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Intrapartum antibiotics for known maternal Group B streptococcal colonization

  1. Arne Ohlsson1,*,
  2. Vibhuti S Shah2

Editorial Group: Cochrane Pregnancy and Childbirth Group

Published Online: 10 JUN 2014

DOI: 10.1002/14651858.CD007467.pub4


How to Cite

Ohlsson A, Shah VS. Intrapartum antibiotics for known maternal Group B streptococcal colonization. Cochrane Database of Systematic Reviews 2014, Issue 6. Art. No.: CD007467. DOI: 10.1002/14651858.CD007467.pub4.

Author Information

  1. 1

    University of Toronto, Departments of Paediatrics, Obstetrics and Gynaecology and Institute of Health Policy, Management and Evaluation, Toronto, ON, Canada

  2. 2

    University of Toronto, Department of Paediatrics and Institute of Health Policy, Management and Evaluation, Toronto, ON, Canada

*Arne Ohlsson, Departments of Paediatrics, Obstetrics and Gynaecology and Institute of Health Policy, Management and Evaluation, University of Toronto, 600 University Avenue, Toronto, ON, M5G 1X5, Canada. aohlsson@mtsinai.on.ca.

Publication History

  1. Publication Status: Edited (no change to conclusions), comment added to review
  2. Published Online: 10 JUN 2014

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Characteristics of included studies [ordered by study ID]

MethodsRandomized controlled trial.
I. Blinding of randomization - no.
II. Blinding of intervention - no.
III. Complete follow-up - no.
IV. Blinding of outcome measurement - no.


Participants180 women with vaginal, rectal or both specimens positive for group B streptococcus (in the majority of women the interval between the time of cultures and parturition was > 10 weeks) and at the time of giving birth had the following risk factors (selective intrapartum prophylaxis): preterm labor (< 37 weeks of gestation) or prolonged rupture of membranes (> 12 hours).

If women in the control group developed intrapartum fever (temperature > 37.5ºC) they were excluded from the study group and were treated with ampicillin.

Exclusion criteria: penicillin allergy or need for other antimicrobial agents.

Study period: prior to May 1982 (first report in abstract form by Boyer 1982).

Study period: May 1979 to September 1981 (second report Boyer 1983).

Study period: May 1979 to September 1984 (final report Boyer 1986).

Multicenter study, USA (Private obstetrician’s clinics, a health maintenance organization and the obstetric clinics of Micheal Reese Hospital and Medical Center).


InterventionsWomen in the treatment group (n = 94): received 2 g of ampicillin intravenously followed by 1 g every 4 hours until giving birth.

Women in the control group (n = 86) received no ampicillin.

If the mother had received ampicillin, the infant was treated with 4 doses of intramuscular ampicillin (50 mg/kg) every 12 hours.

Infants born to untreated women received antibiotics only if symptoms of sepsis were observed.

In all symptomatic infants (presence of respiratory distress, asphyxia, or signs of infection at birth regardless of maternal treatment) cerebrospinal fluid examination was performed and treatment with ampicillin and kanamycin commenced until the results of blood and surface cultures were available.


OutcomesPrimary outcomes

Neonatal

All cause mortality

Mortality from early (postnatal age less than 7 days) onset culture positive neonatal GBS infection including 1 or more of the following conditions.

a) Sepsis - defined as symptoms and signs of sepsis and a bacterial culture positive for GBS (obtained in a sterile manner from normally sterile body fluids such as blood, cerebrospinal fluid or urine, or culture from internal organs at autopsy).

b) Pneumonia in the neonate (postnatal age less than 7 days) - defined as symptoms and signs and radiographic findings consistent with pneumonia and positive culture for GBS (obtained from tracheal aspirate or by culture of lung tissue at autopsy).

Mortality from infections (as per a and b above) caused by bacteria other than GBS.

Secondary outcomes

Neonatal

Early (postnatal age less than 7 days) GBS infection in a neonate - defined as symptoms and signs of sepsis or pneumonia in a neonate born to a GBS positive mother, and positive GBS bacterial cultures (from normally sterile body fluids obtained from the neonate).

Late onset GBS sepsis - sepsis due to GBS in an infant at least 7 days old.

Neonatal sepsis due to bacterial organisms other than GBS.

Maternal

Sepsis in the peri/postpartum period.


NotesDetermined the incidence of group B streptococcus bacteraemia in infants born to 1648 women with prenatal colonization who did not participate in the randomized study. Antibiotics were administered to 232 of these women and blood culture obtained from mother or their infant if sepsis was suspected.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskParticipants were assigned to ampicillin or control groups (with an allocation ratio of 1:1) on the basis of sequential selection of sealed opaque envelopes containing assignments generated from a table of random numbers.

Allocation concealment (selection bias)High riskSequential selection of opaque envelopes. Although there was adequate sequence generation it would very soon become obvious to which group the next mother would be assigned as the allocation ratio was 1:1. Although the allocation ratio was 1:1 there is an imbalance in the numbers of women allocated to the 2 groups: 94 in the ampicillin group and 86 in the control group. After excluding 20 women (13 women who developed intrapartum fever and 7 for whom there were randomization errors or incomplete data, 83 women (85 infants) remained in the ampicillin group and 77 (79 infants) in the control group.

Blinding of participants and personnel (performance bias)
All outcomes
High risk"Neither the patient nor the obstetricians were blinded to the assignment to study groups." We have interpreted the information as that the sequence generation was adequate but from then on the study was open to patients and care-givers.

Blinding of outcome assessment (detection bias)
All outcomes
High riskOutcomes were not assessed by staff blinded to the intervention.

Incomplete outcome data (attrition bias)
All outcomes
High risk13 women were excluded as they developed intrapartum fever (7 in the ampicillin group and 6 in the control group) and 7 in whom there were randomization errors or incomplete data (4 in the ampicillin group and 3 in the control group).

Selective reporting (reporting bias)High riskConcerns addressed in the cells above and below.

Other biasHigh riskThe results of this ongoing study has been reported on 3 occasions. In the first report (Boyer 1982) there were 71 infants in the ampicillin group and there were 128 infants in the control group (the number of mothers randomized was not reported). Blood cultures were positive in 4 heavily colonized infants whose mothers were not treated with ampicillin; no blood cultures were positive among infants whose mothers were treated (P = .17).

In the second report (Boyer 1983), 80 women were randomized; 43 received ampicillin chemoprophylaxis and 37 did not. 1 infant in the control group had GBS bacteraemia.

Between the second (Boyer 1983) and third (final, Boyer 1986) publication Gotoff in a letter to the editor (Gotoff 1984) wrote "In order to show efficacy in preventing GBS disease, we need an additional case in our control group". It seems clear that the researchers were aware of study results throughout the study and stopped recruitment when statistical significance (1-tailed) had been achieved. Between the second (Boyer 1983) and the third publication (Boyer 1986) the authors changed their test of significance for comparisons of colonization, bacteraemia, and the rate of postpartum febrile morbidity from a 2-tailed to a 1-tailed test.

It is remarkable that in a study of perinatal infections 13 women were excluded as they developed intrapartum fever (7 in the ampicillin group and 6 in the control group).


MethodsRandomized controlled trial.
I. Blinding of randomization - yes.
II. Blinding of intervention - cannot tell.
III. Complete follow-up - yes.
IV. Blinding of outcome measurement - cannot tell.


ParticipantsWomen who were at a gestational age of 36 weeks or more, were in spontaneous or induced labor and were culture-proven carriers of group B streptococci. Cultures for GBS were obtained at the time of admission for spontaneous or induced labor. Exclusion criteria included planned caesarean section, antibiotics taken within the preceding 7 days, a history of allergy to penicillins, multifetal gestation, or antepartum fetal death.

Study period 26 February 2000 to 22 May 2001.


Interventions175 women received ampicillin (2 g of ampicillin IV followed by 1 g every 4 hours until giving birth) and 177 received penicillin (5 million units of penicillin G IV, followed by 2.5 million units every 4 hours until giving birth).


OutcomesAll cause mortality.
Suspected infection (the authors do not provide a definition).
Initial hospital stay (neonatal).
Chorioamnionitis (definition not provided).
Endometritis (definition not provided).
Allergic reactions to antibiotics (maternal).


NotesWe contacted (5 January 2009) the primary author to provide us with information in which treatment group the early-onset neonatal infection occurred and what their definition of suspected infection was. As of 7 May 2009, we have not received an answer.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskA random number-generating software program was used to assign participants to groups.

Allocation concealment (selection bias)Low riskParticipants were randomized, by selection of the next opaque envelope containing an order sheet, to receive intrapartum antibiotic prophylaxis with ampicillin or penicillin.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskIt is not stated whether the women and the care-givers were aware of what antibiotic was administered.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskIt is not stated whether the women and the care-givers were aware of what antibiotic was administered to the participants.

Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcomes reported for all women randomized.

Selective reporting (reporting bias)Low riskThe authors report on an intent-to-treat analysis and a per-protocol analysis (Changed to low risk).

Other biasLow riskThe study appears to be free of other sources of bias.


MethodsRandomized controlled trial.
I. Blinding of randomization - no.
II. Blinding of intervention - no.
III. Complete follow up - yes.
IV. Blinding of outcome measurement - no.


Participants121 women with group B streptococcal colonization (vaginal and/or rectal swabs). The gestational age at which cultures were obtained ranged from 17 and 42 weeks (mean 32.98 weeks; standard deviation +/- 5.03 weeks).
Study period: not reported.  

Single centre study, Spain.


InterventionsWomen in the treatment group (n = 57) received 500 mg of ampicillin IV every 6 hours until delivery. If induction of labor, antibiotics were administered at the beginning of induction, and if caesarean section without labor, 2 hours prior to surgery.

Patients allergic to penicillin received erythromycin.

In the control group (n = 64) no ampicillin prophylaxis or placebo was administered.


OutcomesInformation on the different parameters analyzed was obtained retrospectively from clinical histories.

Early (postnatal age less than 7 days) GBS infection in a neonate - defined as symptoms and signs of sepsis or pneumonia in a neonate born to a GBS positive mother, and positive GBS bacterial cultures (from normally sterile body fluids obtained from the neonate) (Matorras 1991).

Probable early (postnatal age less than 7 days) GBS infection in a neonate - defined as symptoms and signs of sepsis or pneumonia in a neonate born to a GBS positive mother, and bacterial cultures from normally sterile body fluids obtained from the neonate that were negative for GBS (Matorras 1991).

Late onset GBS sepsis - sepsis due to GBS in an infant at least 7 days old.

Neonatal sepsis due to bacterial organisms other than GBS (Matorras 1991).

Late onset sepsis (Matorras 1991).

Puerperal infection: defined according to clinical criteria- uterine tenderness, uterine subinvolution and fever in the absence of any other known cause of infection.


NotesIn order to assess the impact of GBS maternal colonization for infective puerperal morbidity, the non-carrier patients were compared with the GBS carrier patients who did not receive prophylaxis.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information was provided on how the random sequence was generated.

Allocation concealment (selection bias)Unclear riskIt is stated that "....women were randomly divided" into 2 groups. Insufficient information to permit judgement of "yes" or "no".

Blinding of participants and personnel (performance bias)
All outcomes
High riskThe control group received no intervention (no placebo).

Blinding of outcome assessment (detection bias)
All outcomes
High riskThe placebo group received no intervention and therefore outcomes were assessed by staff aware of group assignment.

Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcomes reported for all women randomized.

Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement of "yes" or "no".

Other biasUnclear riskThe study appears to be free of other sources of bias. The results of the randomized part of this study, which formed the part of a larger cohort study has been reported on at least 3 occasions. The number of randomized women was the same in all 3 reports (n = 121). The rate of puerperal infection was reported in Matorras 1990. In an abstract (Omenaca 1987) the rate of neonatal sepsis caused by GBS was reported as 3 % (2/57) in babies whose mothers received prophylaxis and 13.8% (9/64) in infants of untreated mothers. In the final report (Matorras 1991), the authors report that there was no case of GBS sepsis in the prophylaxis group compared to 3 cases in the control group. Clinically infected newborns represented 3.3% in the prophylaxis group vs 13.8% in the control group.


MethodsRandomized controlled trial.
I. Blinding of randomization - no.
II. Blinding of intervention - no.
III. Complete follow up - yes.
IV. Blinding of outcome measurement - no.


ParticipantsWomen with a positive group B streptococcus latex test before giving birth (in labor), no history of penicillin allergy and no elective term caesarean section without labor or rupture of fetal membranes were eligible.

In woman with a positive streptolatex test admitted for induction of labor but who did not give birth and returned home, the test was repeated if 3 or more days had passed since the first test.

Study period: December 1983 and January 1986 except for a 6-month period in 1984 to 1985.

Single centre, Finland.


InterventionsWomen in the treatment group (n = 88) received 5 million units penicillin G IV every 6 hours during labor. If labor lasted more than 18 hours, 1 million units penicillin V administered orally every 8 hours until parturition (penicillin was chosen as no resistant strains of group B streptococcus had been detected in the institution where the study was conducted).

In the control group (n = 111) women received no prophylaxis or placebo.

Newborns born to group B streptococcus positive women were evaluated as follows.

  1. Blood culture was obtained within 2 hours of birth.
  2. Pharyngeal aspirate and other superficial samples for culture from the external ear canal, eye, and umbilicus were taken within 30 minutes of birth.
  3. Urine sample for streptolatex text was collected.


Cerebrospinal fluid examined was performed if the infant had symptoms and/or signs of sepsis or of meningeal involvement.


OutcomesEarly (postnatal age less than 7 days) GBS infection in a neonate - defined as symptoms and signs of sepsis or pneumonia in a neonate born to a GBS positive mother, and positive GBS bacterial cultures (from normally sterile body fluids obtained from the neonate).

Probable early (postnatal age less than 7 days) GBS infection in a neonate - defined as symptoms and signs of sepsis or pneumonia in a neonate born to a GBS positive mother, and bacterial cultures from normally sterile body fluids obtained from the neonate that were negative for GBS.


NotesNo mention of severity of illness in the newborn or details provided regarding duration of hospitalization and antibiotic administration.

No mention of benefits/adverse reactions to the mother.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information about sequence generation process to permit judgement of "yes" or "no".

Allocation concealment (selection bias)High riskParticipants were assigned to the penicillin or control group based on sequential selection of sealed envelopes containing the treatment instructions. However, the authors state "There was no blinding in the assignment to study groups". There was imbalance in allocation of participants to the two groups; 44% of the participants were allocated to the intervention group and 56% to the control group.

Blinding of participants and personnel (performance bias)
All outcomes
High riskNo blinding as the control group received no intervention (no placebo was used).

Blinding of outcome assessment (detection bias)
All outcomes
High riskThe control group received no intervention and no placebo and staff were not blinded to group assignment. Thus the outcome assessors were not blinded to group assignment.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data.

Selective reporting (reporting bias)Low riskThe authors reported outcomes for women with positive streptolatex test who were randomized (199) and those who were not randomized (157 women who gave birth before the test results were available and 21 women with a history of penicillin allergy. Outcomes for 8565 women who were streptolatex negative were reported. These women gave birth to six neonates with early-onset GBS disease.

Other biasHigh riskResults of the study were first reported in abstract form in 1986 (Tuppurainen 1986) when 94 patients had been randomized, 36 received intrapartum penicillin and 58 did not. 7 of the 58 (12%) neonates whose mother did not receive penicillin developed early onset GBS disease. 1 neonate whose mother received penicillin had intrauterine pneumonia probably due to GBS. It appears that results of the study were known on an ongoing basis.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Belady 1996Randomized controlled trial comparing ampicillin versus penicillin for group B streptococcus prophylaxis. No placebo or untreated control group was included. Reports only on colonization rates. In a separate abstract from the same study (Davies 1998) the authors do not report on maternal infections as per randomized groups.

Dykes 1987This study reported on the effects of chlorhexidine for prevention of neonatal colonization with group B streptococci. This intervention is the topic of another Cochrane review.

Easmon 1983This randomized controlled study reports only on maternal and neonatal colonization, which were not considered important outcomes in our review.

Facchinetti 2002The objective of this randomized controlled trial was to study the efficacy of intrapartum vaginal flushing with chlorhexidine compared with ampicillin in preventing group B streptococcus transmission to neonates. This is the topic of a separate Cochrane review.

Gibbs 1996This randomized controlled study reported on the effect of 2% clindamycin cream administered intravaginally during labor to group B streptococcal-colonized pregnant women. Outcomes included only maternal and neonatal colonization, which were not considered important outcomes for this review.

Håkansson 2014This study consisted of 2 phases (Phase 1 was a randomized controlled trial and Phase 2 was non-randomized, assessing an improved version of the assay). Phase 1 involved 6 Swedish delivery units. The women included in phase 1 were randomized into 2 groups (1A or 1B). The randomization was performed in advance and each hospital had received sealed and consecutively numbered envelopes containing protocols for either group 1A or 1B. Randomization was performed in blocks of 4. In the PCR group (group 1A) swabs in duplicate (Copan Italia S.P.A., Brescia, Italy) were obtained from vagina and rectum (V/R) in this order. 1 swab was used for PCR and the other for conventional, enhanced culture for detection of GBS [16]. IAP was administered if the PCR assay was positive for GBS or indeterminate. In the control group" (group 1B), swabs were taken from V/R for conventional culture with the intention to treat all with IAP according to recommended guidelines. The study did not compare an intervention to placebo. The study (Phase 1) was excluded as both groups received IAP. Phase 2 was not a randomized controlled trial.

Merenstein 1980In this study treatment with antibiotics started at 38 weeks postmenstrual age not intrapartum.

Morales 1986In this study the control group included randomly selected patients and those with a history of ampicillin allergy.

Pinette 2005In this study pregnant women positive for GBS at 35 to 37 weeks' postmenstrual age were randomized to receive intramuscular benzathine penicillin G suspension versus no treatment. Intrapartum all the women received prophylaxis according to CDC guidelines.

Sáez-Llorens 1995This study was an open, non-randomized trial.

 
Comparison 1. Intrapartum antibiotics versus placebo or no treatment for GBS positive women

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Neonatal mortality from all causes1164Risk Ratio (M-H, Fixed, 95% CI)0.19 [0.01, 3.82]

 2 Neonatal mortality from early onset GBS infection1164Risk Ratio (M-H, Fixed, 95% CI)0.31 [0.01, 7.50]

 3 Neonatal mortality from infections caused by bacteria other than GBS1164Risk Ratio (M-H, Fixed, 95% CI)0.31 [0.01, 7.50]

 4 Early (postnatal age less than 7 days) GBS infection in a neonate3488Risk Ratio (M-H, Fixed, 95% CI)0.17 [0.04, 0.74]

 5 Probable early (postnatal age less than 7 days) GBS infection in a neonate2324Risk Ratio (M-H, Fixed, 95% CI)0.17 [0.03, 0.91]

 6 Late onset (7 days old or more) GBS infection in a neonate2289Risk Ratio (M-H, Fixed, 95% CI)0.36 [0.01, 8.69]

 7 Neonatal sepsis due to bacterial organisms other than GBS2289Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.15, 6.79]

 8 Maternal sepsis in the peri/postpartum period1160Risk Ratio (M-H, Fixed, 95% CI)0.31 [0.01, 7.49]

 9 Puerperal infection (not prespecified outcome, definition not provided)1121Risk Ratio (M-H, Fixed, 95% CI)0.16 [0.01, 3.03]

 
Comparison 2. Intrapartum ampicillin versus penicillin for GBS positive women

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Neonatal mortality from all causes1352Risk Ratio (M-H, Fixed, 95% CI)3.03 [0.12, 73.98]

 2 Suspected neonatal infection (definition not provided)1352Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.49, 1.46]

 3 Initial hospital stay (days) for neonates1352Mean Difference (IV, Fixed, 95% CI)0.20 [-0.28, 0.68]

 4 Maternal allergic reactions to antibiotics1352Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 5 Chorioamnionitis (not prespecified outcome, definition not provided)1352Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.38, 2.19]

 6 Endometritis (not prespecified outcome, definition not provided)1352Risk Ratio (M-H, Fixed, 95% CI)3.03 [0.32, 28.89]