Early neonatal group B streptococcal disease: Degree of colonisation as an important determinant

Journal of Infection (I985) II, I I9--I24

Early neonatal group B streptococcal disease: degree of c o l o n i s a t i o n as a n i m p o r t a n t d e t e r m i n a n t L. J. Gerards, B. P. Cats and J. A. A. Hoogkamp-Korstanje University Children's Hospital, 'Het Wilhelmina Kinderziekenhuis', Nieuwe Gracht z37, 3512 L K Utrechr, The Netherlands Accepted for publication 7 November I984 Summary During a period of 5 years (I January I977 to I January I982) I45 infants colonised with group B streptococci (GBS) were admitted to the neonatal intensive care unit of the University Children's Hospital, Utrecht. In 87 of these infants (60%) vertical transmission of GBS was established; in 43 of these 87 infants (49%) the degree of colonisation was moderate to heavy. Early-onset (EO) GBS disease arose in zI of I45 infants (attack rate: I4-5 %). Of the 43 infants moderately to heavily colonised with GBS, however, I9 suffered from EO GBS disease (attack rate: 44"2 %), whereas there were only two cases among the 44, lightly colonised infants (attack rate: 4"5%), a highly significant difference (P < 0-0005). Similarly, probable sepsis (PS), defined as signs and symptoms of sepsis but without positive blood cultures, was observed significantly more often in moderately to heavily colonised infants (I5/43, attack rate: 34'9 %) compared with those lightly colonised (4/44, attack rate: 9.I %) (P < 0.005). Infants moderately to heavily colonised with GBS at birth appear to have a significantly higher risk of developing serious GBS disease (EO or PS) than do infants only lightly colonised.

Introduction G r o u p B streptococci ( G B S ) are an important cause of septicaemia and meningitis in the neonatal period and during the first m o n t h s of life. T w o clinical s y n d r o m e s are c o m m o n l y distinguished: 'early onset (EO) disease', arising from a few hours up to 7 days after birth, and ' d e l a y e d onset ( D O ) disease ', presenting after the first week of life 1, 2. T h e mortality rate varies from 50 to 70 % in E O G B S disease to 20-50 % in D O G B S disease. A third type of G B S disease observed in the immediate postnatal period was described in I973 b y Franciosi and colleagues 1, b u t has rarely been m e n t i o n e d b y others. It includes all the clinical features of septicaemia in the absence of positive blood cultures in infants colonised with G B S . F o r this s y n d r o m e the n a m e ' p r o b a b l e sepsis' (PS) has been proposed. Acquisition of G B S b y neonates with E O G B S disease and P S is p r e s u m e d to result from vertical transmission i.e. from the m o t h e r 3, 4. D O disease may result from b o t h vertical and horizontal transmission i.e. from persons other than the m o t h e r ~, 5. In the perinatal period the n u m b e r of infants colonised with G B S through vertical transmission is a b o u t 4 o % of those b o r n to mothers themselves colonised with G B S . T h e maternal carriage rate varies from 4 to zo % 6. T h e incidence of G B S disease, however, is only o" r-5" 4 cases per ~ooo ox63-4453/85/o5oi 19 +06 $02.00/0

© I985 The British Society for the Study of Infection

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L . J . GERARDS E T A L .

live births 8, 7. This implies that only a small fraction of infants colonised with GBS actually develops serious GBS disease. In an attempt to gain further insight into the factors determining the onset of serious GBS disease in infants colonised with organism by vertical transmission, we evaluated clinical and bacteriological data derived from all GBS positive infants admitted to the neonatal intensive care unit during a period of 5 years. P a t i e n t s and m e t h o d s

All GBS positive infants admitted to the neonatal intensive care unit ( N I C U ) of the Wilhelmina Children's Hospital from I January 1977 to I January 1982 were included in the study. T h e N I C U serves as a referral unit for a region with 2o,ooo-25,ooo live births per year. Race, age, n u m b e r of previous pregnancies and deliveries, pregnancy complications, delivery circumstances of the mother, sex, birth-weight, gestational age and Apgar-scores of the infants were recorded. T h e diagnosis of EO disease was based on clinical features of septicaemia (decreased peripheral circulation, apnoeic attacks, signs of respiratory distress), haematological changes (leucocytosis or leucopenia, granulocytopenia, shift to the left, thrombocytopenia) and positive cultures of blood a n d / o r cerebrospinal fluid in infants aged 7 days or less. T h e diagnosis of PS was based on the same clinical features and the isolation of GBS from various body sites, but without positive blood a n d / o r cerebrospinal fluid cultures, in infants aged 7 days or less, as defined by Franciosi and colleagues. 1 T h e diagnosis of D O disease was based on clinical features of septicaemia a n d / o r meningitis and positive blood a n d / o r cerebrospinal fluid cultures in infants aged i week or more. Swabs from the nose, throat, external auditory meatus, eyes, umbilicus, skin and rectum were taken and cultured immediately after admission and repeated twice a week. All indwelling lines and endotracheal tubes were cultured on their removal. Blood, cerebrospinal fluid and other specimens were cultured when indicated. All samples were investigated by standard microbiological techniques as previously described. 6 For culturing GBS 5 % sheep blood agar and Pike's selective broth m e d i u m were used. T h e heaviness of growth on primary isolation was scored on a scale of + , + + and + + + (IO, lO-5O and > 5o colonies per plate respectively). Colonisation of neonates was scored as follows: /> three sites positive ( + + + ) heavy; < three sites positive ( + + + ) or >i three sites positive ( + or + + ) moderate; < three sites positive ( + or + + ) slight. Vertical transmission of GB S was assumed when cultures taken immediately after birth were positive; horizontal transmission when sites which had been culture negative for GBS during the first week of life subsequently became positive. Antibiotics (penicillin + aminoglycosides) were administered on admission to every neonate with clinical features of infection. Mechanical ventilation, plasma transfusion and an infusion of tolazoline were instituted when indicated. All surviving children were seen regularly in the outpatient department after leaving hospital. T h e X~test without Yates' correction and Student's unpaired r-test were used for statistical analysis.

Neonatal group B streptococcal disease

121

Table I Maternal and pregnancy data of mothers of infants with early onset

(EO) disease, probable sepsis (PS) and colonised infants

Number of neonates Race Caucasian Non-caucasian Age-range (mean years) Pregnancies (mean number) Pregnancy complications Deliveries (mean number) Vacuum extraction Caesarian section Membranes ruptured > 24 h Fever

Group I EO

Group II PS

Group III Colonised

2I

I9

47

19 2 20-35 (28" I) 1.75 7 1"65 o 3 6/15

18 i 18-33 (28"3) 1.77 4 1"61 5 o 8/15

43 4 19-37 (27'0) 1.77 13 1'61 1 2 3/34'~

I

2

O

* EO + PS versus colonised, statistically significant(P < 0.005) Results Patient population

During the period of the study (i January 1977 to I January I982 ) 1150 infantS (474 female and 676 male) were admitted to the N I C U . Group B streptococci were cultured from I45 infants (12-6 % of the total population). Of these, 2I (I4"5 %) had EO (group I), 19 (I3 %) had PS (group II), 5 (3"5 %) had D O and IOO (69 %) were colonised without infection (group III). Eighty-seven infants acquired GBS by vertical transmission. O f these 2I (24 %) developed EO, 19 (22 ~o) PS while 47 infants were colonised only with GBS. Horizontal transmission was established in 28 colonised infants and in one infant (20 %) with DO. For the remaining 30 (20 %) infants the mode of transmission could not be established with certainty. T h e study was confined to the 87 infants who acquired GBS by vertical transmission. M a t e r n a l data

Maternal and pregnancy data are presented in Table I. T h e r e were no statistically significant differences between the EO, PS and colonised infants, except for prolonged rupture of the membranes. From 64 mothers, information about the period that had elapsed between the moment of rupture of the amniotic membranes and delivery could be obtained. Of 3o mothers with infected neonates (EO + PS) 14 (47 %) had prolonged rupture of the membranes compared with only 3 of 34 (9%) mothers with colonised infants. This difference was statistically significant (P < o'oos). N e o n a t a l data

Among the three groups there were no significant differences in sex ratio, birth-weight or gestational age (Table II). Gestational age ranged from 25-43 weeks, with 65 (75 %) neonates being premature. Shock was significantly more common in neonates with EO (71%) than in those with PS (26 % ) (P < o'oos).

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L.J. GERARDS ET AL.

Table II Neonatal data of infants with early onset (EO) disease, probable

sepsis (PS) and of colonised infants Group I Neonatal data Male Female Birthweight (Mean g) Range (g) Gestational age (mean weeks) ~< 32 weeks 33-38 weeks /> 38 weeks

[] Early onset

Group II

Group I I I

EO

PS

Colonised

z4

zI

7

8

25 22

2o8I 9o0-460o 33-0 iI 6 4

I97I 890-449o 33'2 8 6 5

I947 820-495 ° 32"7 2I I3 I3

[] Probable sepsis

[] Colonised

I00

o~

75

~ 5o

i

~ i::ili

"~ 25 O.

0

Throat

Nose

Ear

Eye

Skin

Umb. Rectum

Fig. I. Isolation of group B streptococci from sites sampled routinely. Umb., Umbilicus.

Respiratory distress and apnoeic attacks arose in 86 % of infants with EO and in too% of those with PS. Haematological evidence of infection was present in all neonates with EO and PS. T h e incidence of neutropenia was significantly higher in EO (57%) than in pS (26%) (P < 0"o5). All infants with EO and PS were treated with antibiotics (kanamycin or gentamicin with penicillin). T h e mortality rate in EO (62 %) was significantly higher than that in PS (2I %) (o.oI < P < o"o5) or that of colonised infants (I5 %) (P < o.ooI). Twelve infants with EO and only one with PS died within 72 h after birth. Review later revealed psychomotor handicaps in five of eight surviving neonates with EO and in four of x5 with PS (P < o'o5). Bacteriology Seven sites were sampled routinely (Fig. i). Every site sampled except the rectum was more often positive in neonates with GBS disease than in colonised infants (P < o'0o5). T h e umbilicus was most often positive in EO (81%). This compares with 58 % in PS and 3 ° % in colonised infants. Throat, nose, ear, eye and skin were positive in 57-79 % of all neonates with G B S disease and

Neonatal group B streptococcal disease

I2 3

T a b l e I I I Rate of colonisation of infants with early onset (EO) disease,

probable sepsis (PS) and of those colonised without infection Number of infants Colonisation Heavy Moderate Light

Positive sites

Rate

EO

PS

Colonised

f> 3 <3 0I" >~3 <3

+++ +++

4 -15 -2

4 -II -4

o -9 -38

+or+ + +or+ +

in 21-36 % of the colonised infants. T h e m e a n n u m b e r of positive sites was 4"6 in EO, 4"I in PS and 2"I in colonised infants (GBS disease versus colonisation: P < o , o o I ) . T h e grade ofcolonisation is shown in T a b l e I I I . M o s t infants with G B S disease were moderately to heavily colonised in contrast to neonates w i t h o u t disease (P < o-oo5). H e a v y colonisation was not f o u n d in these colonised neonates w i t h o u t disease. Moreover, EO disease was seen in ~9 of 43 (44"2 %) infants moderately to heavily colonised with G B S , b u t in only 2 of 44 (4.5%) of lightly colonised infants (P < o'ooo5). PS also arose significantly more often in moderately to heavily colonised infants (I5 of 43, 34"9 %) than it did in those lightly colonised (o'ooI < P < o'oo5). Serotyping of strains isolated from blood and from cerebrospinal fluid yielded the following distribution: type I I I 50 % , type II 20 % , type Ia io %, type Ic Io %. O f all G B S strains isolated IO ~o were not typable. Strains isolated from the blood and C S F of the same infant were always identical. Discussion

T h e admission to hospital of 45 neonates with G B S disease d u r i n g a 5-year period indicates an incidence of neonatal G B S disease in our region (approximately 2o,ooo live births per year) of at least o'45 cases per Iooo live births. T h i s is similar to the incidence reported in other studies2, v T h e fact that we did not observe cases of EO or PS due to horizontal transmission of G B S supports the view 1 that vertical transmission is the prevalent m o d e of transmission in infants developing early onset G B S disease. I n a previous study we d e m o n s t r a t e d that vaginal carriage and the degree of vaginal colonisation of the m o t h e r , are important determinants for vertical transmission of GBS. 8 P r e m a t u r e labour, prolonged r u p t u r e of m e m b r a n e s , i n t r a p a r t u m fever, twin pregnancy and lack of transplacentally acquired type-specific antibodies are all associated with an increased risk of an infant developing early onset G B S disease), s, 9 T h e present s t u d y demonstrates that in the n e w b o r n the n u m b e r o f positive sites and the degree of colonisation per site are also i m p o r t a n t determinants of neonatal G B S disease. Neonates with G B S disease had significantly more G B S positive sites than infants w i t h o u t such infection. T h e attack rate of

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L. J. GERARDS E T A L .

n e o n a t a l G B S disease ( e i t h e r E O o r P S ) was significantly h i g h e r in m o d e r a t e l y or h e a v i l y c o l o n i s e d i n f a n t s t h a n in infants o n l y lightly c o l o n i s e d . I n fact, h e a v i l y c o l o n i s e d infants w i t h o u t clinical signs o f i n f e c t i o n w e r e n o t e n c o u n t e r e d in o u r s t u d y . A n c o n a a n d colleagues 1° h a v e p r e v i o u s l y s h o w n t h a t infants b o r n to h e a v i l y c o l o n i s e d m o t h e r s w e r e m o r e o f t e n p o s i t i v e at m u l t i p l e sites a n d w e r e m o r e h e a v i l y c o n t a m i n a t e d w i t h G B S at b i r t h t h a n infants b o r n to lightly c o l o n i s e d m o t h e r s . B o y e r a n d colleagues 11 r e p o r t e d t h a t i n t r a p a r t u m a d m i n i s t r a t i o n o f a m p i c i l l i n significantly l o w e r s vaginal c o l o n i s a t i o n w i t h G B S a n d results in a d e c r e a s e o f vertical t r a n s m i s s i o n . O u r findings, t o g e t h e r w i t h t h o s e o f A n c o n a a n d colleagues 1° a n d B o y e r a n d colleagues 11 s u g g e s t t h a t i n t r a p a r t u m a d m i n i s t r a t i o n o f a m p i c i l l i n c o u l d b e e x t r e m e l y effective in p r e v e n t i n g early o n s e t G B S disease. ( T h e authors thank the staff of the diagnostic department of the Laboratory for Microbiology (Utrecht), D r C. v. d. Heiden for statistical analysis and Antje ten Brug, M y r i a m de Kok and Anne Marike T r i p for typing the manuscript.) References

1. Franciosi RA, Knostman JD, Zimmerman PhD. Group B streptococcal neonatal and infant infections, ff Pediatr 1973; 82: 7o7-718. 2. Baker CJ, Barrett FF. Transmission of group B streptococci among parturient women and their neonates, ff Pediatr 1973; 83: 919-925. 3. Pass MA, Gray BM, Santosh K, Dillon HC. Prospective studies of Group B streptococcal infections in infants, ff Pediatr I979; 95: 437-443. 4. Baker CJ. Summary of the workshop on perinatal infections due to group B streptococcus. J Infect Dis 1977; 136: 137-152. 5. Aber RC, Allen N, Howell JT, Wilkinson HW, Facklam RR. Nosocomial transmission of group B streptococci. Pediatrics 1976; 58:346-353 • 6. Hoogkamp-Korstanje JAA, Gerards L J, Cats BP. Maternal carriage and neonatal acquisition of group B streptococci, ff Infect Dis 1982; 145: 80o-803. 7. Editorial. Neonatal infection with Group B streptococci. Lancet 1981 ; ii: 181-182. 8. Stewardson-Krieger PB, Gotoff SP. Risk factors in early onset neonatal group B streptococcal infections. Infection 1978; 6:5o-53 . 9. Boyer KM, Gadzala CA, Burd LI, Fisher DE, Paton JB, Gotoff SP. Selective intrapartum chemoprofylaxis of neonatal group B streptococcal early-onset disease. I. Epidemiologic rationale, ff Infect Dis 1983; 148:795-80 I. IO. Ancona RJ, Ferrieri P, Williams PP. Maternal factors that enhance the acquisition of group B streptococci by newborn infants. J Med Microbiol 198o; 13: 273-28o. I I. Boyer KM, Gadzala CA, Kelly PD, Gotoff SP. Selective intrapartum chemoprofylaxis of neonatal group B streptococcal early-onset disease. III. Interruption of mother to infant transmission, ff Infect Dis 1983; 148: 81o-816.