantly associated with sequelae; however, some children with these findings had a normal outcome.
This study has a number of limitations. First, siblings were not included as a control group to eliminate factors of genetics and environment. We believe that the high rate of impairment was distinct from that expected among sibling controls, but the study design does not permit attribution of all impairments to GBS. Second, our findings are applicable only to term and near-term GBS meningitis survivors because we restricted enrollment to infants ≥36 weeks to avoid confounding issues among more immature infants.30 Finally, the length of follow-up ranged from 3 to 12 years, and subtle defects might not have been detected in the youngest children.
In summary, our study provides contemporary long-term outcome data for infant GBS meningitis survivors with 3 key findings: (1) despite reduced mortality acutely long-term outcomes of GBS meningitis are similar to those reported from our group 25 years ago with approximately one-half of our children having some degree of impairment and one-half functioning normally8; (2) clinical and laboratory data at admission and cranial imaging results at discharge are predictive of children who will have severe impairment but not children who will have mild-to-moderate impairment or normal functioning; and (3) parental completion of developmental screens accurately identifies children who are functioning in the normal or severely delayed range but have poor sensitivity in identifying children with mild-to-moderate impairments. These findings highlight a need for awareness regarding the possibility of deficits at follow-up evaluation that can affect developmental and behavioral futures for these children. They also underscore the need for prevention strategies, such as development of GBS glycoconjugate vaccines for maternal immunization, to prevent this potentially devastating infection.
We gratefully acknowledge the children surviving GBS meningitis and their family members. We thank each person who contributed to the study through support, time, and participation. We also thank LuAnn Papile, MD, and Sherry S. Vinson, MD, for their helpful suggestions regarding the study design and Robin D. Schroeder for assistance in preparation of the manuscript.
- Accepted March 2, 2012.
- Address correspondence to Morven S. Edwards, MD, 1102 Bates St, Suite 1120, Houston, TX 77030. E-mail:
All authors contributed to the following: (1) conception and design of study, acquisition of data, or analysis and interpretation of data; (2) drafting the article or revising it critically for important intellectual content; and (3) final approval of the version to be published.
FINANCIAL DISCLOSURE: Dr M. Edwards is a consultant to Novartis Vaccines & Diagnostics and she receives consultancy fees and research funding from Novartis Vaccines & Diagnostics; the other authors have no financial relationships relevant to this article to disclose.
FUNDING: Funded in part by The Max It Out Foundation for Pediatric Research, Vanderbilt University Medical Center, Nashville, Tennessee, and the Group B Strep Association, Chapel Hill, North Carolina.
- Verani JR,
- McGee L,
- Schrag SJ,
- Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention (CDC)
- ↵Centers for Disease Control and Prevention. 2010. Active Bacterial Core Surveillance Report, Emerging Infections Program Network, Group B Streptococcus, 2009. Available at: www.cdc.gov/abcs/reports-findings/survreports/gbs09.pdf. Accessed November 9, 2011
- Jordan HT,
- Farley MM,
- Craig A,
- et al.,
- Active Bacterial Core Surveillance (ABCs)/Emerging Infections Program Network, CDC
- Wald ER,
- Bergman I,
- Taylor HG,
- Chiponis D,
- Porter C,
- Kubek K
- Stoll BJ,
- Hansen NI,
- Adams-Chapman I,
- et al.,
- National Institute of Child Health and Human Development Neonatal Research Network
- Committee on Practice and Ambulatory Medicine, Section on Ophthalmology, American Association of Certified Orthoptists,
- American Association for Pediatric Ophthalmology and Strabismus,
- American Academy of Ophthalmology
- Mullen EM
- Wechsler D
- Ireton H
- Glascoe FP
- Lancefield R
- Fletcher JM,
- Morris RD,
- Lyon GR
- Krause JC,
- Ghandil P,
- Chrabieh M,
- et al
- Georget-Bouquinet E,
- Bingen E,
- Aujard Y,
- Levy C,
- Cohen R,
- Groupe des Pédiatres et Microbiologistes de l’Observatoire National des Méningites Bactériennes de l’Enfant
- Stevens JP,
- Eames M,
- Kent A,
- Halket S,
- Holt D,
- Harvey D
- Bedford H,
- de Louvois J,
- Halket S,
- Peckham C,
- Hurley R,
- Harvey D
- Klinger G,
- Chin C-N,
- Beyene J,
- Perlman M
- Doctor BA,
- Newman N,
- Minich NM,
- Taylor HG,
- Fanaroff AA,
- Hack M
- Copyright © 2012 by the American Academy of Pediatrics