The Contribution of HIV to Mortality in Pregnant and Postpartum Women CLARA ANN DURIE ...

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Calvert, C; (2015) The Contribution of HIV to Mortality in Pregnant and Postpar-
tum Women. PhD thesis, London School of Hygiene & Tropical Medicine. DOI:
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The Contribution of HIV to Mortality in Pregnant and Postpartum
Women

CLARA ANN DURIE CALVERT

Thesis submitted in accordance with the requirements for the degree of
Doctor of Philosophy

University of London
February 2015

Department of Infectious Disease Epidemiology

Faculty of Epidemiology and Population Health

LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE

Funded by the Economic and Social Research Council

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STATEMENT OF OWN WORK

I, Clara Ann Durie Calvert, confirm the work presented in this thesis is my own. Where
information has been derived from other sources, I confirm that this has been indicated
in the thesis.

Signed: …………………………………….. Date: ………………………………

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ABSTRACT

Background: High levels of HIV and maternal mortality go hand in hand in many
regions of sub-Saharan Africa. Therefore, understanding the interaction between
pregnancy and HIV is important, not only for the clinical management of pregnant
women, but also for the measurement of maternal mortality, the standard definition of
which excludes infectious causes of death not aggravated by pregnancy.

Methods: In this thesis the excess mortality attributable to HIV in pregnant and
postpartum women is calculated by comparing the risk of mortality in HIV-infected
pregnant and postpartum women to their uninfected counterparts using two different
data sources: 1) studies identified through a systematic review and; 2) data from six
demographic surveillance sites (DSS) in sub-Saharan Africa. Verbal autopsy (VA) data
from the DSS are also used to explore the percentage of deaths classified as
HIV/AIDS-related. Two additional systematic reviews are conducted to assess whether
HIV increases the risk of obstetric complications, or pregnancy accelerates HIV
disease progression.

Results: HIV-infected women have eight times the risk of pregnancy-related mortality
compared with HIV-uninfected women. Based on this estimate, we predict that roughly
a quarter of deaths in pregnant or postpartum women are attributable to HIV in sub-
Saharan Africa. A lower percentage of pregnancy-related deaths are attributed to
HIV/AIDS using VA data. There is little evidence that HIV-infected women are at
increased risk of direct obstetric complications, with the exception of sepsis, or that
pregnancy increases the risk of HIV disease progression.

Conclusion: HIV may cause up to 25% of deaths during pregnancy and in the
postpartum period in areas of high HIV prevalence. Most of the evidence suggests that
this excess pregnancy-related mortality attributable to HIV is largely coincidental to
pregnancy. This implies that there is little reason to discourage healthy, HIV-infected
women from becoming pregnant if they desire to do so.

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ACKNOWLEDGEMENTS

There are many people who I need to acknowledge for their help and support over the
course of this PhD. I am hugely grateful to my supervisor Carine Ronsmans for her
ideas, guidance, training and enthusiasm, all of which were essential to this project.
Basia Zaba has been a brilliant co-supervisor, providing invaluable advice over the
course of this thesis.

It has been a pleasure to work with everyone involved in the ALPHA network. In
particular, thanks go to Kobus Herbst, Chifundo Kajala, Tom Lutalo, Denna Michael,
Jessica Nakiyingi-Miiro, Alison Price and Laura Robertson for helping with the data
preparation and for taking time to help me understand the intricacies of the data from
each site. I have no doubt the PhD process would have been a much longer and more
frustrating experience had it not been for Milly Marston and Emma Slaymaker, who
taught me how to make STATA do most the hard work. Additional thanks go to Milly for
all the time she spent helping me prepare the data for the analyses in this thesis (most
notably in being the mastermind behind PregRates.do).

I would like to acknowledge Samuel Clark, Tyler McCormick and Richard Li for
generously hosting me the University of Washington, for making time in their busy
schedules to mentor me and for introducing me to the joys of Seattle. I learnt a huge
amount during my two months working in their group.

I have been lucky to share the ups and downs of PhD research with many fantastic
students at LSHTM. In particular, I am grateful to my wonderful office mates –
Francesca Cavallaro, Marina Daniele, Susie Schaffnit and Rachel Scott – who were
always willing to lend an ear, answer my questions or go for a drink. There are many
other colleagues at LSHTM who I would like to thank including Alma Adler, Oona
Campbell, Jenny Cresswell, Calum Davey, Lisa Hurt, Veronique Filippi, Judith Glynn,
Christopher Grollman, Lenka Benova and Elizabeth Millet, all of whom have supported
me through this work by providing guidance, critique or words of encouragement.

Finally, I would like to thank all my family and friends for all the fun times during the
past three years.

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CONTENTS

STATEMENT OF OWN WORK .................................................................................................... 2
ABSTRACT .................................................................................................................................. 3
ACKNOWLEDGEMENTS ............................................................................................................. 4
LIST OF TABLES ......................................................................................................................... 8
LIST OF FIGURES ..................................................................................................................... 10
ACRONYMS AND ABBREVIATIONS ....................................................................................... 12
1 BACKGROUND ......................................................................................... 14
1.1 INTRODUCTION ............................................................................................................. 14
1.2 INTERSECTING EPIDEMICS: MATERNAL MORTALITY AND HIV ............................ 15
1.2.1 Measuring the burden of maternal mortality ............................................................. 15
1.2.2 Estimating the contribution of HIV to maternal mortality ........................................... 17
1.2.3 Interaction between HIV and pregnancy ................................................................... 20
1.2.4 Impact of ART on association between HIV and pregnancy .................................... 22
1.3 OVERALL AIMS AND OBJECTIVES ............................................................................ 23
1.4 STRUCTURE OF THIS THESIS ..................................................................................... 25
2 METHODS ................................................................................................. 26
2.1 SYSTEMATIC REVIEW .................................................................................................. 27
2.1.1 Search strategy ......................................................................................................... 27
2.1.2 Study selection and inclusion criteria ........................................................................ 27
2.1.3 Data extraction and data quality ............................................................................... 28
2.1.4 Data analysis ............................................................................................................. 29
2.2 ALPHA NETWORK DATA ANALYSIS .......................................................................... 30
2.2.1 The study areas ........................................................................................................ 30
2.2.2 Data collection methods ............................................................................................ 31
2.2.3 Data sources ............................................................................................................. 33
2.2.4 Data management and preparation .......................................................................... 34
2.2.5 Ethical considerations ............................................................................................... 38
2.3 ROLE OF THE CANDIDATE .......................................................................................... 38
3 THE CONTRIBUTION OF HIV TO PREGNANCY-RELATED MORTALITY:
A SYSTEMATIC REVIEW AND META-ANALYSIS ......................................... 39
3.1 INTRODUCTION ............................................................................................................. 39
3.2 ARTICLE ......................................................................................................................... 42
3.2.1 Abstract ..................................................................................................................... 42
3.2.2 Introduction................................................................................................................ 42
3.2.3 Methods ..................................................................................................................... 44
3.2.4 Results ...................................................................................................................... 46
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3.2.5 Discussion ................................................................................................................. 51
3.3 CONCLUSION ................................................................................................................ 66
4 HIV AND THE RISK OF DIRECT OBSTETRIC COMPLICATIONS: A
SYSTEMATIC REVIEW AND META-ANALYSIS ............................................. 67
4.1 INTRODUCTION ............................................................................................................. 67
4.2 ARTICLE ......................................................................................................................... 70
4.2.1 Abstract ..................................................................................................................... 70
4.2.2 Introduction................................................................................................................ 70
4.2.3 Methods ..................................................................................................................... 72
4.2.4 Results ...................................................................................................................... 74
4.2.5 Discussion ................................................................................................................. 82
4.3 CONCLUSION .............................................................................................................. 117
5 PREGNANCY AND HIV DISEASE PROGRESSION: A SYSTEMATIC
REVIEW AND META-ANALYSIS ................................................................... 118
5.1 INTRODUCTION ........................................................................................................... 118
5.2 ARTICLE ....................................................................................................................... 121
5.2.1 Abstract ................................................................................................................... 121
5.2.2 Introduction.............................................................................................................. 121
5.2.3 Methods ................................................................................................................... 123
5.2.4 Results .................................................................................................................... 125
5.2.5 Discussion ............................................................................................................... 136
5.3 CONCLUSION .............................................................................................................. 150
6 EFFECT OF HIV INFECTION ON PREGNANCY-RELATED MORTALITY
IN SUB-SAHARAN AFRICA: SECONDARY ANALYSES OF POOLED
COMMUNITY BASED DATA FROM THE NETWORK FOR ANALYSING
LONGITUDINAL POPULATION-BASED HIV/AIDS DATA ON AFRICA
(ALPHA) ......................................................................................................... 151
6.1 INTRODUCTION ........................................................................................................... 151
6.2 ARTICLE ....................................................................................................................... 154
6.2.1 Abstract ................................................................................................................... 154
6.2.2 Introduction.............................................................................................................. 155
6.2.3 Methods ................................................................................................................... 156
6.2.4 Results .................................................................................................................... 160
6.2.5 Discussion ............................................................................................................... 166
6.3 SUPPLEMENTARY MATERIAL: TESTING THE SENSITIVITY OF THE PUBLISHED
RESULTS.................................................................................................................................. 171
6.3.1 Varying the definition of HIV status ......................................................................... 171
6.3.2 Varying the postpartum length of follow-up ............................................................. 175
6.3.3 Adjusting for multiple covariates ............................................................................. 175
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6.4 CONCLUSION .............................................................................................................. 177
7 IDENTIFIYING HIV/AIDS-RELATED DEATHS USING VERBAL
AUTOPSY DATA: EVIDENCE FROM THE NETWOK FOR ANALYSING
LONGITUDINAL POPULATION-BASED HIV/AIDS DATA ON AFRICA
(ALPHA) ......................................................................................................... 178
7.1 INTRODUCTION ........................................................................................................... 178
7.2 METHODS .................................................................................................................... 181
7.2.1 Data sources ........................................................................................................... 181
7.2.2 Data preparation ..................................................................................................... 181
7.2.3 Data analysis ........................................................................................................... 182
7.3 RESULTS ...................................................................................................................... 190
7.3.1 Description of verbal autopsy data .......................................................................... 190
7.3.2 Cause of death amongst women of reproductive age ............................................ 194
7.3.3 Cause of death by pregnancy status ...................................................................... 202
7.4 DISCUSSION ................................................................................................................ 206
8 DISCUSSION ........................................................................................... 210
8.1 SUMMARY OF FINDINGS ........................................................................................... 210
8.1.1 What is the excess mortality attributable to HIV amongst pregnant and postpartum
women? ……………………………………………………………………………………………...210
8.1.2 Is there any evidence for an interaction between HIV and pregnancy? ................. 212
8.1.3 Can we distinguish indirect and coincidental deaths among pregnancy-related
deaths attributed to HIV? ...................................................................................................... 213
8.2 RECOMMENDATIONS ................................................................................................. 213
8.2.1 Public Health ........................................................................................................... 213
8.2.2 Measurement and modelling of all-cause and HIV-related mortality in pregnant and
postpartum women ................................................................................................................ 215
8.2.3 Future research ....................................................................................................... 218
9 REFERENCES ......................................................................................... 220

APPENDIX A SYSTEMATIC REVIEW PROTOCOL ...................................... 234
APPENDIX B SYSTEMATIC REVIEW SEARCH STRATEGY ...................... 243
APPENDIX C ALPHA DATA SPECIFICATIONS ........................................... 250
APPENDIX D SUPPLEMENTARY TABLES .................................................. 260
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LIST OF TABLES

TABLE 2.1: TYPE OF STUDIES REQUIRED FOR EACH REVIEW .......................................... 28
TABLE 2.2: CHARACTERISTICS OF ALPHA STUDY SITES CONTRIBUTING DATA ON HIV
AND PREGNANCY-RELATED MORTALITY ..................................................................... 31
TABLE 2.3: TYPE OF BIRTH DATA AVAILABLE AT EACH STUDY SITE ............................... 33
TABLE 2.4: DATES FOR THE INTRODUCTION OF ART, AND THE FULL ROLL-OUT OF ART
............................................................................................................................................ 37
TABLE 3.1: META-ANALYSIS OF THE RISK RATIO FOR PREGNANCY-RELATED
MORTALITY IN HIV-INFECTED WOMEN COMPARED WITH UNINFECTED WOMEN
STRATIFIED BY REGION, WHETHER THE STUDY WAS POPULATION OR FACILITY-
BASED, ART AVAILABILITY AND THE LENGTH OF THE POSTPARTUM PERIOD
INCLUDED .......................................................................................................................... 49
TABLE 3.2: META-ANALYSIS OF THE RISK RATIO FOR PREGNANCY-RELATED
MORTALITY IN HIV-INFECTED WOMEN COMPARED WITH UNINFECTED WOMEN
STRATIFIED BY QUALITY OF STUDIES FOR EACH QUALITY CRITERION ................. 50
TABLE 3.3: SUMMARY OF STUDIES OF HIV AND PREGNANCY-RELATED MORTALITY .. 55
TABLE 3.4: METHODOLOGICAL QUALITY ASSESSMENT FOR EACH OF THE STUDIES
INCLUDED IN THE SYSTEMATIC REVIEW ...................................................................... 63
TABLE 4.1: SUMMARY OF STUDIES OF HIV AND OBSTETRIC COMPLICATIONS WHICH
INCLUDED BIRTHS BY VAGINAL DELIVERY .................................................................. 86
TABLE 4.2: SUMMARY OF STUDIES OF HIV AND OBSTETRIC COMPLICATIONS WHICH
ONLY LOOKED AT BIRTHS BY CAESAREAN SECTION .............................................. 103
TABLE 4.3: RISK OF BIAS WITHIN STUDIES WHICH INCLUDE VAGINAL DELIVERIES ... 108
TABLE 4.4: RISK OF BIAS WITHIN CAESAREAN SECTION STUDIES ................................ 115
TABLE 5.1: DEFINITIONS FOR HIV PROGRESSION ............................................................ 127
TABLE 5.2: STRATIFIED ANALYSES EXPLORING THE EFFECT OF ANTIRETROVIRAL
THERAPY (ART) AVAILABILITY ON THE POOLED EFFECT ESTIMATE ..................... 132
TABLE 5.3: STRATIFIED ANALYSES EXPLORING THE EFFECT OF COUNTRY INCOME
LEVEL ON THE POOLED EFFECT ESTIMATE .............................................................. 133
TABLE 5.4: STRATIFIED ANALYSES EXPLORING THE EFFECT OF USING RISK RATIO
VERSES HAZARD RATIOS ON THE POOLED EFFECT ESTIMATE ............................ 133
TABLE 5.5: STRATIFIED ANALYSES EXPLORING THE EFFECT OF STUDY QUALITY ON
THE POOLED EFFECT ESTIMATE ................................................................................. 134
TABLE 5.6: DESCRIPTION OF STUDIES WHICH COMPARE HIV PROGRESSION IN
PREGNANT AND NON-PREGNANT WOMEN ................................................................ 140
TABLE 5.7: ASSESSMENT OF THE QUALITY OF THE STUDIES ........................................ 145
TABLE 6.1: CHARACTERISTICS OF ALPHA STUDY SITES CONTRIBUTING DATA FOR HIV
AND PREGNANCY-RELATED MORTALITY ................................................................... 160
TABLE 6.2: MORTALITY IN POOLED ALPHA NETWORK DATA BY PREGNANCY AND HIV
STATUS, 1990-2012 ......................................................................................................... 161
TABLE 6.3: DEATHS IN WOMEN AGED 15-49 YEARS BY STUDY SITE AND HIV STATUS
.......................................................................................................................................... 163
TABLE 6.4: CRUDE RATE RATIO OF MORTALITY RATES IN HIV-INFECTED AND HIV-
UNINFECTED WOMEN AND POPULATION ATTRIBUTABLE FRACTIONS FOR HIV, BY
STUDY SITE ..................................................................................................................... 165
TABLE 6.5: CRUDE RATE RATIO OF MORTALITY RATES IN HIV-INFECTED AND HIV-
UNINFECTED WOMEN AND POPULATION ATTRIBUTABLE FRACTIONS FOR HIV, BY
VARYING LENGTHS OF POSTPARTUM FOLLOW-UP ................................................. 175
TABLE 6.6: MORTALITY RATES RATIOS FROM A POISSON REGRESSION MODEL FOR
PREGNANT AND POSTPARTUM WOMEN .................................................................... 176
TABLE 6.7: MORTALITY RATES RATIOS FROM A POISSON REGRESSION MODEL FOR
NON-PREGNANT NOR POSTPARTUM WOMEN ........................................................... 177
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TABLE 7.1: VERBAL AUTOPSY SYMPTOMS USED TO CATEGORISE DEATHS AS INJURY-
RELATED AND PERIPARTUM ........................................................................................ 183
TABLE 7.2: CREATING THE SIGNS AND SYMPTOMS WHICH WERE IDENTIFIED FOR THE
LOPMAN ALGORITHM USING THE ALPHA DATA ........................................................ 185
TABLE 7.3: GROUPING OF INTERVA-4 CAUSES OF DEATH .............................................. 187
TABLE 7.4: VERBAL AUTOPSY COVERAGE AND THE ASSOCIATION BETWEEN STUDY
CHARACTERISTICS AND RISK OF GETTING A VERBAL AUTOPSY AMONGST
WOMEN OF REPRODUCTIVE AGE ................................................................................ 190
TABLE 7.5: NUMBER OF DEATHS WITH MISSING DATA FOR THE KEY HIV/AIDS
SYMPTOMS, BY SITE ...................................................................................................... 192
TABLE 7.6: PERCENTAGE OF DEATHS WITH MISSING DATA FOR SYMPTOMS FOR
IDENTIFYING OBSTETRIC AND INJURY DEATHS, BY SITE ....................................... 193
TABLE 7.7: PERCENTAGE OF DEATHS WITH MISSING DATA FOR KEY HIV/AIDS
SYMPTOMS IN THE POOLED DATA, BY HIV STATUS ................................................. 194
TABLE 7.8: DISTRIBUTION OF DEATHS WITH A VERBAL AUTOPSY BY STUDY AND HIV
STATUS ............................................................................................................................ 194
TABLE 7.9: CAUSE OF DEATH ASCERTAINED USING THE LOPMAN ALGORITHM, BY SITE
.......................................................................................................................................... 195
TABLE 7.10: CAUSE OF DEATH DISTRIBUTIONS ASSIGNED USING THE LOPMAN
ALGORITHM, STRATIFIED BY HIV STATUS AND SITE ................................................ 196
TABLE 7.11: SPECIFICITY OF THE LOPMAN ALGORITHM, AND THE INDIVIDUAL SIGNS
AND SYMPTOMS WHICH MAKE UP THE ALGORITHM, FOR THE ALPHA DATA SET,
OVERALL AND BY SITE .................................................................................................. 197
TABLE 7.12: CAUSE OF DEATH ASCERTAINED USING INTERVA-4, BY SITE .................. 199
TABLE 7.13: CAUSE OF DEATH DISTRIBUTIONS ASSIGNED USING INTERVA-4,
STRATIFIED BY HIV STATUS AND SITE ....................................................................... 200
TABLE 7.14: PERCENTAGE OF DEATHS ATTRIBUTED TO HIV/AIDS USING DIFFERENT
METHODS ........................................................................................................................ 200
TABLE 7.15: NUMBER OF PREGNANCY-RELATED DEATHS BY SOURCE OF
INFORMATION AND STUDY SITE .................................................................................. 203
TABLE 7.16: DISTRIBUTION OF DEATHS WITH A VERBAL AUTOPSY BY STUDY,
PREGNANCY AND HIV STATUS .................................................................................... 203
TABLE 7.17: CAUSE OF DEATH ASCERTAINED USING THE LOPMAN ALGORITHM, BY
PREGNANCY AND HIV STATUS .................................................................................... 204
TABLE 7.18: CAUSE OF DEATH DISTRIBUTIONS ASSIGNED USING INTERVA-4 IN THE
POOLED DATA, STRATIFIED BY HIV AND PREGNANCY STATUS ............................. 205

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