Article
Reference
Timing of combination antiretroviral therapy (cART) initiation is not associated with stillbirth among HIV-infected pregnant women in
Malawi
MSUKWA, Malango T, et al.
Abstract
OBJECTIVE: To assess the association between timing of maternal combination ART (cART) initiation and stillbirth among HIV-infected pregnant women in Malawi's Option B+
programme. METHODS: Cohort study of HIV-infected pregnant women delivering singleton live or stillborn babies at ≥28 weeks of gestation using routine data from maternity registers between 1 January 2012 and 30 June 2015. We defined stillbirth as death of a foetus at ≥28 weeks of gestation. We report proportions of stillbirth according to timing of maternal cART initiation (before pregnancy, 1st or 2nd trimester, or 3rd trimester or labour). We used logistic regression, with robust standard errors to account for clustering of women within health facilities, to investigate the association between timing of cART initiation and stillbirth.
RESULTS: Of 10 558 mother-infant pairs abstracted from registers, 8380 (79.4%) met inclusion criteria. The overall rate of stillbirth was 25 per 1000 deliveries (95% confidence interval 22-29). We found no significant association between timing of maternal cART initiation and stillbirth. In multivariable models, older [...]
MSUKWA, Malango T, et al. Timing of combination antiretroviral therapy (cART) initiation is not associated with stillbirth among HIV-infected pregnant women in Malawi. Tropical Medicine &
International Health, 2019
DOI : 10.1111/tmi.13233 PMID : 30891866
Available at:
http://archive-ouverte.unige.ch/unige:115710
Disclaimer: layout of this document may differ from the published version.
1 / 1
Timing of combination antiretroviral therapy (cART) initiation is not associated 1
with stillbirth among HIV-infected pregnant women in Malawi 2
3
Malango T. MSUKWA1,2, Olivia KEISER1, Andreas JAHN3, Joep J. VAN 4
OOSTERHOUT4,5, Andrew EDMONDS6, Nozgechi PHIRI1,2, Ronald MANJOMO2, 5
Mary-Ann DAVIES7, Janne ESTILL1,8 6
1) Institute of Global Health (IGH), University of Geneva, Geneva, Switzerland.
7
2) Baobab Health Trust, Lilongwe, Malawi.
8
3) Department of HIV and AIDS, Ministry of Health, Lilongwe, Malawi.
9
4) Dignitas International, Zomba, Malawi.
10
5) Department of Medicine, College of Medicine, University of 11
Malawi, Blantyre, Malawi.
12
6) The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
13
7) Centre of Infectious Disease Epidemiology and Research (CIDER), University of 14
Cape Town, Cape Town, South Africa.
15
8) Institute of Mathematical Statistics and Actuarial Science, University of Bern, 16
Bern, Switzerland.
17 18
Short title:
19
Maternal cART initiation and stillbirth 20
21
Correspondence to:
22
Malango Msukwa, BSc 23
Baobab Health Trust 24
P.O. Box 31797 25
Lilongwe 26
Malawi 27
malango.msukwa@bht-mw.org 28 29
30
Olivia Keiser, PhD 31
University of Geneva 32
Institute of Global Health 33
Geneva, Switzerland 34
olivia.keiser@unige.ch 35 36
Abstract: 235 words, main text: 2,532 words, 2 tables, 1 figure, 41 references.
37
ABSTRACT 38
OBJECTIVE: To assess the association between timing of maternal combination ART 39
(cART) initiation and stillbirth among HIV-infected pregnant women in Malawi’s 40
Option B+ programme.
41
DESIGN: A cohort study of HIV-infected pregnant women delivering singleton live or 42
stillborn babies at ≥28 weeks of gestation using routine data from maternity registers 43
between January 1, 2012 and June 30, 2015.
44
METHODS: We defined stillbirth as death of a fetus at ≥28 weeks of gestation. We 45
report proportions of stillbirth according to timing of maternal cART initiation (before 46
pregnancy, 1st or 2nd trimester, or 3rd trimester or labour). We used logistic regression, 47
with robust standard errors to account for clustering of women within health facilities, 48
to investigate the association between timing of cART initiation and stillbirth.
49
RESULTS: Of 10,558 mother-infant pairs abstracted from registers, 8,380 (79.4%) met 50
inclusion criteria. The overall rate of stillbirth was 25 per 1,000 deliveries (95%
51
confidence interval 22-29). We found no significant association between timing of 52
maternal cART initiation and stillbirth. In multivariable models, older maternal age, 53
male sex of the infant, breech vaginal delivery, delivery at <34 weeks of gestation, and 54
experience of any maternal obstetric complication were associated with higher odds of 55
stillbirth. Deliveries managed by a mission hospital or health centre were associated 56
with lower odds of stillbirth.
57
CONCLUSION: Pregnant women’s exposure to cART, regardless of time of its 58
initiation, was not found to be associated with increased odds of stillbirth.
59
Keywords: Stillbirth, Option B+, combination antiretroviral therapy, Malawi, HIV 60
INTRODUCTION 61 62
An estimated 2.6 million stillbirths, defined by the World Health Organization as a baby 63
born with no signs of life at or after 28 weeks of gestation [1], occur every year 64
worldwide, of which 98% are in low- and middle-income countries [2]. In sub-Saharan 65
Africa, more than 3% of deliveries each year result in stillbirth [3]. The major causes of 66
stillbirth include childbirth complications, maternal infections in pregnancy, maternal 67
disorders (especially hypertension, obesity and diabetes), fetal growth restriction and 68
congenital abnormalities [1,4].
69 70
Maternal antiretroviral therapy (ART) exposure may also be associated with increased 71
risk of stillbirth [5]. By the year 2015, 91% of the 1.1 million women receiving 72
antiretroviral drugs for prevention of mother-to-child transmission of HIV (PMTCT) 73
were being offered lifelong ART as a result of the implementation of the Option B+ policy 74
(lifelong ART for all HIV-infected pregnant and breastfeeding women regardless of CD4 75
cell count or clinical stage) [6]. Untreated HIV infection can increase the risk of stillbirth 76
by about 1.7 times [7]. It has been described that exposure to ART, especially from the 77
time of conception, may further increase the risk of stillbirth [5]. In Botswana, a study 78
that included more than 33,000 women between 2009 and 2011 reported that 6.3% of 79
women who conceived while receiving nevirapine-based ART had a stillbirth, compared 80
with 4.1% all other HIV-infected women, including those who initiated zidovudine, other 81
ART, or no antiretroviral drugs during pregnancy, and 2.5% of HIV-uninfected women 82
[8]. Higher risk of stillbirth has also been reported in different settings among 83
antiretroviral-exposed women when ART was initiated prior to conception or early in 84
pregnancy [9–13]. However, a Ugandan study in the era of Option B+ and a systematic 85
review by Uthman et al. found no association between stillbirth and pre-conception ART 86
or timing of ART initiation, respectively [14,15].
87 88
In this study, we used routine programme data from large health facilities in Malawi to 89
investigate the association between timing of maternal combination ART (cART) 90
initiation and stillbirth among HIV-infected women in the Option B+ era.
91
METHODS 92
Study setting and population 93
We abstracted routinely collected data from maternity registers at 20 large health facilities 94
in central and southern Malawi. The selected facilities were among the 21 facilities that 95
participated in our previous studies to evaluate the implementation of Option B+ in 96
Malawi [16–22] and included 12 district hospitals, two central hospitals, three faith-based 97
hospitals, and three large health centres. We included all women who received cART 98
during pregnancy and delivered a singleton live birth or stillbirth at a gestational age of 99
≥28 weeks between January 1, 2012 and June 30, 2015. We excluded all women with 100
missing data on age, gestational age, or timing of cART initiation. Exclusion criteria was 101
hierarchical.
102 103
Data collection and management 104
In the Malawi government’s health care system, observations from labour and delivery 105
are recorded on labour charts and summarized in the maternity register. These standard 106
monitoring and evaluation tools capture demographic characteristics, obstetrical history, 107
and infant outcomes. Data on HIV and ART status (for HIV-infected women) is obtained 108
from the woman’s personal health passport, a government-issued book containing 109
information on general history, diagnoses, treatments, antenatal consultations, and 110
deliveries and summarised in the register. We took digital images from the paper-based 111
maternity registers, followed by double data entry and cleaning.
112 113
Outcomes and main exposure 114
The main outcome was stillbirth, defined as a baby born with no sign of life at ≥28 115
completed weeks of gestation [1]. Stillbirth was based on gestational age at delivery, 116
calculated by the health service providers as the difference between delivery date and the 117
last menstrual period (LMP) self-reported by pregnant women at the first antenatal care 118
(ANC) visit.
119
The main exposure was timing of maternal cART initiation (before pregnancy, 1st or 2nd 120
trimester, or 3rd trimester or labour). We defined cART as a combination of at least three 121
antiretroviral drugs. During the study period, adult cART patients in Malawi received 122
tenofovir/lamivudine/efavirenz, zidovudine/lamivudine/nevirapine or 123
stavudine/lamivudine/nevirapine as first-line regimen, and either lopinavir or atazanavir 124
(each boosted with small dose of ritonavir) plus tenofovir/lamivudine or 125
zidovudine/lamivudine as second-line regimen [23,24].
126
127
Statistical analyses 128
We used Chi-square tests to test differences in proportions by timing of maternal cART 129
initiation, and Kruskal-Wallis tests to test for differences in medians. We used logistic 130
regression, with cluster-based robust standard errors [25] to account for clustering of 131
women within health facilities, to model stillbirth. We calculated unadjusted and adjusted 132
odds ratios (ORs and aORs, respectively) with 95% confidence intervals (CIs) of the 133
associations between timing of cART initiation and stillbirth. P-values were obtained 134
from the Wald test. We considered the following explanatory variables: infant sex, 135
maternal complications (none, haemorrhage, obstructed/prolonged labour, other, with 136
only the leading complication recorded in case of multiple complications), delivery 137
setting (health facility, home, unknown), mode of delivery (spontaneous vaginal, vacuum 138
extraction, caesarean, breech vaginal, unknown), parity (0, 1, >1), maternal age at 139
delivery (<20, 20-34, >35 years), gestational age at delivery (<34, 34-36, >37 weeks), 140
facility type (health centre, faith-based hospital, district hospital, central hospital), and 141
location of facility (urban, rural). Explanatory variables that were significant in 142
univariable analyses were included in the multivariable model.
143
All statistical tests were 2-sided, with p<0.05 considered significant. Analyses were 144
performed using STATA version 14.1 (Stata Corporation, College Station, Texas, USA).
145
The Malawi National Health Sciences Research Committee and the Cantonal Ethics 146
Committee of Bern in Switzerland granted ethical approval for the study.
147
RESULTS 148
Characteristics of women and infants by timing of cART initiation 149
A total of 10,558 HIV-infected mothers and their infants were recorded in the maternity 150
registers at the 20 health facilities since the implementation of Option B+. Of these 151
women, 643 (6.1%) were excluded because of delivery before 28 weeks or missing data 152
on gestational age, 666 (6.3%) because they did not receive cART before or during their 153
pregnancy, 156 (1.5%) because of delivery before January 1, 2012 or after June 30, 154
2015, 608 (5.8%) because of multiple gestation, and 105 (1.0%) because of missing 155
maternal age (Figure 1).
156
Of the included 8,380 HIV-infected women, 5,961 (71.1%) started cART before the 157
current pregnancy, 1,128 (13.5%) started cART in the 1st or 2nd trimester of the 158
pregnancy, and 1,291 (15.4%) started cART in the 3rd trimester or during labour (Table 159
1). The median (interquartile range [IQR]) gestational age at delivery was 37 (36-38) 160
weeks with no differences by timing of maternal cART initiation. Most women (76.4%) 161
were between 20 and 34 years old at delivery. Most deliveries were spontaneous, 162
vaginal (85.5%) and took place in a health facility (97.3%). Stillbirths were rare: 210 163
(2.5%) of the 8,380 deliveries. Of the 210 stillbirths, 108 (51.4%) were described as 164
macerated and 102 (48.6%) as fresh.
165
166
Factors associated with stillbirth 167
We found no significant differences in the proportion of stillbirth by timing of maternal 168
cART initiation (Table 2). Timing of maternal cART initiation was not associated with 169
odds of stillbirth in either the univariable or multivariable analysis. The odds of stillbirth 170
increased with age of the woman at delivery. Women aged ≥35 years were more likely 171
(aOR 1.49 [95% CI, 1.18-1.88]) to experience a stillbirth than women aged between 20 172
and 34 years. In the univariable analysis, delivery through caesarean section increased 173
the odds of stillbirth (OR 2.51 [95% CI, 1.51-4.17]) but this association was non- 174
significant in the multivariable analysis. Compared to spontaneous vaginal delivery, 175
breech vaginal delivery had an almost four times higher odds (aOR 3.87 [95% CI, 1.88- 176
8.00]) to result in a stillbirth. When compared with term delivery, a non-significant 177
increase in the odds of a stillbirth was noted among deliveries at 34-36 weeks of 178
gestation (aOR 1.26 [95% CI, 0.81-1.97]); the odds increased substantially in 179
pregnancies of less than 34 weeks of gestation (aOR 5.66 [95% CI, 4.02-7.97]). Male 180
babies had higher odds (aOR 1.21 [95% CI, 1.02-1.43]) of stillbirth than female babies.
181
Women who had haemorrhage (aOR 5.46 [95% CI, 3.01-9.91]), obstructed or prolonged 182
labour (aOR 4.00 [95% CI, 1.73-9.20]), or any other obstetric complication (aOR 8.52 183
[95% CI, 9.74-17.38]) were more likely to experience a stillbirth than those who had no 184
complications. Deliveries managed by a mission hospital (aOR 0.63 [95% CI, 0.50- 185
0.79]) or health centre (aOR 0.53 [95% CI, 0.30-0.95]) were less likely to result in 186
stillbirth than those managed at a central hospital.
187
DISCUSSION 188
In this study of infants born to HIV-infected mothers after implementation of Option B+
189
in Malawi, we found a stillbirth rate of 25 per 1,000 births. This figure, though higher 190
than the worldwide target of <12 stillbirths per 1000 births by 2030 set by the World 191
Health Organization’s Every Newborn Action Plan to end preventable deaths [26], is 192
close to the 2015 estimate of 22 stillbirths per 1,000 births (95% CI, 20-30) in the 193
Malawian general population [2]. In settings without widespread availability of 194
effective ART, the risk of stillbirth is generally higher [2]. In our study, stillbirths were 195
not more common among women who initiated cART before pregnancy compared to 196
those who started cART either during the 1st or 2nd trimester or during the 3rd trimester 197
or labour. The demographic characteristics of the study population were similar to those 198
of pregnant women in the general population [27]. However, the percentage of women 199
delivering in health facilities (97.3%) and the percentage of caesarean sections (11.1%) 200
were higher than in the Malawian general population (91% and 6%, respectively) [27].
201
This difference may be due to several reasons. We excluded delivery data from primary 202
health care facilities where caesarean sections do not take place. HIV-infected women 203
may be more likely to deliver in health facilities. Furthermore, the national percentages 204
exclude stillbirths.
205 206
Our finding that exposure to antiretroviral combinations used in this study 207
(nucleotide/nucleoside reverse transcriptase inhibiting (N(t)RTI) and non-NRTI 208
(NNRTI)), irrespective of timing of initiation, was not associated with increased odds of 209
stillbirth is consistent with previous studies. A cross-sectional study in Western Uganda 210
found that stillbirth was not more common among women who were on 211
N(t)RTI/NNRTI-based antiretroviral combinations than in HIV-uninfected women, 212
regardless of timing of initiation and adherence to antiretrovirals. The authors suggested 213
that the positive effect of antiretrovirals on maternal HIV infection counterbalances 214
their potential toxicity [14]. A study conducted in Botswana found no differences in 215
stillbirths between pregnant women taking either tenofovir/emtricitabine/efavirenz, 216
other triple ART regimens, or zidovudine only [12]. Despite the failure to distinguish 217
between women who started ART before conception from those who started during 218
pregnancy, results from a study in Malawi and Mozambique reported that a longer 219
course of ART during pregnancy was protective against stillbirth [28].
220 221
We found a number of factors to be associated with stillbirth. The increased odds of 222
stillbirth for older women found in our study has also been reported in systematic 223
reviews on stillbirth [2,29]. Consistent with the study by Chi et al. [30], pregnancies 224
lasting less than 34 weeks had an almost six times higher odds of resulting in stillbirth 225
than term deliveries. The higher odds of stillbirth in breech vaginal deliveries was also 226
reported in a meta-analysis that included data from clinical trials and observational 227
studies [31]. The proportion of stillbirth was higher among deliveries managed by 228
central hospitals, with only minor differences in proportions among deliveries managed 229
by health centres, mission hospitals and district hospitals. In Malawi, health centres and 230
mission hospitals offer primary healthcare and refer complicated cases to district 231
hospitals, which in turn, depending on the degree of complexity, may refer to a central 232
hospital. Therefore, the higher proportion of stillbirths among deliveries managed by 233
central hospitals and lower odds of stillbirth among those managed by mission or health 234
centre suggests a flow of delayed and complicated cases to central hospitals from 235
surrounding health facilities. Our finding of a higher odds of stillbirth among male 236
babies was also reported in a systematic review and meta-analysis of more than 30 237
million births by Mondal et al. [32]. Presence of any maternal complication during 238
delivery was strongly correlated with stillbirth in our study, similar to findings from a 239
systematic review by Lawn et al. [2]. Maternal co-morbidities during pregnancy may be 240
higher among HIV-infected women on ART [33,34]. Many of these covariates are 241
important predictors of stillbirth in the general population.
242
Strengths and limitations 243
Our study included a large sample of mother-infant pairs from a large geographical area 244
and from diverse health facility settings, including health centres, district hospitals, 245
mission hospitals and central hospitals. We controlled for several important factors 246
associated with stillbirth. However, because of our reliance on routine data, we could 247
not include some factors that may influence the association between maternal cART 248
initiation and stillbirth, such as ART adherence, CD4 cell count or viral load. Poor ART 249
adherence may result in drug resistance [35,36] and lower CD4 cell counts, which may 250
further lead to adverse maternal and birth outcomes. Some studies have reported that 251
reaching optimal ART adherence during pregnancy is challenging, particularly during 252
the postpartum period [20,37]. However, data from the PROMOTE trial and the Kisumu 253
Breastfeeding Study that included pregnant women regardless of clinical or 254
immunological stage suggested high and constant levels of adherence during pregnancy 255
and breastfeeding [38,39].
256
We however had no data on other factors that may be associated with stillbirth, such as 257
co-infections and comorbidities, distance to healthcare facility, or socio-economic 258
status. Tuberculosis, syphilis and malaria are common among HIV-infected people and 259
have been shown to correlate with stillbirth [2,40]. Low socio-economic status is 260
associated with increased risk of stillbirth [41] and delayed ART initiation [42], 261
possibly because women with low socioeconomic status are less likely to make use of 262
ANC, even if it is free.
263
Our study has also other limitations. First, there may have been some misclassification 264
of stillbirth due to use of gestational age estimated from self-reported LMP. The 265
consistency of our findings with other analyses suggests that such misclassification may 266
be minimal. Second, we had no data on the ART regimen the women received.
267
However, programme data report that by the end of June 2015 93% of adult ART 268
patients were on the tenofovir/lamivudine/efavirenz regimen which is also 269
recommended for Option B+, 5% on other NRTI- or NNRTI-based first-line ART 270
regimens, and there was no use of integrase inhibitors [43,44]. Third, the use of 271
routinely collected data may have affected data quality. Fourth, we did not have data on 272
timing of entering ANC and hence we were not able to verify if the results were 273
confounded by the coincidence of ANC and ART start.
274
Conclusion 275
The continued scale-up of ART programmes in most HIV-endemic countries and the 276
introduction of universal eligibility of ART for all people living with HIV means that 277
increasing numbers of pregnant women will be on ART throughout pregnancy. It is 278
therefore encouraging that long exposure to cART was not found to be associated with 279
increased odds of stillbirth. This finding is supported by the argument that ART keeps 280
the woman healthy and prevents a number of complications that are risk factors for 281
stillbirth. In our setting, this seems to outweigh any potential detrimental effects of 282
antiretroviral drugs on a live birth. The strongest predictors of stillbirth were maternal 283
obstetric complications. Analyses of routine programme data can play a relevant role in 284
evaluating effects of ART on birth outcomes, including when new regimens are 285
introduced on a large scale.
286
Acknowledgements 287
We would like to acknowledge all the health facility staff and MoH and CHAM 288
management who supported the data collection. Further, we would like to thank Lyson 289
Tenthani, Adrian Spoerri, Andreas Haas, Bryan Mthiko and Frank Chimbwandira for 290
their contributions to the project, the data entry team who diligently entered the data, 291
and the staff of Baobab Health Trust for the support provided during this study.
292 293
Declaration of interests 294
Research reported in this publication was supported by the National Institute of Allergy 295
and Infectious Diseases of the National Institutes of Health under award number 296
U01AI069924. The Bill and Melinda Gates Foundation (Global Health Grant 297
OPP1090200), The United States Agency for International Development - Partnerships 298
for Enhanced Engagement in Research Health (PEER Health) grant AID OAA-A-11- 299
0012, provided additional support. OK was supported by a professorship grant from the 300
Swiss National Science Foundation (grant number 163878). The content is solely the 301
responsibility of the authors and does not necessarily represent the official views of the 302
sponsors.
303 304
Author contributions 305
MM, OK and JE conceived the study that was critically reviewed by JvO and NP. MM 306
and NP coordinated data digitalization and data entry. MM did data management. MM 307
did statistical data analysis under the supervision of JE and OK. All authors contributed 308
to the interpretation of results. MM wrote the first draft of the report, which was 309
reviewed by OK, JE, AE, JvO, NP, RM, MAD and AJ. All authors contributed to the 310
final version of the manuscript. AJ coordinates monitoring and evaluation of the 311
Malawian ART/PMTCT programme. MAD and OK are the principal investigators of 312
the study. All authors reviewed and approved the final version for submission.
313
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Table 1: Characteristics of women and infants stratified by timing of maternal combination antiretroviral therapy (cART) initiation
Timing of cART initiation
P Before
pregnancy
1st or 2nd trimester
3rd trimester or during labour Number of women 5961 (71.1) 1128 (13.5) 1291 (15.4)
Maternal age (years)
<20 341 (5·7) 97 (8·6) 89 (6·9)
<0.0001
20-34 4501 (75·5) 886 (78·5) 1019 (78·9)
≥35 1119 (18·8) 145 (12·9) 183 (14·2)
Median (IQR) 29 (24-33) 27 (22-32) 28 (23-32)
Parity
0 629 (10·6) 160 (14·2) 142 (11·0)
<0.0001
1 1069 (17·9) 233 (20·7) 275 (21·3)
>1 4238 (71·1) 734 (65·1) 872 (67·5)
Missing 25 (0·4) 1 (0·1) 2 (0·2)
Median (IQR) 2 (1-4) 2 (1-3) 2 (1-3)
Gestational age (weeks)
<34 319 (5·4) 51 (4·5) 67 (5·2)
<0.0001
34-36 1682 (28·2) 385 (34·1) 515 (39·9)
≥37 3960 (66·4) 692 (61·3) 709 (54·9)
Median (IQR) 37 (36-38) 37 (36-38) 37 (36-38)
Mode of delivery
Spontaneous vaginal 5007 (84·0) 1008 (89·4) 1137 (88·1)
<0.0001
Vacuum extraction 110 (1·9) 14 (1·2) 12 (0·9)
Breech vaginal 105 (1·8) 14 (1·2) 26 (2·0)
Caesarean section 722 (12·1) 90 (8·0) 116 (9·0)
Missing 17 (0·3) 2 (0·2)
Delivery setting
Health facility 5813 (97·5) 1103 (97·8) 1239 (96·0) <0.0001
Home 56 (0·9) 12 (1·1) 35 (2·7)
Other 84 (1·4) 13 (1·2) 14 (1·1)
Missing 8 (0·1) 3 (0·2)
Birth attendant
Trained attendant 5332 (89·4) 1065 (94·4) 1179 (91·3)
0.094
Other 114 (1·9) 25 (2·2) 38 (2·9)
Missing 515 (8·6) 38 (3·4) 74 (5·7)
Maternal obstetric
complications#
None 5111 (85·7) 1007 (89·3) 1136 (88·0)
0.002
Haemorrhage 177 (3·0) 25 (2·2) 44 (3·4)
OPL 228 (3·8) 41 (3·6) 40 (3·1)
Other 414 (6·9) 49 (4·3) 63 (4·9)
Missing 31 (0·5) 6 (0·5) 8 (0·6)
Facility type
Central hospital 1233 (20·7) 155 (13·7) 237 (18·4)
<0.0001
Health centre 557 (9·3) 213 (18·9) 442 (34·2)
Mission hospital 387 (6·5) 78 (6·9) 74 (5·7)
District hospital 3784 (63·5) 682 (60·5) 538 (41·7)
Facility location
Rural 4173 (70·0) 817 (72·4) 639 (49·5)
<0.0001
Urban 1788 (30·0) 311 (27·6) 652 (50·5)
Infant sex
Male 3068 (51·5) 584 (51·8) 643 (49·8)
0.547
Female 2840 (47·6) 537 (47·6) 633 (49·0)
Unknown 53 (0·9) 7 (0·6) 15 (1·2)
Data are n (%) unless indicated otherwise. OPL, Obstructed/prolonged labour; cART, Combination antiretroviral therapy; IQR, Interquartile range.
# Health care workers only record one leading complication
Table 2: Association between timing of maternal combination antiretroviral therapy (cART) initiation and other factors with stillbirth
Proportion with stillbirth (%)
Univariable (n = 8,380)
Multivariable (n = 8,316)
OR (95% CI) P* aOR (95% CI) P*
Timing of cART initiation
Before pregnancy 158/5,961 (2.7) 1.23 (0.82-1.83) 0.218 1.01 (0.68-1.49) 0.600 1st or 2nd trimester 24/1,128 (2.1) 0.98 (0.63-1.52) 0.86 (0.47-1.57)
3rd trimester or labour 28/1,291 (2.2) 1 1
Maternal age (years)
<20 7/527 (1.3) 0.55 (0.26-1.18) <0.0001 0.50 (0.24-1.02) 0.0001
20-34 152/6,406 (2.4) 1 1
≥35 51/1,447 (3.5) 1.50 (1.19-1.90) 1.49 (1.18-1.88)
Parity
0 17/931 (1.8) 1 0.131
1 30/1,577 (1.8) 1.04 (0.54-2.00)
>1 160/5,844 (2.7) 1.51 (0.91-2.52)
Missing 3/28 (10.7)
Gestational age (weeks)
<34 55/437 (12.6) 7.57 (5.46-10.51) <0.0001 5.66 (4.02-7.97) <0.0001
34-36 55/2,582 (2.1) 1.15 (0.74-1.78) 1.26 (0.81-1.97)
≥37 100/5,361 (1.9) 1 1
Mode of delivery
Spontaneous vaginal 139/7,152 (1.9) 1 <0.0001 1 <0.0001
Vacuum extraction 4/136 (2.9) 1.53 (0.53-4.38) 0.92 (0.29-2.85)
Breech vaginal 20/145 (13.8) 8.07 (4.70-13.85) 3.87 (1.88-8.00)
Caesarean section 44/928 (4.7) 2.51 (1.51-4.17) 0.65 (0.31-1.37)
Missing 3/19 (15.8)
Birth attendant
Trained 190/7,576 (2.5) 1 0.252
Other 2/177 (1.1) 0.44 (0.11-1.78)
Missing 18/627 (2.9)
Maternal obstetric complications#
None 111/7,254 (1.5) 1 <0.0001 1 <0.0001
Haemorrhage 22/246 (8.9) 6.32 (3.54-11.27) 5.46 (3.01-9.91)
OPL 13/309 (4.2) 2.83 (1.46-5.48) 4.00 (1.73-9.20)
Other 62/526 (11.8) 8.60 (5.84-12.67) 9.74 (5.45-17.38)
Missing 2/45 (4.4)
Facility type
Central hospital 58/1,625 (3.8) 1 <0.0001 1 0.0006
Health centre 16/1,212 (1.3) 0.36 (0.25-0.53) 0.53 (0.30-0.95)
Mission hospital 13/539 (2.4) 0.67 (0.53-0.83) 0.63 (0.50-0.79)
District hospital 123/5,004 (2.5) 0.68 (0.56-0.83) 0.85 (0.63-1.14)
Facility location
Rural 134/5,629 (2.4) 1 0.471
Urban 76/2,751 (2.8) 117 (0.77-1.77)
Infant sex
Female 112/4,295 (2.6) 1 0.177 1 0.040
Male 94/4,010 (2.3) 1.12 (0.94-1.32) 1.21 (1.02-1.43)
Unknown 4/75 (5.3) 2.35 (0.88-6.29) 2.90 (1.07-7.88)
OR, Odds ratio; aOR, Adjusted odds ratio; CI, Confidence interval; OPL, Obstructed/prolonged labour; cART, Combination antiretroviral therapy; IQR, Interquartile range.
# Health care workers only record one leading complication
*P-value obtained using a Wald test
Figure 1: Study eligibility flow chart
¥ Exclusion criteria was hierarchical; cART, combination antiretroviral therapy Mother-infant pairs: 10,558
Excluded¥: 2,178 (20.6%)
• Multiple gestation: 608
• Delivered before 01 Jan 2012 or after 30 Jun 2015: 156
• Weeks of gestation <28 or missing: 643
• Missing maternal age: 105
• Did not receive cART at any stage: 666
Included in the analysis: 8,380
