British Journal of Obstetrics and Gynaecology August 2001, Vol. 108, pp.

840847

Choosing a strategy to prevent neonatal early-onset group B streptococcal sepsis: economic evaluation
Catalin M. Stan a,*, Michel Boulvain a, Patrick A. Bovier b, Raymond Auckenthaler c, Michel Berner d, Olivier Irion a
Objective To determine the most appropriate strategy to prevent neonatal streptococcal sepsis in a setting with a low incidence of the disease. Design Decision analysis and economic evaluation. Setting Geneva University Hospitals, Switzerland. Population Pregnant women at 35-37 weeks of gestation and in labour. Methods Local data and data from the literature were used in a decision analysis to compare the current policy of antibiotic administration at Geneva University Hospitals with the recommended preventive strategies. Main outcome measures Number of episodes of sepsis averted; cost and number needed to treat to prevent one episode of sepsis; and proportion of women receiving antibiotics during labour. Results Compared with the current policy, the risk factors strategy would prevent 69 streptococcal sepsis per million deliveries and the screening strategy would prevent 102 cases of sepsis per million deliveries. Cost per averted sepsis case would be 60, 700 and 473, 600, respectively. The number needed to treat to prevent one sepsis would be 1087 with a risk factors strategy and 1029 with a screening strategy. Preventive strategies would increase the proportion of women receiving antibiotics during labour from 6% with the current policy, to 13.5% and 16.5% respectively. Conclusions Preventive strategies are more effective than the current policy, but imply increased hospital costs and a notable increase in the proportion of women receiving antibiotics during labour, which may be unjustied in a low incidence setting.

INTRODUCTION Early-onset group B streptococcal sepsis is the leading cause of neonatal infectious mortality 1. Asymptomatic genital colonisationwith groupB streptococcus is observed in 2%-35% of pregnant women 2,3. The risk of colonisation of a neonate born to a colonised mother is 40%-70% 2,4,5. Early-onset sepsis develops in 1% to 2% of colonised infants 2,6 with a reported incidence of 0.2-3.0 per 1000 births 711. Despite recent advances in perinatal care, mortality up to 10% 1,8 and neurologic sequelae in 10%20% 2,12 of babies with streptococcal sepsis are reported. Preventing early-onset streptococcal sepsis is an

Department of Obstetrics and Gynaecology, Geneva University Hospitals, Switzerland b Department of Community Medicine, Geneva University Hospitals, Switzerland c Central Laboratory of Microbiology, Geneva University Hospitals, Switzerland d Department of Pediatrics, Geneva University Hospitals, Switzerland
des Ho pitaux Universitaires * Correspondence: Dr C. M. Stan, Maternite ve, CH-1211 Geneva 14, Switzerland. de Gene q RCOG 2001 British Journal of Obstetrics and Gynaecology PII: S03 06-5456(00)0020 1-1

important public health objective. Antibiotic treatment of colonised women before the onset of labour is not an effective prevention 13, but intrapartum antibiotic administration has been shown to decrease the risk of vertical transmission and of streptococcal sepsis 6,1418. Timely detection of maternal colonisation during labour is not currently feasible, given the low reliability of available rapid tests 19,20. In 1996 the Centres for Disease Control and Prevention, supported by the American College of Obstetricians and Gynaecologists and the American Academy of Paediatrics, issued guidelines for the prevention of early-onset streptococcal sepsis 21. Two strategies were considered acceptable: antenatal culture screening and a risk factors strategy (Table 1). In the United States and Australia, adoption of these strategies have been associated with a decrease in the incidence of the disease from 1.4-2.0 per 1000 births to 0.2-0.8 per 1000 births 810,22,23. Some authors have suggested that the implementation of either preventative strategy may not be justied when the baseline incidence of earlyonset disease is below 0.6 per 1000 births 24,25. The incidence of early-onset streptococcal sepsis at Geneva University Hospitals from 1989 to 1999 was 0.4 per 1000 births, with a mortality of 8.3%. In our institution, antenatal screening for group B streptococcus is not routine. Genital cultures, including culture for group B
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PREVENTION OF NEONATAL STREPTOCOCCAL SEPSIS 841 Table 1. Recommended strategies to prevent early-onset group B streptococcal sepsis, and current policy at Geneva University Hospitals. Intrapartum antibiotic administration if any criteria is present 1. Current policy 2. Risk factors 3. Rectovaginal GBS culture screening at 3537 weeks of gestation Intrapartum temperature $ 388C; Premature rupture of membranes before 34 weeks; Positive genital GBS culture during pregnancy. Delivery before 37 weeks of gestation; Intrapartum temperature $ 388C; Membrane rupture $ 18h; GBS bacteriuria during pregnancy; Previous infant with streptococcal sepsis. GBS culture positive at 3537 weeks of gestation; Delivery before 37 weeks of gestation; GBS bacteriuria during pregnancy; Previous infant with streptococcal sepsis; If culture is not done, results are incomplete or unknown, prophylaxis is given according to the risk factors' strategy.

streptococcus, are performed if women present with preterm labour, preterm premature rupture of membranes, or vaginal discharge. Women presenting with intrapartum fever ($ 388C), a positive culture for group B streptococcus during pregnancy, or ruptured membranes before 34 weeks of gestation are given antibiotics during labour. This policy identies only a fraction of babies at risk of developing streptococcal sepsis. The objective of this study was to evaluate the effectiveness and costs associated with the adoption of recommended policies and to determine the most appropriate strategy for preventing early-onset disease in our epidemiological context. METHODS A decision analysis model was constructed to compare

three strategies: current policy in our institution, considered as the reference; a strategy based on risk factors; and a strategy based on universal group B streptococcus culture screening of pregnant women at 35-37 weeks (Fig. 1). For the screening strategy, a node was added to include the probability of preterm labour, as women delivering before 37 weeks would receive intrapartum antibiotics following the risk factors strategy. The number of expected episodes of streptococcal sepsis with each strategy was calculated taking into account the following variables: the prevalence of maternal colonisation and of risk factors; the sensitivity and specicity of antenatal group B streptococcus cultures and of risk factors in predicting intrapartum maternal colonisation; the probability of receiving antibiotics during labour; their efcacy in preventing vertical transmission; the probability of vertical transmission; and the

Fig. 1. Simplied decision tree comparing strategies based on antenatal culture screening, on risk factors and the current policy of antibiotic administration at Geneva University Hospitals. * Sensitivity and specicity of antenatal culture screening and risk factors for the prediction of maternal colonisation during labour. A refers to the probability of receiving intrapartum antibiotics in the presence of risk factors or positive antenatal culture screening. B refers to the probability of receiving intrapartum antibiotics with the current policy.

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842 C. M. STAN ET AL. Table 2. Variables used in the decision analysis model. a Base case value Prevalence of maternal GBS colonisation in labour (%) Prevalence of risk factors (%) Delivery before 37 weeks (%) Sensitivity of antenatal GBS cultures (%) Specicity of antenatal GBS cultures (%) Sensitivity of risk factors (%) Specicity of risk factors (%) Probability of receiving antibiotics during labour for a woman with positive antenatal screening (%) Probability of receiving antibiotics during labour for a woman presenting with risk factors (%) Effectiveness of intrapartum antibiotic prophylaxis to prevent vertical transmission (RR, 95% CI) Probability of vertical transmission (%) Probability of GBS sepsis in colonised neonates (%) Probability of mild maternal antibiotic reaction (%) Probability of severe maternal antibiotic reaction (%) Cost of a rectovaginal GBS culture Cost of maternal antibiotic prophylaxis Cost of mild maternal antibiotic reaction Cost of severe maternal antibiotic reaction
a

Range used in sensitivity analyses 2 to 35 c 14.6 b to 24.0 c 5.4 b to 12.0 c 14 b to 100 c 89 to 100 c 14 b to 68 c 80 to 88 bc 44 to 90 c 42 to 81 c 0.04 to 0.14 c 35 to 70 c 1 to 2 c 0.7 to 10 c 0.004 to 0.015 c $17 to $58 c (10 to 36) $29 to $283 c (18 to 175)

References
2-6,26-40 41-44 42-47 16,27,48,49 27,48,49 42,49 49 10,31,50,51 9,42,51,52 6,14-18,53 2,4-6,29,31,40,48,54 2,5,55 56,57 56-58 24,59-61 43,59-63 64 43

7.8 (5.2 to 11.3) b 17.7 (14.6 to 21.1) b 7.4 (5.4 to 10.0) b 33 (14 to 59) b 95 (90 to 97) b 31 (14 to 52) b 84 (80 to 88) b 80 c 80 c 0.08 c 50 c 1c 5c 0.01 c Sw fr 35 d (14) Sw fr 85 d (33) Sw fr 141 b (55) $68 c (42) $902 c (557)

Cost estimates in $ or Swiss francs (Sw fr), adjusted to the consumer price index at 31 December 1999 and converted in UK on a conversion base of 1 1.62$ 2.58 Swiss francs. b Estimates (95% condence intervals) at Geneva University Hospitals. c Value derived from the literature. d Cost of a negative and of a positive GBS culture at Geneva University Hospitals.

probability of sepsis in colonised babies 26,9,10,1418,24,2664 (Table 2). The prevalence of maternal colonisation and of risk factors, sensitivity and specicity of antenatal screening and of risk factors to predict intrapartum colonisation were estimated in a prospective cohort study conducted in our institution between 1 October 1998 to 31 December 1998. The study was approved by the institutional review board and participants gave written informed consent. Rectovaginal group B streptococcus cultures were performed at 35-37 weeks and during labour. Swabs of the vaginal introitus and anorectum were sent to the microbiology laboratory on a transport medium (Venturi Transystem, Copan, Italy) within 12 hours after sampling. According to the recommendations of the Centres for Disease Control, swabs were inoculated in a selective broth medium (Todd-Hewitt), and subcultured on blood sheep agar after 18 hours 21,65. Beta-hemolytic colonies were identied by Gram staining, catalase and latex agglutination (Slidex Streptokit, Biomerieux, France). Maternal colonisation was dened as a positive vaginal and/or anal group B streptococcus culture. Sensitivity of the antenatal culture was dened as the proportion of women with positive cultures at delivery whose prenatal cultures were positive at 35-37 weeks. Specicity was dened as the proportion of women with negative cultures at delivery whose antenatal cultures were

negative. The proportion of women receiving intrapartum antibiotics with the current policy was recorded. The most plausible values for the probability of receiving intrapartum antibiotics following the adoption of a screening or risk factors strategy, the probability of colonisation of the neonate and of streptococcal sepsis in colonised neonates were derived from a systematic search of the literature. Effectiveness of intrapartum antibiotic prophylaxis was derived from a meta-analysis of randomised trials 14. In formulating our model, we made several assumptions: 1. rectovaginal group B streptococcus culture during labour was considered as the gold standard for maternal colonisation; 2. women with negative antenatal cultures had the same probability of receiving intrapartum antibiotics as the general population; and 3. that only babies born to colonised mothers were at risk for earlyonset disease 55. The model was used to compute the number of expected episodes of sepsis with each strategy, the proportion of women receiving antibiotics and the number of women given antibiotics to prevent an additional episode of sepsis (number needed to treat). The cost effectiveness analysis evaluated the impact of each strategy on hospital resources. Cost of a negative group B streptococcus culture, including material and staff time, was estimated at Swiss francs (Sw fr) 35
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PREVENTION OF NEONATAL STREPTOCOCCAL SEPSIS 843

(equivalent to 14) in our institution. Because of the additional cost of the identication of the bacteria, a positive culture was estimated at Sw fr 85 (equivalent to 33). The cost of intrapartum antibiotic treatment was estimated at Sw fr 141 (equivalent to 55) and included the cost of two doses of antibiotics (amoxicillin 2g), the infusion device and intravenous uids, and the cost of 30 minutes of a midwife's time. The probability and cost of maternal anaphylaxis to antibiotics were abstracted from the literature and included in the cost estimate of each strategy 43,5658,64. The effectiveness measure was the number of episodes of sepsis averted. Each variable was tested for its inuence in sensitivity analyses. Sensitivity analysis for all variables was performed using Monte Carlo simulation, sampling within the condence intervals of the estimates, or in the range of distributions of the values reported in the literature. The decision and the economic analyses were conducted using DATA 3.5 (TreeAge Software, Williamstown, Massachusetts, USA). RESULTS Rectovaginal cultures were performed in 264 women at 35-37 weeks of gestation, and in 335 women during labour. Both cultures were performed in 209 women. Colonisation with group B streptococcus at 35-37 weeks of gestation and during labour was found in 28 of 264 (10.6%) and in 26 of 335 women (7.8%), respectively. Sensitivity of antenatal culture to predict maternal colonisation in labour was 33% (95% CI, 14% to 59%) and specicity 95% (95% CI, 90% to 97%). The proportion of women with one or more of the risk factors for early onset disease was 17.7% (95% CI, 14.6% to 21.1%). According to the decision analysis model, 378 episodes of streptococcal sepsis per million births can be expected with the current policy (Table 3). Adoption of a risk factors strategy would avert 69 episodes of sepsis per million births. A screening strategy would avert 102

episodes of sepsis per million births when compared with the present policy, and 33 episodes of sepsis per million births when compared with the risk factors strategy. Firstorder Monte Carlo simulation showed the same range of values for effectiveness. In our institution, 6.0% of women receive antibiotic treatment during labour. This proportion would increase to 13.5% with the adoption of a risk factors strategy, and to 16.5% with a screening strategy. Assuming a risk of 1 per 10 000 women receiving antibiotics, severe anaphylaxis would occur in 6, 13.5, and 16.5 women per million deliveries, respectively 58. The number of women treated to avert episodes of one sepsis would be 1087 with a risk factors strategy, and 1029 with a screening strategy. The marginal cost to prevent one sepsis would be 60, 700 for a risk factors' strategy and 473, 620 for a screening strategy. Sensitivity analysis using Monte Carlo simulations showed the same ranking in 93.6% of the iterations. Yancey et al. 27 reported a sensitivity of 87% and specicity of 96% for the antenatal group B streptococcus cultures. Using these values, a screening strategy would prevent 234 episodes of sepsis per million births, and the marginal cost effectiveness would decrease to 105, 140. The proportion of women receiving antibiotic prophylaxis during labour would increase to 18.6%, but the number needed to treat would decrease to 538. Varying prevalence (5% to 30%) and sensitivity of antenatal cultures (30% to 100%), the screening strategy was the most effective for any value of these variables, but its cost effectiveness ratio remained the highest (Table 4). Sensitivity analyses for the other variables in the model showed that the ranking of effectiveness and costs did not change for the ranges of values listed in Table 2. DISCUSSION Lower incidence of early-onset group B streptococcus sepsis is reported in Europe 6669, compared with the United States 1,41,42. The incidence at Geneva University

Table 3. Effectiveness and cost effectiveness of current policy, risk factors' strategy, and screening strategy. Expected no. of sepsis/10 6 births (95% CI) a Current policy Risk factors Screening (sensitivity b 33%)
a b

Averted sepsis/10 6 births 69 102

Total cost in /10 6 births (95% CI) a 3 370 000 (2 580 000 to 4 350 000) 7 560 000 (4 230 000 to 7 920 000) 23 190 000 (20 190 000 to 25 350 000)

Marginal cost effectiveness ratio () 60 700 473 620

378 (252 to 575) 309 (213 to 500) 276 (184 to 428)

95% CI derived from Monte Carlo simulation (centiles 2.5 to 97.5). Sensitivity of antenatal group B streptococcal culture (35-37 weeks) at Geneva University Hospitals.

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844 C. M. STAN ET AL. Table 4. Marginal cost effectiveness and effectiveness of preventive strategies, varying prevalence of maternal colonisation, and sensitivity of the antenatal GBS culture. Prevalence of maternal colonisation 5% Risk factors Screening Sensitivity 33% Sensitivity 87%
a b

7.8% 60 700 69 473 620 102 105 140 234

10% 50 450 86 380 120 127 87 900 292

20% 29 210 171 200 500 255 53 440 584

30% 22 130 257 140 630 382 41 960 876

CE a Eb CE a Eb CE a Eb

92 920 43 739 350 64 156 810 146

Marginal cost effectiveness ratio in per averted GBS sepsis. Effectiveness of a strategy as compared with the current policy: averted GBS sepsis per million births.

Hospitals is similar to that observed in other European countries. Despite its rarity, group B streptococcus sepsis is a constant concern for neonatologists and obstetricians due to the rapid onset and severity of the disease 11,22. Before implementing one of the recommended strategies in our hospital, local epidemiological data were needed to evaluate the benets and costs of each of the strategies. The decision analysis model included probabilities estimated in our hospital, using literature data only when local estimates were not available. The prevalence of genital group B streptococcus colonisation in pregnant women in Geneva is similar to other European estimates 4,5,3033. Sensitivity of the antenatal group B streptococcus culture to predict colonisation in labour is lower than previously reported 27,48. Sampling methodology, transport to the laboratory, and culture techniques were performed as recommended by the Centres for Disease Control 21,65. We hypothesise that our lower sensitivity may be due to a lower burden of group B streptococcus in our population. A sensitivity of antenatal group B streptococcus cultures as low as 30% has been reported in women with light colonisation 38. The predicted estimate of the risk of group B streptococcus sepsis with our current policy (0.38 per 1000 births) is consistent with the observed incidence in our hospital (0.40 per 1000 births). We considered the current policy as the reference in the model rather than a `do-nothing' policy, as 6% of women in labour receive antibiotics for suspected chorioamnionitis. According to our model, both preventive strategies would be more effective than the current policy, and a screening strategy would be more effective than a risk factors strategy. In our institution, with an average of 3200 deliveries per annum, the implementation of a preventive strategy would prevent one additional episode of sepsis every three or four years. On the other hand, either strategy would be associated with a notable increase in the proportion of women receiving antibiotics in labour. This may increase the risk of anaphylaxis and of antibiotic resistance 70,71. In addition, other bacteria (e.g. Escherichia coli) may cause neonatal sepsis at an increased frequency 71.

The cost of a screening strategy to prevent one episode of group B streptococcus sepsis would be higher than a risk factors strategy in a context of low prevalence of maternal colonisation and low incidence of early-onset disease. Even with a high sensitivity of the antenatal culture, the cost effectiveness ratio of a screening strategy remains higher. We have not considered the paediatric costs in our analysis because there is no evidence that the adoption of neonatal care guidelines would decrease the incidence of group B streptococcus sepsis and that the surveillance of neonates would be modied following the adoption of either strategy 72. In addition, these costs largely depend on the duration of postpartum hospital stay. When postpartum hospital stay is less than 48 hours, the total cost related to the prevention of earlyonset group B streptococcus sepsis was estimated to increase by 51% for a screening strategy, and by 112% for a risk factors strategy 73. The sensitivity analyses showed that varying the value of the included variables did not have an impact on the ranking of the effectiveness and of the cost effectiveness ratio of the strategies. However, improvement in the sensitivity of screening would result in increased effectiveness in preventing early-onset sepsis, and in a more favourable cost effectiveness ratio. Other economic analyses have been conducted in settings with a higher prevalence of maternal group B streptococcus colonisation and a higher incidence of streptococcal sepsis 24,60,63. In these contexts, both preventative strategies were estimated to have a more reasonable cost effectiveness ratio than our estimates. Given the high cost and the risk of anaphylaxis associated with the recommended preventive strategies, alternative interventions to prevent group B streptococcus sepsis may be considered. These include intrapartum prophylaxis limited to women with positive antenatal screening and presenting with risk factors 6,74, or selective neonatal prophylaxis 75. Methods for the rapid detection of colonised mothers during labour based on immunouorescent antibodies, agglutination, colorimetric, enzyme or optical immunoassays, have poor sensitivq RCOG 2001 Br J Obstet Gynaecol 108, pp. 840847

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ity 19,20. Use of vaginal disinfection with chlorhexidine during labour has been shown to be ineffective in decreasing the risk of group B streptococcus sepsis 76,77. Group B streptococcus vaccines, as yet unavailable for clinical use, may become important components of future preventive programmes 78. Recently, Bergeron et al. 79 reported a rapid polymerase chain reaction assay, which has the potential to accurately identify during labour pregnant women colonised with group B streptococcus. We adapted our decision analysis model to include the newly developed polymerase chain reaction test. A strategy using this test would prevent 300 episodes of group B streptococcus sepsis per million deliveries (79% of the expected episodes of sepsis) and the number needed to treat would be 266 women to prevent one neonatal sepsis. The cost effectiveness ratio of a strategy based on polymerase chain reaction would be lower than that of a risk factors strategy if the cost of testing one woman is less than 18, and lower than a screening strategy if the cost is less than 35. CONCLUSION Preventive strategies decrease the risk of early-onset group B streptococcus sepsis, but their cost is high. Adoption of either preventive strategy would be associated with a notable increase in the proportion of women receiving antibiotics in labour, with the associated risk of anaphylaxis and of bacterial resistance. In our epidemiological context, the implementation of either preventive strategy might not be justied given the low incidence of early-onset group B streptococcus disease. If results with the new polymerase chain reaction assay are conrmed in larger studies, a strategy based on this test may signicantly reduce the current incidence of neonatal streptococcal sepsis with a lower number of women receiving antibiotics during labour.
Acknowledgements The authors would like to thank Ms P. Oester and Dr A. Stainier who contributed to the recruitment of women, data collection and keying. We are indebted to Ms R. Sudan for her contribution in editing the manuscript. This study was supported by a grant from the Quality of Care Unit of the Geneva University Hospitals. References
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