VERTICAL TRANSMISSION OF HIV AMONG HIV INFECTED MOTHERS WITH TERM PRE-LABOUR RUPTURE OF MEMBRANES IN MULAGO HOSPITAL

Principal Investigator: DR. UMOREN, MAGDALENE JAMES MB.Bch (UNICAL) Postgraduate student, M Med Obstetrics & Gynaecology Makerere University.

SUPERVISORS: DR. NAMAGEMBE IMELDA MB.ChB, M Med Obs/Gynae (MUK), MPH (CWRU, USA), Consultant Obstetrician & Gynaecologist, Department of Obstetrics & Gynaecology, Makerere University College of Health Sciences.

DR. KAGAWA MIKE MB.ChB, M Med Obs/Gynae (MUK) Lecturer, Department of Obstetrics & Gynaecology, Makerere University College of Health Sciences.

A DISSERTATION SUBMITTED IN PARTIAL FULFILMENT FOR THE AWARD OF MASTERS OF MEDICINE OF OBSTETRICS AND GYNAECOLOGY OF MAKERERE UNIVERSITY. MAY 2010

DECLARATION

I declare that the work done in this book was personally done by the author in Labour ward of New Mulago Hospital, Kampala District, Uganda and has never been presented to any institution of learning for any academic award. Signed………………………………

Date…………………………

DR. UMOREN, MAGDALENE JAMES (Author)

Signed…………………………

Date…………………………

DR. NAMAGEMBE IMELDA MB.ChB, M Med Obs/Gynae (MUK), MPH (CWRU, USA), Consultant Obstetrician & Gynaecologist, Department of Obstetrics & Gynaecology, Makerere University College of Health Sciences.

Signed……………………………

Date………………………..

DR. KAGAWA MIKE, MB.ChB, M Med Obs/Gynae (MUK) Lecturer, Department of Obstetrics & Gynaecology, Makerere University College of Health Sciences.

Signed…………………………

Date…………………………

DR. JOSAPHAT K. BYAMUGISHA, MB.ChB, M Med, Ph. D Head of Directorate of Obstetrics & Gynecology, Makerere University College of Health Sciences.

ACKNOWLEDGEMENTS My profound gratitude to God for His Love, care and guidance throughout my life; especially during the course of this postgraduate study.

I would like to thank my supervisors, Dr. Imelda Namagembe and Dr. Mike Kagawa and all the senior staff members of the Department of obstetrics and gynaecology for their untiring supervision, encouragement and invaluable input from the conception of the topic to the production of this book. I want to specially thank Dr. Ononge who was very instrumental to me during the formative stages of the study, Professor Mirembe and Dr. Kiggundu who critically reviewed the manuscript and Dr. Mutyaba for analyzing the data with stata and his statistical input. May the good Lord Bless and reward you all abundantly.

My sincere gratitude goes to my colleagues, SHOs, Medical Officers and intern Drs who were always willing to assist whenever I asked their help during the follow-up visit of the mothers. I am grateful to my research assistants for a job well done. Special thanks to all the staff in Labour ward for their help whenever I needed. I would like to mention in a special way, Dr. Moses Galla in the postnatal clinic, Omony Emmanuel, Wekiya Enock & all the staff of Mildmay laboratory – Thanks. I am indebted to my biological and religious families – Umoren’s family and Medical Missionaries of Mary (MMM); for who they are to me. To my sponsors: MMM, Mildmay centre, Uganda and Missean cara – May God richly bless you.

I am deeply grateful to all the mothers and their babies who participated in this study. I have been enriched by them and their confidence in me meant much to me. The pages of this book cannot contain ALL I have learnt from them!

DEDICATION

I dedicate this work to my Beloved parents, Mr. John J. Umoren (late) and Mrs. Christiana J. Umoren; great lovers of education who gave all their children the best education they could afford as a second gift, the first being the knowledge, Love & respected fear of God. Prompted by my curiosity, my father taught me ALL I needed to know in primary one and much more before I could set my tiny feet in school!

TABLE OF CONTENTS DECLARATION ................................................................................................................. i ACKNOWLEDGEMENTS ................................................................................................ ii TABLE OF CONTENTS ................................................................................................... iv ABBREVIATIONS .......................................................................................................... vii OPERATIONAL DEFINITIONS .................................................................................... viii ABSTRACT ..................................................................................................................... viii CHAPTER ONE ................................................................................................................10 1.1INTRODUCTION ........................................................................................................10 1.2LITERATURE REVIEW .............................................................................................11 1.2.PMTCT IN UGANDA .................................................................................................12 1.2PMTCT IN MULAGO HOSPITAL .............................................................................13 1.2.3

MOTHER TO CHILD TRANSMISSION OF HIV .............................................15

1.2.VERTICAL TRANSMISSION OF HIV AND MODE OF DELIVERY ...................15 1.2PROM AND VERTICAL TRANSMISSION OF HIV ................................................16 1.3ANTIRETROVIRAL DRUGS AND VERTICAL TRANSMISSION OF HIV ..........16 1.4PROBLEM STATEMENT ...........................................................................................17 1.5Study Justification .........................................................................................................18 1.6 RESEARCH QUESTION. ...........................................................................................20 1.8 RESEARCH HYPOTHESIS. ......................................................................................20 CHAPTER TWO ...............................................................................................................22 2.0 METHODOLOGY ......................................................................................................22 2.1 Study Design. ...............................................................................................................22 2.2Study setting. ...............................................................................................................22 2.4 Selection criteria ..........................................................................................................24 2.5 Sampling method ........................................................................................................25 2.6Sample size estimation ..................................................................................................25 2.7 Figure 2: Schema of Study. .........................................................................................26 1.8Data collection ..............................................................................................................26 2.9 Data Analysis ..............................................................................................................29 2.10 Quality control ...........................................................................................................29

2.11Ethical consideration ...................................................................................................29 2.12 Study limitation .........................................................................................................30 CHAPTER THREE ...........................................................................................................31 3.0 RESULTS ....................................................................................................................31 Figure 4:

Flow chart of recruitment and six weeks’ follow-up visit of study

.......31

Participants ..................................................................................................31 3.1 RESEARCH RESULTS ............................................................................................31 Table 1: Some characteristics of the study participants. N = 84 .......................................32 Table 2: Comparison of exposure variables with vertical transmission of HIV in babies at six weeks (a bivariate analysis) .....................................................................................33 Table 3: Comparison of adjusted relative risk for CD4 count, clinical stage, genitourinary tract infection and mode of delivery with vertical transmission of HIV in babies at six weeks (a multivariate Analysis). ................................................................................34 CHAPTER FOUR ..............................................................................................................35 4.0DISCUSSION ...............................................................................................................35 CHAPTER FIVE ...............................................................................................................38 5.0

CONCLUSIONS AND RECOMMENDATIONS ...................................................38

5.1

CONCLUSIONS.......................................................................................................38

5.2 RECOMMENDATIONS .............................................................................................38 REFERENCES. .................................................................................................................39 1.Dutta DC, (2004). 6th Edition. Text Book of Obstetrics including Perinatology and ..39 APPENDICES ...................................................................................................................44 Appendix 1: Informed Consent Form ................................................................................44 APPENDIX 11.

STUDY INSTRUMENT.......................................................50

Appendix 111 ...................................................................................................................55 WHO clinical staging of HIV / AIDS disease: ..................................................................55

LIST OF TABLES AND FIGURES

Table 1: Some characteristics of the study participants. ..Error! Bookmark not defined.

Table 2: Comparison of exposure variables with vertical transmission of HIV in babies at six weeks (a bivariate analysis) ......................................Error! Bookmark not defined.

Table 3: Comparison of adjusted relative risk for CD4 count, clinical stage, genitourinary tract infection and mode of delivery with vertical transmission of HIV in babies at six weeks (a multivariate Analysis). ..................................Error! Bookmark not defined.

Figure 1: Conceptual framework .................................................................................. 10

Figure 2: Schema of study .............................................................................................. 17

Figure 3: Sample Collection ........................................................................................... 18

Figure 4: Study flow chart ............................................................................................. 22

ABBREVIATIONS AIDS

Acquired Immunodeficiency syndrome

ANC

Antenatal care

ALARM

Advances in Labour and Risk Management

ARV

Antiretroviral drugs

AZT

Zidovudine (ZDV)

ECS

Elective Caesarean Section

GA

Gestational age

HAART

Highly active antiretroviral therapy

HIV

Human Immunodeficiency Virus

IDI

Infectious disease Institute

LNMP

Last normal menstrual period

MB.Bch

Bachelor of Medicine and Bachelor of Surgery

MB.ChB

Bachelor of Medicine and Bachelor of Surgery

MJAP

Mulago – Mbarara Teaching Hospitals’ Joint AIDS Program

M. Med

Master of Medicine.

MOH

Ministry of health

MTCT

Mother to Child Transmission of HIV

NVP

Nevirapine

PCR

Polymerase chain reaction

PI

Principal Investigator

PMTCT

Prevention of mother to child transmission of HIV

PROM

Pre-labour rupture of membranes.

RA

Research Assistant

SD NVP

Single dose Nevirapine

SVD

Spontaneous vertex delivery

TASO

The AIDS Support Organisation

UNAIDS

United Nations Agency for Acquired Immunodeficiency syndrome.

VT

Vertical Transmission of HIV

OPERATIONAL DEFINITIONS

HIV positive

A person tested for HIV infection using highly sensitive test – determine HIV1/2, HIV 1/2 stat Pak & Uni-Gold test and found to be having antibodies to HIV 1 and 2

HIV Negative

A person tested for HIV infection using highly sensitive test – determine HIV1/2, HIV 1/2 stat Pak & Uni-Gold test and found not to be having antibodies to HIV 1 and 2.

A case of PROM

A pregnant woman at 37 or more weeks of amenorrhoea with no vesico-vaginal fistula having history of draining fluid vaginally and found actively draining liquor on speculum examination with positive litmus paper test.

Vertical Transmission of HIV

Transfer of HIV infection from an infected mother to her child.

ABSTRACT Background The risk of an infected mother transmitting human immuno-deficiency virus (HIV) to her baby ranges from less than 2% in United Kingdom (UK) and North America to 45% in sub-Saharan Africa. Pre-labour rupture of membranes (PROM) is the spontaneous rupture of chorioamniotic membranes of the fetus anytime after 37 weeks but before onset of labour. HIV is one of the risk factors for PROM. Antiretroviral drugs (ARV) given to HIV infected pregnant mothers have been shown to reduce the risk of vertical transmission (VT). There are many HIV infected mothers whose pregnancies are complicated by PROM in Mulago hospital - 4.2 % in 2009 with an average of 7 HIV infected mothers with PROM per week. We did not know how much PROM had contributed to VT in Mulago hospital in this era of ARV. General Objective. To determine the risk of vertical transmission of HIV among HIV infected mothers whose pregnancies were complicated by PROM in Mulago hospital. Methodology. A prospective cohort study was conducted in Mulago labour ward. Fifty one HIV infected pregnant mothers whose pregnancies were complicated by PROM and 51 HIV infected mothers without PROM were recruited for the study. Their babies’ blood sample were collected at six weeks and subjected to a DNA/PCR test. Data Management. Data was collected using a pre tested interviewer administered questionnaire after seeking informed consent. CD4 count and DNC/PCR data were obtained from medical records after test was done. The data collected were entered into the computer using Epi data double entry, cleaned and exported to stata version 10 for analysis. Result: There was an increased risk of HIV transmission in babies born to HIV infected mothers whose pregnancies were complicated by PROM though the significance could not be statistically established at logistic regression analysis. HIV infected mothers who had taken combination ARV therapy had reduced rate of VT of HIV to their babies compared to those who took single dose nevirapine. The study also re-affirmed the protective effect of exclusive breastfeeding in reduction of HIV transmission to babies.

CHAPTER ONE 1.1 INTRODUCTION Pre – labour rupture of membranes is the spontaneous rupture of membrane anytime beyond 28th week of pregnancy but before the onset of labour 1. There are two types: a) Preterm pre - labour rupture of membranes (PPROM) which is the rupture of membranes before 37 completed weeks of gestation. b) Pre-labour rupture of membranes (PROM) which occurs after 37 completed weeks but before onset of labour. Both of these types are common complications of pregnancies seen often in Labour ward of Mulago hospital. The prevalence of PROM in Mulago hospital over three years, 2007 – 2009 ranges between 3.4 - 4.2% with an average of 7 HIV infected mothers whose pregnancies were complicated by PROM per week 2. The emphasis of this study was on PROM. HIV infected mothers had a 25 – 35% chance of transmitting the virus to their babies before the introduction of antiretroviral drugs 3. The risk of vertical transmission before the advent of ARV has been documented to increase if there is pre-labour rupture of membrane by 2% for every hour of PROM after the first 4 hrs from onset of PROM 4. How much PROM has contributed to the incidence of VT of HIV in HIV infected mothers in this era of antiretroviral therapy (ARV) had not been documented in Mulago hospital. This study was conducted in the Mulago setting to address this gap in knowledge.

1.2 LITERATURE REVIEW Human immuno-deficiency virus prevalence among pregnant women attending antenatal clinics in Uganda is 6.2 % with spikes observed in selected sites5 while the prevalence among pregnant women attending antenatal clinic in Mulago hospital is 10%6 being higher in women than men and children. Overall, it is estimated that 59% of HIV infection in Uganda is among women of 15 – 49 years old 7. This demonstrates the significance of mother to child transmission of HIV in the Mulago setting. Term pre-labour rupture of membrane (PROM) occurs in 2 – 10% of pregnancies while preterm pre-labour rupture of membrane (PPROM) occurs in 2 -3% of pregnancies. The risk of infection to mother and fetus is increased after occurrence of PROM, whether at or before term 8. The fetal membrane contains progelatinase, progelatinase activator and progelatinase activator inhibitor. Progelatinase activator activates progelatinase into an active enzyme gelatinase that breaks down gelatin in collagen of amniotic membrane leading to membrane weakness. Progelatinase activator inhibitor inhibits excessive activity of progelatinase activator until late in labour so that the membranes rupture only when labour is near 9. It is pathological then, when membranes rupture before term or before onset of labour. The cause of PROM is not known in majority of cases. Some of the risk factors associated with PROM include polyhydramnious, cervical incompetence, uterine abnormality, previous cervical surgery (conization or cone biopsy), following cervical cerclage or amniocentesis, trauma including motor vehicle accident or domestic violence.

Other risk factors include past obstetrical history of PROM, race – black race more at risk than white race, smoking, use of drugs and stress 8. It is reported that coitus and repeated vaginal examinations increase the risk of PROM 10. Anaemia, previous abortion, previous caesarean section, hypertension are also risk factors for PROM 11. Other risk factors are maternal age at delivery of 35 years and above, primigravida, premature

contractions,

vaginal

bleeding

in

first

trimester12.

Infections

like

chorioamnionitis, urinary tract infection, bacterial vaginosis, lower genital tract infection, HIV infection among others are known risk factors associated with PROM. The prevalence of bacterial vaginosis among women in labour at term in Mulago hospital has been documented as 69% and it had a positive association with PROM

13

. Infections

cause more progelatinase activator activity resulting in more progelatinase being converted into gelatinase. This breaks down the collagen in amniotic membrane leading to weakness of the membrane. Also the inflammatory process of infection and bacteria produce proteases which breakdown protein of the chorioamniotic membrane decreasing its tensile strength. As stated by Buga, it is not known whether the infection of HIV does the same, but it could be that the same process of weakening of the membrane is caused by HIV infection on the membrane or it could be that the high viral load of bacterial vaginosis in HIV infected mothers is the contributing factor 14. 1.2.

PMTCT IN UGANDA

The prevention of mother-to-child transmission (PMTCT) programme in Uganda began in 2000 to address the heavy burden arising from association between HIV/AIDS and pregnancy and the potential benefits of averting VT of HIV15. The programme provides

comprehensive package of care including administration of prophylactic ARVs to the pregnant women living with HIV during pregnancy, labour and immediate post partum period. Records show that by December 2005, the PMTCT programme had provided counseling to about 35% of all pregnant women; test about 20%, identified about 15% of pregnant women living with HIV of which 10% of them were able to access prophylactic ARVs 15. 1.2

PMTCT IN MULAGO HOSPITAL

The PMTCT programme in Mulago hospital started in 2001 after the programme was initiated at the National level by the Ministry of health in 2000. The objectives include 

Increase access to HIV counseling and testing among new antenatal attendees (plus labor & delivery).



Increase the proportion of HIV infected women who enroll into PMTCT and who receive the intervention up through delivery & return for postnatal care



Increase follow up of both mothers and infants post natally through: - Provision of early diagnosis for HIV exposed infants born to HIV infected women in the PMTCT - Linkage for ARV treatment at paediatric clinics offering treatment - Provide follow up & post partum linkage to care and treatment for infected women and their partners identified through the PMTCT program. 

Expand PMTCT core program services to include greater access to:

a) PMTCT ARV prophylaxis as indicated by Ministry of Health (MOH) policy b) Infant feeding counseling c) Peer psychosocial support

d) Uptake of family planning e) Couple counseling f) Male and community involvement in PMTCT services including HIV testing and referral. Mulago hospital PMTCT activities are carried out in three antenatal care (ANC) clinics – upper Mulago, lower Mulago and private outpatient department (OPD); three labour wards – upper Mulago, lower Mulago & private wards (6D&E); three postnatal clinicsupper Mulago, lower Mulago & private OPD and one ART clinic (the PMTCT follow-up clinic). It has an average daily attendance of ANC (new clients) – 90 in upper mulago, 60 in lower mulago & 10 in private OPD; labor & delivery – 3 in upper mulago, 7 in lower Mulago & 1 in private ward; post natal (1st visit) – 5 upper mulago, 3 in lower mulago & 10 %

No symptoms or only  persistent generalized lymphadenopathy.   



1

Sores or cracks  around lips (angular cheilitis).  Itching rash (seborrhea or prurigo). Herpes zoster within last 5 years. Recurrent upper respiratory tract  infections such as sinusitis or otitis). Recurrent mouth ulcers. 

2

Oral thrush (or hairy leukoplakia). More than one month of: - Diarrhoea Or -Vaginal candidiasis Or -Unexplained fever. Severe bacterial infections (pneumonia, muscle infection, etc). Pulmonary Tb within last one year.

3

WHO Clinical Stage 4 Severe disease (AIDS) HIV wasting syndrome  

   

  

Oesophageal thrush. More than one month of Herpes Simplex ulceration. Lymphoma. Kaposi’s sarcoma. Invasive cervical cancer. Pneumocystic carinii pneumonia (PCP). Extrapulmonary Tb. Cryptococcal meningitis. HIV encephalitis. 4