An analysis of the HIV-associated population attributable ...pregnancy outcome in the presence of maternal HIV infection continues to persist. Preterm birth (PTB), low birth weight

1 Dr. OO Wedi Systematic review protocol: Comparative analysis of HIV associated adverse pregnancy outcome, in ARV-naive mothers.

Oxford University

Nuffield Department of Obstetrics & Gynaecology

An analysis of the HIV-associated population attributable risk for adverse

pregnancy outcome, in ART-naïve mothers.

A systematic review and meta-analysis.

Opope Oyaka Wedi Student number: 2823644

Cell no: 07435389225

Email: [email protected]

Supervisors:

Professor Stephen. Kennedy Dr. Joris. Hemelaar

Oxford University Oxford University

Nuffield Department of Obstetrics

& Gynaecology

Nuffield Department of Obstetrics &

Gynaecology

Tel no: +44(0) 1865 221004 Tel no: +44(0) 865 221004

Email: [email protected]

Email:[email protected]


Table of Contents 1 Background ........................................................................................................................ 3

2 Objectives of the review ..................................................................................................... 6

2.1 Primary objective .....................................................................................................................6 2.2 Secondary objectives ................................................................................................................6

3 Methods ............................................................................................................................... 6

3.1 Inclusion and exclusion criteria ..............................................................................................6 3.1.1 Study design ........................................................................................................................6 3.1.2 Setting .................................................................................................................................7 3.1.3 Population of interest ..........................................................................................................7 3.1.4 Exposure of interest .............................................................................................................7

3.2 Outcome measures ....................................................................................................................8 3.2.1 Primary outcomes ................................................................................................................8 3.2.2 Secondary outcomes ............................................................................................................9

3.3 Search methods for identification of studies ..........................................................................9 3.4 Study collection and critical appraisal .................................................................................10

3.4.1 Stage 1: Title and abstract screens ....................................................................................10 3.4.2 Stage 2: Eligibility criteria ................................................................................................11 3.4.3 Stage 3: Quality appraisal of papers ..................................................................................11

3.5 Data Extraction .......................................................................................................................13 3.6 Data synthesis ..........................................................................................................................13

3.6.1 Summary of findings .........................................................................................................13 3.6.2 Data analysis .....................................................................................................................13 3.6.3 Subgroup analysis .............................................................................................................14 3.6.4 Unit of analysis .................................................................................................................14 3.6.5 Sensitivity analysis: ...........................................................................................................14 3.6.6 Assessment of heterogeneity: ............................................................................................15 3.6.7 Publication bias .................................................................................................................15

References ............................................................................................................................... 15


1 Background

As the 2015 Millennium Development Goal (MDG) deadline approaches, concerns about

stagnating perinatal mortality and morbidity statistics are being expressed worldwide.1–6 The

Human Immunodeficiency Virus (HIV) epidemic, a known contributor to poor maternal 7–10

and fetal11 outcome, continues to affect 34 million people (31.4 million-35.9 million)

globally, 69% of which reside in sub-Saharan Africa.12 Despite an overall decline in new

HIV infections since 2001 (20% decline), annual trends in the Middle East and North African

states have shown a 35% increase in the incidence of HIV.12

One of the major gains made during the HIV epidemic has been the decline in mother to child

transmission (MTCT).12 This decline has been attributed to the implementation of prevention

of mother to child transmission (PMTCT) programs, in addition to the adoption of specific

intrapartum guidelines and infant feeding practices.12–14 In the developed world, the initiation

of antiretroviral treatment (ART) has contributed to the reduction in MTCT rates to less than

1-2%.14 Furthermore, PMTCT programs have facilitated the early diagnosis and treatment of

pregnant women affected by the disease, which translates to improved perinatal maternal

outcome and reduced maternal mortality rate.9 Despite the benefits of ART, adverse

pregnancy outcome in the presence of maternal HIV infection continues to persist.

Preterm birth (PTB), low birth weight (LBW) and stillbirth are widely acknowledged global

causes of perinatal morbidity and mortality.15–17 Preterm birth was the leading cause of

neonatal death in 2010 6 accounting for 1.078 million (95%CI 0.916-1.325million) of all

neonatal deaths (3.072 million), 6,18 while an estimated 3.2 million stillbirths occur

annually.16 The debate as to the role of maternal HIV infection as a risk factor for adverse

pregnancy outcome is still ongoing. 19 Some studies have reported an increased incidence of

adverse pregnancy outcome in HIV infected women, 20,21 while others dispute this finding.22

Furthermore, numerous studies have observed an increase risk of adverse pregnancy outcome

in women receiving ART during their pregnancy, but this has also been disputed,23,24 with

one paper stating that preterm birth rates in these women were similar to those found in the

HIV negative population. 25

The association between HIV and adverse pregnancy outcome is a contentious issue, as it

would have over arching implications for millions of HIV infected women. The fact that ART


could potentially exacerbate this effect would mean that millions of neonatal deaths would

have been caused by the only treatment we have available. This dilemma stems from the fact

that to date we still do not know what effect the HIV virus has on pregnancy outcome, in

comparison to healthy uninfected controls. Furthermore, we do not know whether ART

exacerbates this effect or alleviates it. This knowledge would enable us to determine whether

all ART regimens, including those said to have the highest risk of complications,26 are truly

associated with lower risks of adverse pregnancy outcome compared to HIV-positive women

not on treatment.

Numerous studies have attempted to assess the risk of adverse pregnancy outcome in HIV

infected women who are naïve to ART. However, many of these studies have been small with

little statistical power,27 have had biased methodologies,20,21 have not measured or controlled

known confounding factors,21,28 have not reported vital information21 and have reported

different effect sizes.29–31

Over the years systematic reviews and meta-analyses have enabled us to generate an

approximation of an overall effect size of interest, through the combination of independent

studies addressing the same effect.32–35 In 1998, Brocklehurst et al conducted a systematic

review and meta-analysis which assessed the association between maternal HIV infection and

perinatal outcome.19 They found that maternal HIV infection was associated with adverse

perinatal outcome including, PTB (OR 1.83 95%CI 1.63-2.06), LBW (OR 2.09 95%CI 1.86-

2.35), intra-uterine growth restriction (IUGR) (OR 1.7 95%CI 1.43-2.02) and stillbirth (OR

3.91 95% CI 2.65-5.77).19 However, this association was deemed weak due to the

inappropriate methodology used by the included studies, and the lack of control of

confounding factors.19

HIV is known for its genomic variability, with different types (HIV-1 and HIV-2), subtypes

(HIV-1: M, N, O, P and HIV-2: A-H),36 sub-subtypes (e.g. A1-A4),37 and recombinant forms

(e.g. CRFs and URFs).36 Different viral strains have been associated with different levels of

virulence, different rates of mother to child transmission and different levels of resistance to

ART.36,37 However, the influence of HIV diversity on adverse pregnancy outcome has not

been addressed in any review, including the Brocklehurst paper.


The variability of HIV, in addition to other causes of clinical heterogeneity (e.g. genetic

factors, maternal nutritional status, clinical/immunological stage of HIV, difference in

antenatal care availability and quality, as well as obstetric guidelines), and the methodological

heterogeneity (cohort, case-control and controlled trials) results in a substantial amount of

statistical variability which would not be taken into account when using the fixed-effect

model34,38,39 as performed by Brocklehurst et al.19 Although numerous systematic reviews

have been done looking at the influence of ART on pregnancy outcome,40,41 no updated

systematic review has been done addressing the influence of HIV on pregnancy outcome.

We aim to conduct a systemic review assessing the influence of untreated maternal HIV

infection on specific pregnancy outcomes including, PTB, LBW, small for gestational age

(SGA), intrauterine growth restriction (IUGR), and stillbirth. We propose that the

heterogeneity within and between included studies would best be analysed with the use of the

random-effects model.34,35 The fixed-effect model assumes that there is homogeneity between

the studies included in the review, and that any variation in the underlying effect size being

investigated is due to sampling error.33,34,39 Conversely, the random-effect model assumes that

the underlying effect has a normal distribution,34 with the mean representing the overall

average effect.34 In systematic reviews where there is no heterogeneity between studies, the

use of the random-effects model and fixed-effects model yield similar results.35 However, in

studies where heterogeneity is present, the random-effect model incorporates both the clinical

variability and the statistical variability due to sampling error, into the analysis,39 which may

produce different results.34,35 Subgroup analyses will be used to assess the association

between known confounders and specified outcomes. Population attributable risk for adverse

outcomes will be determined and correlated with HIV subtypes identified in the region.

We aim to assess all studies and abstracts which were included in the Brocklehurst paper, in

addition to studies addressing the same questions which have been published since. This

would give us a larger sample of results to incorporate into our analysis, thus translating to

the statistical power needed to estimate the most probable effect size.35 Only when the true

effect of maternal HIV infection on perinatal outcome is clarified, can we truly assess

whether the introduction of ART has improved perinatal outcome.


2 Objectives of the review

2.1 Primary objective

The primary objective of this review is to answer the following question:

1. Do pregnant HIV-positive women, who are not exposed to any ART during the

antenatal period, have an increased risk of adverse birth outcomes compared to HIV-

negative women? The outcomes of interests include: PTB, LBW, SGA, IUGR and

stillbirth.

2.2 Secondary objectives

The secondary objectives of the review are to answer the following questions:

1. Do pregnant HIV-positive women, who are not exposed to ART during the antenatal

period, have an increased risk of miscarriage, compared to HIV-negative women?

2. Do pregnant HIV-positive women, who are not exposed to ART during the antenatal

period, have an increased risk of neonatal death (NND) compared to HIV-negative

women?

3. Do pregnant HIV-positive women infected with different HIV strains have different

risks of adverse pregnancy outcomes?

3 Methods

3.1 Inclusion and exclusion criteria

The eligibility criteria are formulated with guidance from the Cochrane Handbook for

systematic reviews of interventions. 33 (www.cochrane.org/training/cochrane-handbook)

3.1.1 Study design

The review will analyse quantitative data obtained from primary research papers focused on

HIV/AIDS in the pregnant human population. Study designs to be reviewed include

observational studies (cohort, case-control and cross-sectional studies) as well as

interventional studies (randomised controlled trial and controlled clinical trial).


3.1.2 Setting

The setting of the different studies will be taken into consideration, especially when

comparing studies compiled in high-income countries versus middle and low-income

countries as defined by the World-Bank-country-specific-income-status

http://data.worldbank.org/country.

This will enable us to compare the influence of socio-economic status, quality and access to

antenatal care facilities, as well as whether specific HIV subtypes found in different regions

are associated with increased risk of adverse pregnancy outcome.

3.1.3 Population of interest

The review will include studies containing quantitative data on pregnant HIV-positive

women. These participants may be of any ethnicity, social or educational status. Details

pertaining to the maternal demography, pregnancy outcome and information regarding the

newborn should be recorded, e.g. twin deliveries, birth-weight, gestational age at birth,

mortality and morbidity regarding the baby.

Studies containing HIV-positive and HIV-negative cohorts as only a subset of the entire study

cohort will initially be included and discussed amongst the reviewers. After the discussion, a

final decision will be made regarding the retention of the paper. The study will be excluded if

it is deemed irrelevant or unsuitable for the review.

A cohort of HIV-negative pregnant women of any ethnic, social or educational background,

from the same community as the HIV-positive participants, should serve as the control group.

Studies will be excluded if they contain the following:

• Ambiguous inclusion and exclusion criteria.

• No HIV-negative pregnant participants as the control group.

• HIV-positive women who have received more than an intrapartum dose of ART

during their pregnancy

3.1.4 Exposure of interest

The exposure of interest is the HIV infection, which is contracted either before or during

pregnancy by any form of transmission (e.g. heterosexual, intravenous drug use etc.). A


healthcare worker (a doctor, nurse or HIV counsellor) should have diagnosed or confirmed

the participant’s HIV status either before or during the period in which the study was

conducted. If this is not done, the study should explain how HIV status was validated.

Participants presenting with any clinical or biochemical stage of HIV, including AIDS will be

included. Studies will not be excluded if HIV-positive pregnant participants only received

ART before the pregnancy and its use was terminated before the pregnancy for any reason,

(e.g. non-adherence) or a single ART dose was received at delivery.

Studies including HIV-positive pregnant participants who present with comorbidities or

opportunistic infections will be included. Confounding factors will be assessed and taken into

account during statistical analysis. Studies conducted on HIV-positive pregnant women that

assess other exposures will be included and only relevant data will be extracted and

synthesised.

3.2 Outcome measures

3.2.1 Primary outcomes

3.2.1.1 Preterm birth and premature preterm rupture of membrane (PPROM):

In this review we will assess papers reporting PTB, defined as birth before 37+0weeks

gestation.16 These will be categorised as follows: moderately preterm (33+0-36+6weeks), very

preterm birth (<32+0weeks) and extremely preterm birth (<28+0weeks).16 PPROM will be

assessed and the data extracted from all studies.

3.2.1.2 LBW, SGA and IUGR:

Studies will be assessed for the birth-weight of infants born to HIV-positive and negative

mothers. LBW will be defined as a birth-weight <2500g42 and Very Low Birth Weight

(VLBW) will be defined as birth-weight <1500g43 . We will also assess SGA, which for our

purposes will be defined as birth-weight-for-gestational age <10th centile as well as IUGR,

which will be defined as birth-weight-for gestational age <3rd centile.

3.2.1.3 Stillbirth and Fetal death:

The term “stillbirth” is used inconsistently in the literature, which may lead to

misclassification of the variable of interest.44 It is used interchangeably with fetal death,44


which may further result in the exclusion of vital data if we restrict ourselves to just one term.

Therefore, for the purpose of this review, we will extract stillbirth and fetal death data.

It will be defined as any third trimester delivery of a demised fetus with:

• ≥1000g birth-weight 44 or

• ≥24+0 completed weeks or

• ≥ 35cm body length 44

3.2.2 Secondary outcomes

The secondary outcomes of interest include:

3.2.2.1 Neonatal death and miscarriage:

We aim to assess whether HIV-positive women have an increased risk of neonatal death or

miscarriage compared to HIV-negative women.

Neonatal death will be defined as the death of the infant within 28 days of life and

miscarriage will be defined as the spontaneous expulsion of the fetus before 24+0weeks

gestation.

3.2.2.2 Population specific HIV-subtypes

We will assess the influence of known HIV strains in each country where the retrieved studies

are conducted. The different strains will be defined according to the type (HIV-1 and HIV-2),

subtypes (HIV-1: M, N, O, P and HIV-2: A-H), sub-subtypes (e.g. A1-A4), and recombinant

forms (e.g. CRFs and URFs). Different viral strains specific to each population will be

correlated with observed levels of adverse pregnancy outcome including: PTB, LBW, SGA,

IUGR, stillbirth, miscarriage and neonatal death and mother to child transmission rate.

3.3 Search methods for identification of studies

We will identify relevant studies through manual and electronic search strategies. The

electronic database search will include: PubMed, MEDLINE, EMBASE, Global Health, and

CINAHL from January 1980 to March 2013. No methodological or language filters will be

applied. Search terms will include Mesh headings and Emtree terms for pregnancy outcome,

PTB, LBW, IUGR, SGA, stillbirth and HIV or ART in addition to free text words and

possible synonyms. The bibliographies of the relevant retrieved articles will be examined and


all relevant references will be retrieved either manually or electronically. An electronic search

of the grey literature will also be conducted to identify unpublished papers, theses, reports

and conference abstracts relevant to the systematic review. Lastly a number of experts in the

field will be contacted to enquire about additional papers that we may not have identified. All

relevant material will be included in the systematic review.

All retrieved papers will be imported into Endnote reference manager and duplicated articles

will be removed. A record will be made of all papers excluded in the de-duplication process.

3.4 Study collection and critical appraisal

The selection and critical appraisal of the papers will be conducted in 4 stages.

3.4.1 Stage 1: Title and abstract screens

Following the literature search, 2 individual reviewers will scan the titles and abstracts of all

papers retrieved to identify whether they contain data that is relevant to the systematic review.

Only papers reporting case-control, cohort, cross-sectional or interventional studies assessing

perinatal outcome in HIV-positive and HIV-negative women will be included in this initial

stage. All letters, comments, opinion pieces and case-reports will be excluded. Non-English

publications will be considered and those deemed relevant to the review will be included.

Any disagreement regarding inclusion at this stage will be discussed with a third reviewer,

who will make the final decision. All excluded studies will be recorded.


3.4.2 Stage 2: Eligibility criteria

Two independent reviewers will assess each paper as to whether they meet the eligibility

criteria. All studies which do not fulfil the eligibility criteria will be excluded. A record will

be kept as to why each paper was excluded.

Inclusion criteria Exclusion criteria

1. HIV-positive pregnant women

2. HIV-negative pregnant control group

3. Data collected on birth-weight or gestational

age at delivery or stillbirth

1. Ambiguous inclusion criteria

2. > Stat dose of ART received during pregnancy

3. No control group

Table 1: Inclusion and exclusion criteria

3.4.3 Stage 3: Quality appraisal of papers

Two reviewers will assess each paper according to a structured pre-formulated template.

Numerous guidelines have been suggested to facilitate the improvement in the quality of

reporting of observational studies (STROBE statement) and RCTs (CONSORT).35 Although

this improves the quality of the reporting, it does not necessarily translate to a good

methodological quality.45,46 To date there is no consensus regarding a quality assessment

checklist for observational studies. 47

We anticipate a wide range in methodological quality because of the inclusion of

interventional studies as well as observational studies. Due to the vast difference in study

methodology between observational and interventional studies we have chosen to use 2

different quality assessment tools, which are specific for each group.

The quality of the interventional studies (RCT and controlled studies) will be assessed

according to the Cochrane risk of bias tool kit (Appendix 1). Study quality will be categorised

as follows:

• Good quality: This will include studies which have fulfilled all 5 requirements of the

risk assessment tool checklist and have no additional sources of bias.

• Average quality: This will include studies which have fulfilled between 2-4 of the 5

requirements of the risk assessment tool. Furthermore, they should not have any major

methodological flaws, e.g. poor randomisation or additional sources of bias.


• Poor quality studies: Studies which only fulfil <2 of the requirements or contain a

major methodological flaw.

An adaption of the Newcastle-Ottawa quality assessment tool will be used to assess all

observational studies. Study quality will be categorised as follows:

• Good quality: Studies which meet all requirements (9stars).

• Average quality: Studies which achieve >2 stars in the “selection” section and

“exposure” section, but < 9 overall.

• Poor quality: Studies which achieve ≤2 stars in both the “selection” section and the

“exposure” section of the assessment tool.

Two independent reviewers will conduct this process, and any discrepancy in quality score

will be discussed with a third reviewer, who will make the final decision.

A summary of the quality assessment results will be presented for each included study and

correlated with the effect size observed in the study.

All studies will be combined according to the quality category which they have been assigned

to e.g. good, average and low quality. Following data extraction, an overall aggregate effect

size will be calculated for all primary and secondary outcomes in relation to different ART

regimens and displayed as forest plots. Thereafter, the level of evidence will be graded

according to the Grading of Recommendations Assessment, Development and Evaluation

System (GRADE). http://www.gradeworkinggroup.org

Levels of quality of a body of evidence in the GRADE approach

Underlying methodology Quality rating

Randomized trials; or double-upgraded observational studies. High

Downgraded randomized trials; or upgraded observational studies. Moderate

Double-downgraded randomized trials; or observational studies. Low

Triple-downgraded randomized trials; or downgraded observational studies; or case series/case reports.

Very low

Table 2: Grade of evidence


3.5 Data Extraction

Two independent reviewers will extract relevant data from the selected studies. A data

collection sheet has been developed for the purpose of the review. It will allow reviewers to

record data electronically into an Access-based database. The data extracted will include

specific details including: study descriptors (e.g. journal title, author name, year of

publication etc.), population information (e.g. maternal HIV status), outcome measures of

interest, (e.g. MTCT, PTB, LBW, SGA, stillbirth) and confounding factors identified, non-

adjusted and adjusted effect estimates, standard error, standard deviation as well as 95% CI.

Data extracted will be compared between the two reviewers and any disagreement between

authors will be resolved by discussion with the third reviewer.

3.6 Data synthesis

3.6.1 Summary of findings

A tabulated summary of all included studies will be presented with details regarding the

following variables: 33

1. Study type

2. Participants in each group (mother and infants)

3. Maternal demographic and clinical characteristics

4. Outcome measures

5. Quality assessment score and aspects which the study did not fulfil.

3.6.2 Data analysis

Summary statistics will be compiled for individual studies irrespective of quality assessment

score. All binary statistics will be recorded as relative risk ratios (RR), and results reported as

odds ratios in retrieved studies will be converted to relative risk ratios.33,34,48,49 Continuous

data will be recorded as a mean. In addition, the population attributable risk fraction (PAR)

for the adverse outcomes, namely LBW, SGA, PTB, PPROM and stillbirth, will be calculated

for each study. If we assume that maternal HIV infection is a risk factor for the above

mentioned adverse pregnancy outcomes, the PAR would enable us to better demonstrate the

proportion of these outcomes, within the study populations, which would be modified or

prevented if HIV infection were prevented.


We anticipate a heterogeneous sample of studies from the literature search; hence the null

hypothesis will be tested using a random effects model. 34 We plan to conduct several meta-

analyses of the aggregated data, with the aim of assessing the influence of HIV on the

primary outcomes of interest. Forest plots will be used to demonstrate the patterns of effect.

In instances where data cannot be pooled, a narrative summary will be produced.

3.6.3 Subgroup analysis

Subgroup analysis will be conducted to assessed the influence of possible covariates on the

observed adverse pregnancy outcome as well as additional variables:

1. Maternal demography: country, income status of country, alcohol use during

pregnancy, smoking, advanced maternal age, teenage pregnancy, ethnicity, number of

antenatal care receive and intravenous drug use.

2. HIV stage: Immunological stage (mean CD4+) or clinical stage of HIV (WHO/CDC).

3. Mother to child transmission

4. HIV subtypes

3.6.4 Unit of analysis

We aim to analyse the influence of maternal HIV infection on newborn outcome. Therefore,

we will report information relating to both the mother and the infant.

3.6.5 Sensitivity analysis:

The sensitivity analysis aims to assess the robustness of the observed effect size.50 We plan

to conduct 5 sensitivity analyses including:

1. Location of the study: low, middle and high-income country.

2. Methodological quality: high quality versus average quality

3. Study design: observational studies versus RCT

4. Control for confounding factors: studies which used methods for controlling for

known confounders and those which have not.

5. The exclusion of studies with the largest effect size.

Meta-analyses will be conducted and differences between comparisons will be reported.


3.6.6 Assessment of heterogeneity:

The statistical heterogeneity of the studies retrieved will be evaluated by comparing the study

design and setting, in addition to Chi2, τ2 and I2 statistic. The results will be assessed for

clinical and statistical relevance. 33,34 The I2 statistic will be used to test the null hypothesis of

homogeneity and quantify the percentage of heterogeneity in effect size which occur as a

consequence of between-study variability. 38,39 The result will be interpreted as: no

heterogeneity (0%), low heterogeneity (25%), moderate heterogeneity (50%) and high

heterogeneity (75%). 39,51

In the event that a small number of studies are retrieved and included in the review, we will

take the low statistical power of the I2 statistic into consideration when we report our

findings. 39

3.6.7 Publication bias

Small study bias will be assessed with the use of funnel plots.35 If any evidence of publication

bias is identified. We will explore publication bias by looking for unpublished trials on trial

registries.

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An analysis of the HIV-associated population attributable ...pregnancy outcome in the presence of maternal HIV infection continues to persist. Preterm birth (PTB), low birth weight