Ignite Creation Date:
2024-05-05 @ 4:56 PM
Last Modification Date:
2024-10-26 @ 9:25 AM
Study NCT ID:
NCT00343317
Status:
COMPLETED
Last Update Posted:
2006-06-22
First Post:
2006-06-21
Brief Title:
Prophylactic Intrapartum Antibiotics and Immunological Markers for Postpartum Morbidity in HIV Positive Women
Sponsor:
University of KwaZulu
Organization:
University of KwaZulu
Study Overview
Official Title:
Prophylactic Intrapartum Antibiotics and Immunological Markers for Postpartum Morbidity in HIV Positive Women
Status:
COMPLETED
Status Verified Date:
2005-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Postpartum infections are among the leading causes of maternal mortality world-wide particularly in under-resourced countries Available data suggests that HIV infected women are at greater risk of postpartum complications than uninfected women In South Africa HIVAIDS and related infections are now cumulatively the leading causes of maternal deaths though indirectly with puerperal sepsis among the 5 most common causes
This was a prospective longitudinal cohort of HIV infected n 675 and uninfected n 648 women These were women in whom vaginal delivery was anticipated and were recruited at 36 weeks of gestation during the antenatal period
Hypothesis - HIV infected women are at increased risk of postpartum infectious morbidity and this morbidity can be reduced by use of prophylactic intrapartum antibiotics
This was a prospective longitudinal cohort of HIV infected n 675 and uninfected n 648 women These were women in whom vaginal delivery was anticipated and were recruited at 36 weeks of gestation during the antenatal period
Hypothesis - HIV infected women are at increased risk of postpartum infectious morbidity and this morbidity can be reduced by use of prophylactic intrapartum antibiotics
Detailed Description:
INTRODUCTION The World Health Organisation WHO estimates that 582 000 women die world-wide each year due to pregnancy related conditions that could be prevented Most of these deaths occur in developing countries1 Some of the underlying causes of increased maternal morbidity and mortality are HIV-related In South Africa the antenatal HIV seroprevalence surveys report an infection rate of 32 the highest among the Sub-Saharan countries2 According to the Saving Mothers Report NCCEMD pregnancy-related sepsis was the fourth commonest cause of maternal mortality while AIDS was the second leading cause3 Of the 67 women who died of HIVAIDS in 1998 41 died from puerperal sepsis of which 54 had a vaginal delivery and 46 had a caesarean section It is not clear from the report to what extent HIV infection had contributed to the severity of sepsis
The clinical impression is that women with HIV infection have a higher incidence of post delivery morbidity than HIV-negative women Proposed contributory factors include low CD4 count and associated impaired immunological function other obstetric complications and sexually transmitted infections3
The puerperal sepsis rate is about 2-6 in most studies It is however much higher in women with bacterial vaginosis 142 and those who deliver out of health institutions 183 Women with HIV infection are more likely to harbour BV and other sexually transmitted infections For this and other reasons it is generally accepted that HIV-positive women are at increased risk of puerperal infectious morbidity and mortality independent of the mode of delivery and antiretroviral therapy
Di Lieto et al4 reported a 338 incidence of infectious morbidity following emergency caesarean delivery The incidence of infectious morbidity has been reported to be higher in HIV positive women compared to HIV negative women Semprini et al 19955
The role of prophylactic antibiotics in obstetric complications has been previously investigated especially in women with preterm labour prelabour rupture of membranes cardiac disease and women delivered by caesarean section There is good evidence that prophylactic antibiotics significantly reduce postpartum morbidity In these studies prophylactic antibiotics were largely administered intra-operatively The question that remains is whether prophylactic antibiotics need to be given to only women identified as at risk or to all women with HIV infection
The identification of biochemical laboratoryimmune markers will be of value in the timing of clinical interventions The markers that can be used to predict sepsis will be to determine the level of apoptosis in neutrophils neutrophil function C-Reactive protein levels ESR and the levels of the following cytokines viz TNF- IL-1 IL-6 IL-8 IL-10 Less clear is the role that apoptosis and its dysregulation may play in pathological immune states like sepsis autoimmune disease or immunosuppressed states The potential role of apoptosis and the pathogenesis of sepsis have resulted in some unanswered questions- 1 whether impairment of apoptosis as a method of down-regulating pro-inflammatory cells causally results in inappropriate persistence of inflammation under septic conditions and 2 whether increased apoptosis of immune effector cells results in immunosuppression and increased susceptibility to overwhelming infection Neutrophils are the first immune cells to migrate to sites of inflammation and major functions include phagocytosis of bacteriaapoptosis of neutrophils may be one of the mechanisms of limiting tissue injury at sites of inflammation and phagocytosis of apoptotic neutrophils inhibits the release of pro-inflammatory cytokines from monocytes Lower absolute neutrophil counts are associated with increased risk of hospitalization for serious infection among HIV infected patients Because neutrophils are functionally impaired we hypothesize that sepsis observed in HIV infection might be a result of accelerated apoptosis This study will therefore try to define the mechanisms direct or indirect by which HIV infection may dysregulate apoptosis and cytokine production in the pathogenesis of sepsis
In summary puerperal sepsis remains a major cause of maternal mortality in South Africa The clinical experience in Durban is that postpartum infections are on the increase particularly in view of the high prevalence of HIV Clear guidelines are needed for the role of antibiotics among women at risk for postdelivery morbidity associated with infections Current recommendations by the NCCEMD of SA indicate that all women with AIDS and women having caesarean sections be treated prophylactically with antibiotics However guidelines regarding timing of antibitiotic prophylaxis remain unclear6 This study therefore sets out to establish reliable data on the incidence of postdelivery morbidity including puerperal sepsis associated risk factors laboratory markers and an effective antibiotic regimen to reduce the risk of postdelivery morbidity
AIM To evaluate the role of intrapartum prophylactic antibiotics in HIV infected women in reducing the incidence of postdelivery morbidity as assessed by clinical and immunological markers
HYPOTHESIS Antibiotics administered during labour can reduce postdelivery morbidity in HIV infected women STUDY OBJECTIVES Primary To reduce the incidence of post-delivery infections by use of prophylactic antibiotics
Secondary To investigate immunological parameters as markers of post-delivery infections
To identify risk factors for post-delivery infections PRIMARY ENDPOINTS The primary efficacy endpoints for this study will be the incidence of post-delivery infectious morbidity diagnosed between delivery and 6 weeks post-delivery
STUDY DESIGN This is a prospective double blind randomised placebo-controlled trial of prophylactic antibiotics for delivery
STUDY POPULATION The study will be conducted at King Edward VIII Hospital Durban and Umtata Hospital Transkei over a 2 year period
Women who have been counselled and tested for HIV during the antenatal period and who have agreed to know their results will be enrolled during the antenatal period Informed written consent for participation in the study will be obtained from all voluntary participants
Immunological studies will be conducted in a subsample 25 of patients in each study group
Inclusion Criteria
Women with known HIV status as documented by routine rapid HIV tests following pre-test voluntary counselling and testing VCT
Women who gave informed study consent Exclusion Criteria
Women on antibiotic therapy less than 2 weeks prior to study enrolment
Women planned for elective caesarean delivery
Obstetric complications such as preterm prelabour rupture of membranes cardiac disease antepartum haemorrhage
Randomisation will occur on admission to the labour ward The following tests will be performed prior to randomisation ie at enrolment full blood countFBC CD4 count and ano-genital swabs for microbiology The women will be randomly assigned to one of the three groups depending on HIV status
Group 1 HIV-POSITIVE given antibiotics Cefoxitin 2g IVI stat dose Group 2 HIV-POSITIVE given placebo Group 3 HIV-NEGATIVE no placebo or cefoxitin control group Rationale for placebo and choice of antibiotic The current standard practice is not to give prophylactic antibiotics for delivery to women without risk factors irrespective of HIV status This justifies a placebo-controlled design In this unit the current standard practice is to administer intravenous cefoxitin 2g stat dose to women for whom prophylactic antibiotic is indicated We therefore intend to use cefoxitin for the study
Sample Size Considering a 15 puerperal sepsis rate among HIV positive women following vaginal and emergency caesarean section delivery a sample size of 343 will be required in each group placebo and study group to observe a 33 reduction in the sepsis rate This would detect a significant difference at 5 level p 005 with the power of 90 Therefore the appropriate sample sizes are
Group 1 HIV-positive antibiotic 343 Group 2 HIV-positive placebo 343 Group 3 HIV-negative 686
INVESTIGATION PLAN Study procedure at each visit Visit 1 baseline and enrolment will take place at the antenatal clinic at the respective sites
This will occur after the mother has received post-test counselling At the baseline the mother will be informed of the study both verbally and in writing she will then sign the informed consent form
Demographic data maternal medical history and HIV related symptoms and signs will be documented and HIV disease staging will be carried out pap smears and CD 4 counts will be done at enrolment A physical and obstetrical examination will be done and the mothers will be randomised into one of 3 groups depending on their HIV status and the antibiotic regimen to be given
Visit 2 labourdelivery A diagnosis of labour will be made clinically Women with HIV and confirmed to be in labour will be randomised into either the antibiotic or placebo group A single dose of mefoxin or a similarly looking placebo will be administered All women with HIV infection will be given a single dose of nevirapine and their newborns will receive 06ml of nevirapine 24-72 hours post-birth During labour artificial rupture of membranes will be delayed and invasive monitoring use of instruments for delivery and episiotomy will be avoided where possible Women will also be advised on the benefits and risks of exclusive breastfeeding and formula feeding and they will be further informed on their choice of an appropriate feeding method
Blood will be taken for the following apoptosis of neutrophils neutrophil function FBC C-reactive protein Serum samples will also be stored for the determination of cytokines levels A cervical vaginal swab will also be done for microbilogical evaluation Urine will be analysed by means of dipstix and microscopy and culture will be reserved for symptomatic patients on significant findings on dipstix CD4 counts will be done by a private pathologist The reason for this is that the mothers will be enrolled during the day and night and will thus need a 24-hour service for the CD4 counts and the FBC
Visit 3 24-48 hours post delivery An infection symptom review and physical examination will be done In addition blood samples will be take for the evaluation of apoptosis neutrophil function test FBC and C-reactive protein Serum will be stored for cytokines assays A wound swab will be done where indicated
Visit 4 This will take place 1-week post delivery A physical and obstetrical examination will be carried A wound swab will also be done An infant evaluation including laboratory parameters will also be carried out during this visit
Visit 5 This will take place 2 weeks post-delivery A physical and examination and an infection symptoms review will be carried out at this visit A wound swab will also be done where indicated
Visit 6 This will take place 6 weeks post-delivery A physical and infection symptom review will be done Blood samples will be taken for CD4 counts and FBC When necessary a pap smear and wound swab will also be done at this stage
Adherence to protocol Mothers will be encouraged to make every attempt to complete the protocol as specified and will be reimbursed for transport
Dropouts and Withdrawals Patients have the right to withdraw from the study at any time or may be withdrawn if they fail to comply with the study requirements or investigators instructions
OUTCOME MEASURES The primary outcome measure will be puerperal sepsis defined as a temperature of 38C on two separate occasions due to genital tract infection and endometritis Secondary measures will include other clinical infections neonatal sepsis duration of hospital stay and surgery for puerperal sepsis Clinical infections include urinary tract infections pneumonia and wound sepsis
DATA COLLECTION AND MONITORING A standard data form will be completed for each subject Study participants will not be identified by any name on any of the study documents Subjects will be identified by a Study Identification Number The data will be entered into a computerised database EPI info version 6 software program The same shall be used for statistical analysis
The study co-ordinator will be responsible for the accuracy of the database and to determine that all regulatory requirements surrounding the trial are met A data safety and monitoring team will meet quarterly to assess the safety and accuracy of the data collected
Ethical Approval This protocol and the informed consent and any subsequent modifications will be reviewed by the Ethics Committee of the University of Natal Written informed consent will be obtained from the participants The informed consent form will describe the study the procedures to be followed and the risks and benefits of the participation A copy of the informed consent form will be given to the subjects
Subject confidentiality All laboratory specimens reports study data collection process and administrative forms will be identified by a study number to maintain confidentiality All local databases must be secured with a password protected access systems Forms lists appointment log books in a separate locked file in an area with limited access
REFERENCES
1 National Committee on Confidential Enquiry into Maternal Deaths S Afr Med J 2000 90 367-73
2 Fans S Lin Z Chen C Bacterial Vaginosis in pregnant women Abstract Medline Chinese Journal of Obstetrics and Gynaecology 1997 32 84 - 6
3 Duvekot E et al A comparison between health centre deliveries and deliveries out side health institutions Papua New Guinea Med J 199437173
4 Di Lieto A Albano G Cimmino E et al Retrospective study of postoperative infectious morbidity following caesarean section Min Gynecol 1996 48 85-92
5 Semprini AE Catagla C Ralizza M et al The incidence of complications after caesarean section in HIV-positive women AIDS 1995 91913-7
6 Smaill F Hofmeyer GJ Antibiotic prophylaxis for caesarean section Cochrane Review In The Cochrane Library Issue 4 2000 Oxford Update Software
The clinical impression is that women with HIV infection have a higher incidence of post delivery morbidity than HIV-negative women Proposed contributory factors include low CD4 count and associated impaired immunological function other obstetric complications and sexually transmitted infections3
The puerperal sepsis rate is about 2-6 in most studies It is however much higher in women with bacterial vaginosis 142 and those who deliver out of health institutions 183 Women with HIV infection are more likely to harbour BV and other sexually transmitted infections For this and other reasons it is generally accepted that HIV-positive women are at increased risk of puerperal infectious morbidity and mortality independent of the mode of delivery and antiretroviral therapy
Di Lieto et al4 reported a 338 incidence of infectious morbidity following emergency caesarean delivery The incidence of infectious morbidity has been reported to be higher in HIV positive women compared to HIV negative women Semprini et al 19955
The role of prophylactic antibiotics in obstetric complications has been previously investigated especially in women with preterm labour prelabour rupture of membranes cardiac disease and women delivered by caesarean section There is good evidence that prophylactic antibiotics significantly reduce postpartum morbidity In these studies prophylactic antibiotics were largely administered intra-operatively The question that remains is whether prophylactic antibiotics need to be given to only women identified as at risk or to all women with HIV infection
The identification of biochemical laboratoryimmune markers will be of value in the timing of clinical interventions The markers that can be used to predict sepsis will be to determine the level of apoptosis in neutrophils neutrophil function C-Reactive protein levels ESR and the levels of the following cytokines viz TNF- IL-1 IL-6 IL-8 IL-10 Less clear is the role that apoptosis and its dysregulation may play in pathological immune states like sepsis autoimmune disease or immunosuppressed states The potential role of apoptosis and the pathogenesis of sepsis have resulted in some unanswered questions- 1 whether impairment of apoptosis as a method of down-regulating pro-inflammatory cells causally results in inappropriate persistence of inflammation under septic conditions and 2 whether increased apoptosis of immune effector cells results in immunosuppression and increased susceptibility to overwhelming infection Neutrophils are the first immune cells to migrate to sites of inflammation and major functions include phagocytosis of bacteriaapoptosis of neutrophils may be one of the mechanisms of limiting tissue injury at sites of inflammation and phagocytosis of apoptotic neutrophils inhibits the release of pro-inflammatory cytokines from monocytes Lower absolute neutrophil counts are associated with increased risk of hospitalization for serious infection among HIV infected patients Because neutrophils are functionally impaired we hypothesize that sepsis observed in HIV infection might be a result of accelerated apoptosis This study will therefore try to define the mechanisms direct or indirect by which HIV infection may dysregulate apoptosis and cytokine production in the pathogenesis of sepsis
In summary puerperal sepsis remains a major cause of maternal mortality in South Africa The clinical experience in Durban is that postpartum infections are on the increase particularly in view of the high prevalence of HIV Clear guidelines are needed for the role of antibiotics among women at risk for postdelivery morbidity associated with infections Current recommendations by the NCCEMD of SA indicate that all women with AIDS and women having caesarean sections be treated prophylactically with antibiotics However guidelines regarding timing of antibitiotic prophylaxis remain unclear6 This study therefore sets out to establish reliable data on the incidence of postdelivery morbidity including puerperal sepsis associated risk factors laboratory markers and an effective antibiotic regimen to reduce the risk of postdelivery morbidity
AIM To evaluate the role of intrapartum prophylactic antibiotics in HIV infected women in reducing the incidence of postdelivery morbidity as assessed by clinical and immunological markers
HYPOTHESIS Antibiotics administered during labour can reduce postdelivery morbidity in HIV infected women STUDY OBJECTIVES Primary To reduce the incidence of post-delivery infections by use of prophylactic antibiotics
Secondary To investigate immunological parameters as markers of post-delivery infections
To identify risk factors for post-delivery infections PRIMARY ENDPOINTS The primary efficacy endpoints for this study will be the incidence of post-delivery infectious morbidity diagnosed between delivery and 6 weeks post-delivery
STUDY DESIGN This is a prospective double blind randomised placebo-controlled trial of prophylactic antibiotics for delivery
STUDY POPULATION The study will be conducted at King Edward VIII Hospital Durban and Umtata Hospital Transkei over a 2 year period
Women who have been counselled and tested for HIV during the antenatal period and who have agreed to know their results will be enrolled during the antenatal period Informed written consent for participation in the study will be obtained from all voluntary participants
Immunological studies will be conducted in a subsample 25 of patients in each study group
Inclusion Criteria
Women with known HIV status as documented by routine rapid HIV tests following pre-test voluntary counselling and testing VCT
Women who gave informed study consent Exclusion Criteria
Women on antibiotic therapy less than 2 weeks prior to study enrolment
Women planned for elective caesarean delivery
Obstetric complications such as preterm prelabour rupture of membranes cardiac disease antepartum haemorrhage
Randomisation will occur on admission to the labour ward The following tests will be performed prior to randomisation ie at enrolment full blood countFBC CD4 count and ano-genital swabs for microbiology The women will be randomly assigned to one of the three groups depending on HIV status
Group 1 HIV-POSITIVE given antibiotics Cefoxitin 2g IVI stat dose Group 2 HIV-POSITIVE given placebo Group 3 HIV-NEGATIVE no placebo or cefoxitin control group Rationale for placebo and choice of antibiotic The current standard practice is not to give prophylactic antibiotics for delivery to women without risk factors irrespective of HIV status This justifies a placebo-controlled design In this unit the current standard practice is to administer intravenous cefoxitin 2g stat dose to women for whom prophylactic antibiotic is indicated We therefore intend to use cefoxitin for the study
Sample Size Considering a 15 puerperal sepsis rate among HIV positive women following vaginal and emergency caesarean section delivery a sample size of 343 will be required in each group placebo and study group to observe a 33 reduction in the sepsis rate This would detect a significant difference at 5 level p 005 with the power of 90 Therefore the appropriate sample sizes are
Group 1 HIV-positive antibiotic 343 Group 2 HIV-positive placebo 343 Group 3 HIV-negative 686
INVESTIGATION PLAN Study procedure at each visit Visit 1 baseline and enrolment will take place at the antenatal clinic at the respective sites
This will occur after the mother has received post-test counselling At the baseline the mother will be informed of the study both verbally and in writing she will then sign the informed consent form
Demographic data maternal medical history and HIV related symptoms and signs will be documented and HIV disease staging will be carried out pap smears and CD 4 counts will be done at enrolment A physical and obstetrical examination will be done and the mothers will be randomised into one of 3 groups depending on their HIV status and the antibiotic regimen to be given
Visit 2 labourdelivery A diagnosis of labour will be made clinically Women with HIV and confirmed to be in labour will be randomised into either the antibiotic or placebo group A single dose of mefoxin or a similarly looking placebo will be administered All women with HIV infection will be given a single dose of nevirapine and their newborns will receive 06ml of nevirapine 24-72 hours post-birth During labour artificial rupture of membranes will be delayed and invasive monitoring use of instruments for delivery and episiotomy will be avoided where possible Women will also be advised on the benefits and risks of exclusive breastfeeding and formula feeding and they will be further informed on their choice of an appropriate feeding method
Blood will be taken for the following apoptosis of neutrophils neutrophil function FBC C-reactive protein Serum samples will also be stored for the determination of cytokines levels A cervical vaginal swab will also be done for microbilogical evaluation Urine will be analysed by means of dipstix and microscopy and culture will be reserved for symptomatic patients on significant findings on dipstix CD4 counts will be done by a private pathologist The reason for this is that the mothers will be enrolled during the day and night and will thus need a 24-hour service for the CD4 counts and the FBC
Visit 3 24-48 hours post delivery An infection symptom review and physical examination will be done In addition blood samples will be take for the evaluation of apoptosis neutrophil function test FBC and C-reactive protein Serum will be stored for cytokines assays A wound swab will be done where indicated
Visit 4 This will take place 1-week post delivery A physical and obstetrical examination will be carried A wound swab will also be done An infant evaluation including laboratory parameters will also be carried out during this visit
Visit 5 This will take place 2 weeks post-delivery A physical and examination and an infection symptoms review will be carried out at this visit A wound swab will also be done where indicated
Visit 6 This will take place 6 weeks post-delivery A physical and infection symptom review will be done Blood samples will be taken for CD4 counts and FBC When necessary a pap smear and wound swab will also be done at this stage
Adherence to protocol Mothers will be encouraged to make every attempt to complete the protocol as specified and will be reimbursed for transport
Dropouts and Withdrawals Patients have the right to withdraw from the study at any time or may be withdrawn if they fail to comply with the study requirements or investigators instructions
OUTCOME MEASURES The primary outcome measure will be puerperal sepsis defined as a temperature of 38C on two separate occasions due to genital tract infection and endometritis Secondary measures will include other clinical infections neonatal sepsis duration of hospital stay and surgery for puerperal sepsis Clinical infections include urinary tract infections pneumonia and wound sepsis
DATA COLLECTION AND MONITORING A standard data form will be completed for each subject Study participants will not be identified by any name on any of the study documents Subjects will be identified by a Study Identification Number The data will be entered into a computerised database EPI info version 6 software program The same shall be used for statistical analysis
The study co-ordinator will be responsible for the accuracy of the database and to determine that all regulatory requirements surrounding the trial are met A data safety and monitoring team will meet quarterly to assess the safety and accuracy of the data collected
Ethical Approval This protocol and the informed consent and any subsequent modifications will be reviewed by the Ethics Committee of the University of Natal Written informed consent will be obtained from the participants The informed consent form will describe the study the procedures to be followed and the risks and benefits of the participation A copy of the informed consent form will be given to the subjects
Subject confidentiality All laboratory specimens reports study data collection process and administrative forms will be identified by a study number to maintain confidentiality All local databases must be secured with a password protected access systems Forms lists appointment log books in a separate locked file in an area with limited access
REFERENCES
1 National Committee on Confidential Enquiry into Maternal Deaths S Afr Med J 2000 90 367-73
2 Fans S Lin Z Chen C Bacterial Vaginosis in pregnant women Abstract Medline Chinese Journal of Obstetrics and Gynaecology 1997 32 84 - 6
3 Duvekot E et al A comparison between health centre deliveries and deliveries out side health institutions Papua New Guinea Med J 199437173
4 Di Lieto A Albano G Cimmino E et al Retrospective study of postoperative infectious morbidity following caesarean section Min Gynecol 1996 48 85-92
5 Semprini AE Catagla C Ralizza M et al The incidence of complications after caesarean section in HIV-positive women AIDS 1995 91913-7
6 Smaill F Hofmeyer GJ Antibiotic prophylaxis for caesarean section Cochrane Review In The Cochrane Library Issue 4 2000 Oxford Update Software
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None