Prospective randomised controlled trial of an infection screening programme to reduce the rate of preterm delivery
http://www.100md.com
《英国医生杂志》
1 Department of Obstetrics and Gynaecology, University of Vienna Medical School, W?hringer Gürtel 18-20, A-1090 Vienna, Austria
Correspondence to: H Kiss herbert.kiss@akh-wien.ac.at
Abstract
Preterm delivery (birth before 37 completed weeks of gestation) is the leading cause of neonatal morbidity and mortality. In recent years the birth weight of premature babies has been found to be an important determinant of outcome, such that preterm birth is no longer defined solely by gestational age but also in terms of a birth weight below 2500 g. The main focus has been on preterm infants with a birth weight below 2000 g, who bear the greatest burden of morbidity and mortality. The costs of neonatal care for infants born at less than 33 weeks of gestation (birth weight below 2000 g) rise exponentially as gestational age decreases and rise further with birth weights below 1000 g.1
Advances in neonatal practice have improved the chances of survival for preterm infants with a very low birth weight.2 However, low birthweight infants are still at a higher risk of neurodevelopmental morbidity than preterm infants with a higher birth weight and, as a group, incur notable social and healthcare costs,3-5 related not only to acute neonatal intensive care but also to the long term sequelae arising from preterm birth.
Studies have estimated the high direct costs incurred after the initial hospitalisation in the first year of a healthy infant with a birth weight below 2000 g. The lifetime costs per preterm birth have been estimated at 766 339 (￡511 614; $941 640),4 with physical or mental disability resulting in incremental increases in the cost of healthcare services.
Although the causes of preterm delivery are complex and manifold, a prior history of late miscarriage or preterm delivery remains the most predictive risk factor.6 Compelling evidence now exists that infection is not only associated with preterm delivery but that it is a causative factor.7 8 Vaginal infections, particularly bacterial vaginosis, have consistently been shown in many longitudinal population studies to be associated with late miscarriage and preterm delivery.9-13 A review of the current literature shows conflicting data on the benefits of routine screening for bacterial vaginosis,14 15 particularly in populations at low risk.16 Studies of interventions to prevent preterm labour as well as studies aimed at arresting the progression of established preterm labour have largely shown a consistent lack of efficacy.17
Uniform recommendations on effective screening methods to prevent preterm delivery are still lacking. We therefore evaluated a simple antenatal programme to prevent preterm births. This programme entailed general screening for and standardised treatment of the vaginal infections with the highest prevalence, regardless of whether the infection is clearly associated with preterm delivery or whether no link has been established, as is the case in candidiasis.18 The goal of the programme was to reduce the rate of preterm births and late miscarriages.
Methods
Between January 2001 and October 2002 we considered a total of 4429 pregnant women for enrolment into the study. Of these, 4155 women completed the screening programme (fig 1). The mean age of the patients was 28.9 (SD 5.6) years. Mean gestational age at the time we obtained the secretions was 17 (SD 1.6) weeks. Table 1 shows the number of primiparous and multiparous women and the number of previous preterm births in the screened population. About 98% (4080) of women were of white ethnic origin. Almost 80% of examined smears did not show any evidence of infection. The remaining 20% showed an abnormal vaginal flora, with no differences between the intervention and control groups. Table 2 summarises the distribution of the various forms of infection in the screened patient population.
Fig 1 Flow of participants through the trial
Table 1 Obstetric history of study population. Values are numbers (percentages) of pregnant women
Table 2 Distribution of normal and abnormal vaginal flora in the screened patient population. Values are numbers (percentages) of pregnant women
Outcome data were available from 2058 women in the intervention group and 2097 women in the control group. The difference in the rates of spontaneous preterm birth between the intervention group and the control group reached significance (3.0%, v 5.3%, 95% confidence interval 1.2% to 3.6%; P = 0.0001). The number of preterm infants with a birth weight equal to or below 2500 g was significantly lower in the intervention group than in the control group (1.7% v 3.5%, 0.9 to 2.8; P = 0.0002). The number of spontaneous preterm births in the lower weight categories was 50% lower (table 3, fig 2) than in the control group. The rate of late miscarriage was also reduced by 50%, whereas the number of intrauterine deaths was comparable between the two groups (table 4). Table 5 provides an overview of the subgroup analysis of the women diagnosed as having an infection at the initial examination and the number of preterm births by intervention and control group.
Table 3 Cumulative distribution of preterm births at less than 37 weeks by birth weight and gestational age in the intervention (n=2058) versus the control group (n=2097)
Fig 2 Number of spontaneous preterm deliveries in the intervention and control groups
Table 4 Spontaneous and medically indicated (iatrogenic) preterm birth, miscarriage, and intrauterine death
Table 5 Subgroup analysis: women with abnormal vaginal flora (see also table 2) and with spontaneous preterm delivery at less than 37 weeks of gestation. Values are numbers of patients unless otherwise indicated
Among the 447 women who had a follow up Gram stain after the first course of treatment, asymptomatic vaginal infection was still present in 123 (27.5%); 44 had bacterial vaginosis, 8 had bacterial vaginosis and candidiasis, 70 had candidiasis, and 1 had trichomoniasis. We treated all women again according to the study protocol. None of the women reported adverse events during the treatment period. Adverse events would not have been a reason for exclusion from or discontinuation of treatment, because the study focus was to compare a screened with a non-screened population. The groups did not differ significantly with regard to passage of meconium, necrotising enterocolitis, neonatal sepsis, and neonatal death during hospitalisation. Among preterm infants with a birth weight below 1500 g no case of necrotising enterocolitis during the stay at the neonatal intensive care unit was documented in the neonatology (NICU) records (data not shown).
Discussion
St John EB, Nelson KG, Cliver SP, Bishnio RR, Goldenberg RL. Cost of neonatal care according to gestational age at birth and survival status. Am J Obstet Gynecol 2000;182: 170-5.
Ahner R, Kohlhauser C, Bikas D, Rabl M, Langer M, Pollak A, et al. Grenzen der fetalen Lebensf?higkeit und Konsequenzen für das geburtshilfliche Management. Geburtsh Frauenheilk 2000;60: 20-5.
Xu B, Rantakallio P, Jarvelin MR. Mortality and hospitalizations of 24-year-old members of the low-birthweight cohort in northern Finland. Epidemiology 1998;9: 662-5.
Petrou S, Sach T, Davidson L. The long term costs of preterm birth and low birth weight: results of a systematic review. Child Care Health Dev 2001;27: 97-115.
Elgen I, Sommerfelt K, Markestad T. Population based, controlled study of behavioural problems and psychiatric disorders in low birthweight children at 11 years of age. Arch Dis Child Fetal National Ed 2002;87: 128-32.
Mercer BM, Goldenberg RL, Moawad AH, Meis PJ, Iams JD, Das AF, et al. The preterm prediction study: effect of gestational age and cause of preterm birth on subsequent obstetric outcome. Am J Obstet Gynecol 1999;181: 1216-21.
Gibbs RS, Romero R, Hillier SL, Eschenbach DA, Sweet RL. A review of premature birth and subclinical infection. Am J Obstet Gynecol 1992;166: 1515-28.
Hillier SL, Martius J, Krohn M, Kiviat N, Holmes KK, Eschenbach DA. A case-control study of chorioamnionic infection and histologic chorioamnionitis in prematurity. N Engl J Med 1988;319: 972-8.
McGregor JA, French JI, Parker R, Draper D, Patterson E, Jones W, et al. Prevention of premature birth by screening and treatment for common genital tract infection: Results of a prospective controlled evaluation. Am J Obstet Gynecol 1995;173: 157-67.
Gravett MG, Nelson HP, DeRouen T, Critchlow C, Eschenbach DA, Holmes KK. Independent associations of bacterial vaginosis and chlamydia trachomatis infection with adverse pregnancy outcome. JAMA 1986;256: 1899-903.
McGregor JA, French JI. Bacterial vaginosis in pregnancy. Obstet Gynecol Survey 2000;55(suppl): 1-19.
Hay PE, Lamont RF, Taylor-Robinson D, Morgan DJ, Ison C, Pearson J. Abnormal bacterial colonisation of the genital tract and subsequent preterm delivery and late miscarriage. BMJ 1994;308: 295-8.
Meis PJ, Goldenberg RL, Mercer B, Moawad A, Das A, McNellis D, et al. The preterm prediction study: significance of vaginal infections. Am J Obstet Gynecol 1995;173: 1231-5.
Brocklehurst P, Hannah M, McDonald H. Interventions for treating bacterial vaginosis in pregnancy. Cochrane Database Syst Rev 2000;(2): CD000262.
Leitich H, Brunbauer M, Bodner-Adler B, Kaider A, Egarter C, Husslein P. Antibiotic treatment of bacterial vaginosis in pregnancy: a meta-analysis. Am J Obstet Gynecol 2003;188: 752-8.
Carey JC, Klebanoff MA, Hauth JC, Hillier SL, Thom EA, Ernest JM, et al. Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis. N Engl J Med 2000;342: 534-40.
Goldenberg RL. The management of preterm labor. Obstet Gynecol 2002;100: 1020-37.
Cotch MF, Hillier SL, Gibbs RS, Eschenbach DA. Epidemiology and outcomes associated with moderate to heavy Candida colonization during pregnancy. Am J Obstet Gynecol 1998;178: 374-80.
Nugent RP, Krohn MA, Hillier SL. Reliability of diagnosing bacterial vaginosis is improved by a standardized method of Gram stain interpretation. J Clin Microbiol 1991;29: 297-301.
Mattison DR, Damus K, Fiore E, Petrini J, Alter C. Preterm delivery: a public health perspective. Paediatr Perinatal Epidemiol 2001;15(suppl 2):-16.
Hoyme UB, M?ller U, Saling E. Ergebnisse und m?gliche Konsequenzen der Thüringer Frühgeburtenvermeidungsaktion 2000. Geburtsh Frauenheilk 2002;62: 257-63.
Ugwumadu A, Manyonda I, Ried F, Hay P. Effect of early oral clindamycin on late miscarriage and preterm delivery in asymptomatic women with abnormal vaginal flora and bacterial vaginosis: a randomised controlled trial. Lancet 2003;361: 983-8.
Lamont RF, Dunchan SLB, Mandal D, Basset P. Intravaginal clindamycin to reduce preterm birth in women with abnormal genital tract flora. Obstet Gynecol 2003;101: 516-22.
Schaaf VM, Perez-Stable EJ, Borchardt K. The limited value of symptoms and signs in the diagnosis of vaginal infections. Arch Intern Med 1990;150: 1929-33.(Herbert Kiss, associate p)
Correspondence to: H Kiss herbert.kiss@akh-wien.ac.at
Abstract
Preterm delivery (birth before 37 completed weeks of gestation) is the leading cause of neonatal morbidity and mortality. In recent years the birth weight of premature babies has been found to be an important determinant of outcome, such that preterm birth is no longer defined solely by gestational age but also in terms of a birth weight below 2500 g. The main focus has been on preterm infants with a birth weight below 2000 g, who bear the greatest burden of morbidity and mortality. The costs of neonatal care for infants born at less than 33 weeks of gestation (birth weight below 2000 g) rise exponentially as gestational age decreases and rise further with birth weights below 1000 g.1
Advances in neonatal practice have improved the chances of survival for preterm infants with a very low birth weight.2 However, low birthweight infants are still at a higher risk of neurodevelopmental morbidity than preterm infants with a higher birth weight and, as a group, incur notable social and healthcare costs,3-5 related not only to acute neonatal intensive care but also to the long term sequelae arising from preterm birth.
Studies have estimated the high direct costs incurred after the initial hospitalisation in the first year of a healthy infant with a birth weight below 2000 g. The lifetime costs per preterm birth have been estimated at 766 339 (￡511 614; $941 640),4 with physical or mental disability resulting in incremental increases in the cost of healthcare services.
Although the causes of preterm delivery are complex and manifold, a prior history of late miscarriage or preterm delivery remains the most predictive risk factor.6 Compelling evidence now exists that infection is not only associated with preterm delivery but that it is a causative factor.7 8 Vaginal infections, particularly bacterial vaginosis, have consistently been shown in many longitudinal population studies to be associated with late miscarriage and preterm delivery.9-13 A review of the current literature shows conflicting data on the benefits of routine screening for bacterial vaginosis,14 15 particularly in populations at low risk.16 Studies of interventions to prevent preterm labour as well as studies aimed at arresting the progression of established preterm labour have largely shown a consistent lack of efficacy.17
Uniform recommendations on effective screening methods to prevent preterm delivery are still lacking. We therefore evaluated a simple antenatal programme to prevent preterm births. This programme entailed general screening for and standardised treatment of the vaginal infections with the highest prevalence, regardless of whether the infection is clearly associated with preterm delivery or whether no link has been established, as is the case in candidiasis.18 The goal of the programme was to reduce the rate of preterm births and late miscarriages.
Methods
Between January 2001 and October 2002 we considered a total of 4429 pregnant women for enrolment into the study. Of these, 4155 women completed the screening programme (fig 1). The mean age of the patients was 28.9 (SD 5.6) years. Mean gestational age at the time we obtained the secretions was 17 (SD 1.6) weeks. Table 1 shows the number of primiparous and multiparous women and the number of previous preterm births in the screened population. About 98% (4080) of women were of white ethnic origin. Almost 80% of examined smears did not show any evidence of infection. The remaining 20% showed an abnormal vaginal flora, with no differences between the intervention and control groups. Table 2 summarises the distribution of the various forms of infection in the screened patient population.
Fig 1 Flow of participants through the trial
Table 1 Obstetric history of study population. Values are numbers (percentages) of pregnant women
Table 2 Distribution of normal and abnormal vaginal flora in the screened patient population. Values are numbers (percentages) of pregnant women
Outcome data were available from 2058 women in the intervention group and 2097 women in the control group. The difference in the rates of spontaneous preterm birth between the intervention group and the control group reached significance (3.0%, v 5.3%, 95% confidence interval 1.2% to 3.6%; P = 0.0001). The number of preterm infants with a birth weight equal to or below 2500 g was significantly lower in the intervention group than in the control group (1.7% v 3.5%, 0.9 to 2.8; P = 0.0002). The number of spontaneous preterm births in the lower weight categories was 50% lower (table 3, fig 2) than in the control group. The rate of late miscarriage was also reduced by 50%, whereas the number of intrauterine deaths was comparable between the two groups (table 4). Table 5 provides an overview of the subgroup analysis of the women diagnosed as having an infection at the initial examination and the number of preterm births by intervention and control group.
Table 3 Cumulative distribution of preterm births at less than 37 weeks by birth weight and gestational age in the intervention (n=2058) versus the control group (n=2097)
Fig 2 Number of spontaneous preterm deliveries in the intervention and control groups
Table 4 Spontaneous and medically indicated (iatrogenic) preterm birth, miscarriage, and intrauterine death
Table 5 Subgroup analysis: women with abnormal vaginal flora (see also table 2) and with spontaneous preterm delivery at less than 37 weeks of gestation. Values are numbers of patients unless otherwise indicated
Among the 447 women who had a follow up Gram stain after the first course of treatment, asymptomatic vaginal infection was still present in 123 (27.5%); 44 had bacterial vaginosis, 8 had bacterial vaginosis and candidiasis, 70 had candidiasis, and 1 had trichomoniasis. We treated all women again according to the study protocol. None of the women reported adverse events during the treatment period. Adverse events would not have been a reason for exclusion from or discontinuation of treatment, because the study focus was to compare a screened with a non-screened population. The groups did not differ significantly with regard to passage of meconium, necrotising enterocolitis, neonatal sepsis, and neonatal death during hospitalisation. Among preterm infants with a birth weight below 1500 g no case of necrotising enterocolitis during the stay at the neonatal intensive care unit was documented in the neonatology (NICU) records (data not shown).
Discussion
St John EB, Nelson KG, Cliver SP, Bishnio RR, Goldenberg RL. Cost of neonatal care according to gestational age at birth and survival status. Am J Obstet Gynecol 2000;182: 170-5.
Ahner R, Kohlhauser C, Bikas D, Rabl M, Langer M, Pollak A, et al. Grenzen der fetalen Lebensf?higkeit und Konsequenzen für das geburtshilfliche Management. Geburtsh Frauenheilk 2000;60: 20-5.
Xu B, Rantakallio P, Jarvelin MR. Mortality and hospitalizations of 24-year-old members of the low-birthweight cohort in northern Finland. Epidemiology 1998;9: 662-5.
Petrou S, Sach T, Davidson L. The long term costs of preterm birth and low birth weight: results of a systematic review. Child Care Health Dev 2001;27: 97-115.
Elgen I, Sommerfelt K, Markestad T. Population based, controlled study of behavioural problems and psychiatric disorders in low birthweight children at 11 years of age. Arch Dis Child Fetal National Ed 2002;87: 128-32.
Mercer BM, Goldenberg RL, Moawad AH, Meis PJ, Iams JD, Das AF, et al. The preterm prediction study: effect of gestational age and cause of preterm birth on subsequent obstetric outcome. Am J Obstet Gynecol 1999;181: 1216-21.
Gibbs RS, Romero R, Hillier SL, Eschenbach DA, Sweet RL. A review of premature birth and subclinical infection. Am J Obstet Gynecol 1992;166: 1515-28.
Hillier SL, Martius J, Krohn M, Kiviat N, Holmes KK, Eschenbach DA. A case-control study of chorioamnionic infection and histologic chorioamnionitis in prematurity. N Engl J Med 1988;319: 972-8.
McGregor JA, French JI, Parker R, Draper D, Patterson E, Jones W, et al. Prevention of premature birth by screening and treatment for common genital tract infection: Results of a prospective controlled evaluation. Am J Obstet Gynecol 1995;173: 157-67.
Gravett MG, Nelson HP, DeRouen T, Critchlow C, Eschenbach DA, Holmes KK. Independent associations of bacterial vaginosis and chlamydia trachomatis infection with adverse pregnancy outcome. JAMA 1986;256: 1899-903.
McGregor JA, French JI. Bacterial vaginosis in pregnancy. Obstet Gynecol Survey 2000;55(suppl): 1-19.
Hay PE, Lamont RF, Taylor-Robinson D, Morgan DJ, Ison C, Pearson J. Abnormal bacterial colonisation of the genital tract and subsequent preterm delivery and late miscarriage. BMJ 1994;308: 295-8.
Meis PJ, Goldenberg RL, Mercer B, Moawad A, Das A, McNellis D, et al. The preterm prediction study: significance of vaginal infections. Am J Obstet Gynecol 1995;173: 1231-5.
Brocklehurst P, Hannah M, McDonald H. Interventions for treating bacterial vaginosis in pregnancy. Cochrane Database Syst Rev 2000;(2): CD000262.
Leitich H, Brunbauer M, Bodner-Adler B, Kaider A, Egarter C, Husslein P. Antibiotic treatment of bacterial vaginosis in pregnancy: a meta-analysis. Am J Obstet Gynecol 2003;188: 752-8.
Carey JC, Klebanoff MA, Hauth JC, Hillier SL, Thom EA, Ernest JM, et al. Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis. N Engl J Med 2000;342: 534-40.
Goldenberg RL. The management of preterm labor. Obstet Gynecol 2002;100: 1020-37.
Cotch MF, Hillier SL, Gibbs RS, Eschenbach DA. Epidemiology and outcomes associated with moderate to heavy Candida colonization during pregnancy. Am J Obstet Gynecol 1998;178: 374-80.
Nugent RP, Krohn MA, Hillier SL. Reliability of diagnosing bacterial vaginosis is improved by a standardized method of Gram stain interpretation. J Clin Microbiol 1991;29: 297-301.
Mattison DR, Damus K, Fiore E, Petrini J, Alter C. Preterm delivery: a public health perspective. Paediatr Perinatal Epidemiol 2001;15(suppl 2):-16.
Hoyme UB, M?ller U, Saling E. Ergebnisse und m?gliche Konsequenzen der Thüringer Frühgeburtenvermeidungsaktion 2000. Geburtsh Frauenheilk 2002;62: 257-63.
Ugwumadu A, Manyonda I, Ried F, Hay P. Effect of early oral clindamycin on late miscarriage and preterm delivery in asymptomatic women with abnormal vaginal flora and bacterial vaginosis: a randomised controlled trial. Lancet 2003;361: 983-8.
Lamont RF, Dunchan SLB, Mandal D, Basset P. Intravaginal clindamycin to reduce preterm birth in women with abnormal genital tract flora. Obstet Gynecol 2003;101: 516-22.
Schaaf VM, Perez-Stable EJ, Borchardt K. The limited value of symptoms and signs in the diagnosis of vaginal infections. Arch Intern Med 1990;150: 1929-33.(Herbert Kiss, associate p)