Sequential pregnancies among women living with HIV in the United Kingdom and Ireland

346 Pages·2014·13.57 MB·English

Sequential pregnancies among
women living with HIV in the
United Kingdom and Ireland
Thesis presented for the degree of
Doctor of Philosophy
University College London
Clare Elizabeth French
UCL Institute of Child Health
2014
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Declaration
I, Clare French, confirm that 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
This thesis investigates the epidemiology of sequential pregnancies among HIV-positive
women in the United Kingdom and Ireland, and explores the health, therapeutic and
obstetric management, and pregnancy outcomes, of the women experiencing them. Data
from the UK and Ireland’s National Study of HIV in Pregnancy and Childhood (NSHPC) are
analysed. This is a well-established, active, comprehensive national surveillance study with
over 1500 pregnancies currently reported each year.
The findings demonstrate that a substantial and increasing proportion of pregnancies are
women’s second or subsequent since their HIV diagnosis (39% in 2009), with a rate of 6.7
(95% CI: 6.5-6.9) per 100 woman-years during 1990-2009. Analyses revealed potential
missed opportunities for the timely initiation of antiretroviral therapy (ART) in this group of
previously diagnosed women, both within and outside the context of pregnancy. Variations
in women’s engagement with HIV and pregnancy-related care are explored.
In the contemporary context of effective prevention of mother-to-child transmission
(PMTCT) interventions there are unanswered questions around the optimal management of
HIV-positive women of childbearing age. Exposure to short-course protease inhibitor-based
combination ART for PMTCT did not impact on response to therapy in subsequent
pregnancies, supporting current UK recommendations. However, analyses of the
immunological status and virological outcomes in second pregnancies to women not on
ART at conception suggest that initiating lifelong ART in pregnancy may have benefits for
maternal health and the risk of vertical transmission in future pregnancies. Adverse
pregnancy and perinatal outcomes are investigated among women’s repeat pregnancies,
which were for example, more likely to be conceived on ART than index pregnancies.
Finally, patterns in mode of delivery for women’s sequential births are explored.
The analyses presented in this thesis inform the evidence-base for the effective
management of HIV-positive women in the context of current and potential future
pregnancies.
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Contents
Declaration… .............................................................................................................. 2
Abstract……................................................................................................................ 3
Contents……............................................................................................................... 4
List of Tables .............................................................................................................. 9
List of Figures........................................................................................................... 11
Acknowledgements .................................................................................................. 13
Abbreviations............................................................................................................ 14
Publications arising from this work ........................................................................ 16
Chapter 1 Introduction ......................................................................................... 18
1.1 Overview of HIV..................................................................................................... 18
1.1.1 Global epidemiology of HIV............................................................................ 18
1.1.2 Epidemiology of HIV in the United Kingdom (UK).......................................... 19
1.1.3 Natural history and transmission.................................................................... 21
1.1.4 Diagnosis ........................................................................................................ 22
1.1.5 Treatment ....................................................................................................... 23
1.2 HIV in pregnant women ........................................................................................ 26
1.2.1 Antenatal HIV screening................................................................................. 26
1.2.2 Epidemiology of HIV in pregnant women in the UK and Ireland.................... 27
1.2.3 Mother-to-child transmission (MTCT) of HIV.................................................. 29
1.2.4 Prevention of mother-to-child transmission (PMTCT) of HIV......................... 29
1.2.5 Summary ........................................................................................................ 34
Chapter 2 Literature review.................................................................................. 35
2.1 Methods.................................................................................................................. 35
2.2 Fertility of HIV-positive women ........................................................................... 36
2.3 Women’s engagement with antenatal care ........................................................ 41
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2.4 Engagement with HIV care, and the health and management of women
in the context of pregnancy and beyond............................................................ 45
2.5 Impact of short-course antenatal ART on subsequent response to
therapy ................................................................................................................... 51
2.6 Adverse perinatal outcomes among HIV-positive women ............................... 57
2.7 Obstetric management of sequential pregnancies ........................................... 66
2.8 Rationale for this PhD........................................................................................... 70
2.9 Aim and objectives ............................................................................................... 73
Chapter 3 Data sources and methods................................................................. 74
3.1 National Study of HIV in Pregnancy and Childhood (NSHPC)......................... 74
3.1.1 Obstetric scheme............................................................................................ 74
3.1.2 Paediatric scheme .......................................................................................... 75
3.1.3 Data items....................................................................................................... 77
3.1.4 Data management, checking and cleaning.................................................... 78
3.1.5 Definitions and categorisation of variables..................................................... 79
3.1.6 Datasets for analysis ...................................................................................... 82
3.2 Survey of Prevalent HIV Infections Diagnosed (SOPHID) ................................ 87
3.3 Ethical approval and governance........................................................................ 87
3.4 Missing data........................................................................................................... 88
3.5 Statistical analyses ............................................................................................... 89
3.6 Role of the researcher .......................................................................................... 92
Chapter 4 Incidence, patterns and predictors of repeat pregnancies............... 93
4.1 Incidence and patterns of repeat pregnancies .................................................. 93
4.1.1 Methods .......................................................................................................... 93
4.1.2 Study population............................................................................................. 98
4.1.3 Number and proportion of repeat pregnancies ............................................ 102
4.1.4 Rate of repeat pregnancies .......................................................................... 103
4.1.5 Probability of repeat pregnancies................................................................. 104
4.1.6 Birth spacing intervals .................................................................................. 106
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4.2 Predictors of repeat pregnancies...................................................................... 109
4.2.1 Methods ........................................................................................................ 109
4.2.2 Study population........................................................................................... 111
4.2.3 Demographic predictors ............................................................................... 111
4.2.4 Clinical and immunological predictors.......................................................... 120
4.2.5 Previous adverse pregnancy outcomes ....................................................... 126
4.3 Discussion ........................................................................................................... 129
4.4 Key findings......................................................................................................... 137
Chapter 5 Engagement with care, and the health and management of
women experiencing sequential pregnancies................................. 139
5.1 Timing of presentation for antenatal care........................................................ 139
5.1.1 Methods ........................................................................................................ 139
5.1.2 Study population........................................................................................... 142
5.1.3 Timing of antenatal booking ......................................................................... 145
5.1.4 Factors associated with late booking for antenatal care.............................. 149
5.1.5 Time lag between antenatal booking and laboratory testing ....................... 154
5.1.6 Time lag between antenatal booking and ART initiation.............................. 156
5.2 Immunological status, timing of antenatal ART, and virological
outcomes among women not on ART at conception...................................... 160
5.2.1 Methods ........................................................................................................ 160
5.2.2 Study population........................................................................................... 162
5.2.3 Immunological status.................................................................................... 163
5.2.4 Factors associated with an immunological indication for treatment
among women not on ART at conception .................................................... 165
5.2.5 Timing of antenatal ART initiation ................................................................ 168
5.2.6 Factors associated with timing of antenatal ART initiation .......................... 172
5.2.7 Virological outcomes .................................................................................... 178
5.3 Attendance for HIV care after pregnancy......................................................... 185
5.3.1 Methods ........................................................................................................ 185
5.3.2 Study population........................................................................................... 187
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5.3.3 Completeness of matching of the NSHPC and SOPHID............................. 187
5.3.4 Characteristics of matched and unmatched women.................................... 187
5.3.5 Attendance for HIV care after pregnancy..................................................... 190
5.4 Discussion ........................................................................................................... 192
5.5 Key findings......................................................................................................... 203
Chapter 6 Influence of short-course antenatal cART on response to
therapy in subsequent pregnancies................................................. 205
6.1 Methods................................................................................................................ 205
6.2 Probability of detectable viral load at delivery ................................................ 207
6.2.1 Study population........................................................................................... 207
6.2.2 Patterns of cART use among cART-experienced women ........................... 211
6.2.3 Availability of data on viral load at delivery .................................................. 213
6.2.4 Detectable viral load among ART-naive and cART-experienced women.... 215
6.3 Risk of MTCT ....................................................................................................... 226
6.4 Discussion ........................................................................................................... 228
6.5 Key findings......................................................................................................... 234
Chapter 7 Adverse pregnancy and perinatal outcomes, and mode of
delivery............................................................................................... 235
7.1 Adverse pregnancy and perinatal outcomes................................................... 235
7.1.1 Methods ........................................................................................................ 235
7.1.2 Study population........................................................................................... 238
7.1.3 Characteristics of first and repeat pregnancies............................................ 239
7.1.4 Pregnancy outcomes among first and repeat pregnancies ......................... 241
7.1.5 Preterm delivery............................................................................................ 244
7.1.6 Low birthweight and small for gestational age ............................................. 254
7.1.7 Congenital abnormalities.............................................................................. 254
7.2 Mode of delivery.................................................................................................. 256
7.2.1 Methods ........................................................................................................ 256
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7.2.2 Study population........................................................................................... 257
7.2.3 Planned and actual mode of delivery ........................................................... 261
7.2.4 Mode of delivery patterns within women...................................................... 262
7.2.5 Women with two or more caesarean sections ............................................. 267
7.2.6 Adverse obstetric outcomes that may be related to mode of delivery ......... 267
7.3 Discussion ........................................................................................................... 270
7.3.1 Adverse pregnancy and perinatal outcomes................................................ 270
7.3.2 Mode of delivery ........................................................................................... 276
7.4 Key findings......................................................................................................... 281
Chapter 8 Discussion ......................................................................................... 283
8.1 Key findings and implications for policy and practice ................................... 283
8.1.1 High and increasing occurrence of repeat pregnancies............................... 283
8.1.2 Women’s engagement with HIV and pregnancy-related care ..................... 285
8.1.3 Optimising management............................................................................... 287
8.2 Strengths and limitations................................................................................... 291
8.3 Conclusions and recommendations for future research ............................... 293
References…........................................................................................................... 298
Appendices….......................................................................................................... 333
Appendix I Peer reviewed publication reprints ................................................... 334
Appendix II British HIV Association guidelines – key recommendations......... 356
Appendix III NSHPC data collection forms ........................................................... 358
Appendix IV Log-log plots of time to second pregnancy.................................... 363
Appendix V Log-log plots of time to initiation of antenatal ART....................... 365
Appendix VI Algorithm used to match NSHPC with SOPHID.............................. 367
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List of Tables
Table 1.1 Main classes of antiretrovirals..................................................................................... 24
Table 2.1 Selected studies investigating development of drug resistance following
exposure to short-course cART for PMTCT ........................................................... 54
Table 4.1 Maternal characteristics for pregnancies reported to the NSHPC, overall and
by time period, 1990-2009.................................................................................... 100
Table 4.2 Number and rate of second pregnancies by time period, 1990-2009....................... 103
Table 4.3 Comparison of the demographic characteristics of women with a single
pregnancy and those with repeat pregnancies..................................................... 112
Table 4.4 Comparison of women with complete information on key demographic
variables and those with missing information (on one or more variable) ............. 113
Table 4.5 Univariable and multivariable analyses of demographic characteristics
associated with having a second pregnancy........................................................ 119
Table 4.6 Comparison of clinical and immunological characteristics of women with a
single pregnancy and those with repeat pregnancies .......................................... 121
Table 4.7 Comparison of women with complete information on key clinical and
immunological factors (CD4 count or HIV/AIDS symptoms) and those with
missing information on these variables ................................................................ 122
Table 4.8 Univariable analyses of clinical and immunological factors associated with
having a second pregnancy.................................................................................. 125
Table 4.9 Comparison of the outcomes of first pregnancies among women with a single
pregnancy and those with repeat pregnancies..................................................... 126
Table 5.1 Antenatal care booking analyses – characteristics of first and subsequent
pregnancies .......................................................................................................... 143
Table 5.2 Patterns in timing of booking for antenatal care in women’s first and
subsequent pregnancies ...................................................................................... 148
Table 5.3 Characteristics of women according to timing of antenatal booking for
subsequent pregnancies ...................................................................................... 150
Table 5.4 Univariable and multivariable analyses of factors associated with later booking
for antenatal care among subsequent pregnancies ............................................. 153
Table 5.5 Univariable and multivariable analyses of factors associated with having a
CD4 count of <350 cells/µl at second pregnancy among women not on
ART at conception ................................................................................................ 167
Table 5.6 Median gestation at antenatal ART initiation, by time period ................................... 169
Table 5.7 Univariable and multivariable analyses of time to antenatal ART initiation .............. 174
Table 5.8 Multivariable analysis of time to ART initiation, restricted to 2008-2010 .................. 177
Table 5.9 Characteristics of second pregnancies ending in a live or stillbirth according to
whether the woman was on ART at conception ................................................... 179
Table 5.10 Univariable and multivariable analyses of the association between timing of
ART and detectable viral load at delivery............................................................. 183
Table 5.11 Demographic characteristics of women reported to the NSHPC according to
whether they were matched to SOPHID .............................................................. 189
Table 6.1 Demographic, clinical and obstetric characteristics of pregnancies in ART-
naive and cART-experienced women .................................................................. 209
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Table 6.2 Type of cART received in current and previous pregnancy among cART-
experienced women ............................................................................................. 212
Table 6.3 Key characteristics of women with and without information on viral load at
delivery (based on imputed viral load variable) .................................................... 214
Table 6.4 Univariable and multivariable analyses of the association between previous
antenatal cART and detectable viral load at delivery in a subsequent
pregnancy ............................................................................................................. 217
Table 6.5 Univariable and multivariable analyses of the association between type of
previous antenatal cART received and detectable viral load at delivery in a
subsequent pregnancy ......................................................................................... 219
Table 6.6 Univariable and multivariable analyses of the association between previous
PI-based antenatal cART receipt and detectable viral load at delivery in a
subsequent pregnancy (among those who received PI-based cART in their
current pregnancy)................................................................................................ 221
Table 6.7 Univariable and multivariable analyses of the association between previous
NNRTI-based antenatal cART receipt and detectable viral load at delivery
in a subsequent pregnancy (among those who received NNRTI-based
cART in their current pregnancy).......................................................................... 223
Table 6.8 Univariable and multivariable analyses of the association between previous
antenatal NNRTI-based cART receipt and detectable viral load at delivery
in a subsequent pregnancy (among those who received PI-based cART in
their current pregnancy) ....................................................................................... 225
Table 6.9 Univariable and multivariable analyses of the association between previous
antenatal cART and MTCT occurring in a subsequent pregnancy ...................... 227
Table 7.1 Adverse pregnancy and perinatal outcomes analyses - characteristics of
women in their first and subsequent pregnancies ................................................ 240
Table 7.2 Pregnancy outcomes according to pregnancy number ............................................ 242
Table 7.3 Comparison of the characteristics of women with preterm and term deliveries ....... 245
Table 7.4 Univariable and multivariable analyses of factors associated with preterm
delivery among repeat pregnancies ..................................................................... 248
Table 7.5 Sensitivity analyses of the association between previous and subsequent
preterm delivery .................................................................................................... 251
Table 7.6 Sub-analyses: conceiving on ART as a predictor of preterm delivery ...................... 253
Table 7.7 Congenital abnormalities among live and stillbirths.................................................. 255
Table 7.8 Mode of delivery analyses - characteristics of subsequent pregnancies.................. 258
Table 7.9 Current and previous mode of delivery among women who had HIV-positive
infants in their last reported pregnancy ................................................................ 269
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