Effect of HIV and substance use disorder comorbidity on the placenta, fetal and maternal health outcomes: systematic review and meta-analysis protocol

Abstract

Background

Substance use disorders and HIV infection have a bidirectional relationship. People who use illicit drugs are at increased risk of contracting HIV/AIDS, and people living with HIV/AIDS are at increased risk of using substances due to disease-related complications like depression and HIV-associated dementia. There is no adequate evidence on the effect of HIV/AIDS and substance use disorder comorbidity-related effects on placental, fetal, maternal and neonatal outcomes globally.

Methods and analysis

We will search articles written in the English language until 30 January 2024, from PubMed/Medline, Cochrane Library, Embase, Scopus, Web of Sciences, SUMsearch2, Turning Research Into Practice database and Google Scholar. A systematic search strategy involving AND/OR Boolean Operators will retrieve information from these databases and search engines. Qualitative and quantitative analysis methods will be used to report the effect of HIV/AIDS and substance use disorders on placental, fetal and maternal composite outcomes. Descriptive statistics like pooled prevalence mean and SD will be used for qualitative analysis. However, quantitative analysis outcomes will be done by using Comprehensive Meta-Analysis Software for studies that are combinable. The individual study effects and the weighted mean difference will be reported in a forest plot. In addition to this, the presence of multiple morbidities like diabetes, chronic kidney disease and maternal haemoglobin level could affect placental growth, fetal growth and development, abortion, stillbirth, HIV transmission and composite maternal outcomes. Therefore, subgroup analysis will be done for pregnant women with multiple morbidities.

Ethics and dissemination

Since systematic review and meta-analysis will be conducted by using published literature, ethical approval is not required. The results will be presented in conferences and published in peer-reviewed journals.

PROSPERO registration number

CRD42023478360.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• Evaluating the effect of HIV/AIDS and substance use disorder comorbidity on broader (placental, fetal, maternal and neonatal) outcomes.

• Inclusion of robust study designs with clear causal inferences with baseline HIV viral load and substance use disorder assessments.

• The use of standard tools and protocols for the risk of bias assessment.

• Inclusion of studies since the introduction of HIV/AIDS.

• However, only articles published in the English language are included.

Introduction

A systematic analysis of the global burden of disease 2019 study showed the highest health and economic burden of HIV/AIDS in sub-Saharan Africa (attributable to higher behavioural risks, drug use, partner violence and unsafe sex).¹ A scoping review conducted in Latin America involving 196 articles showed a 2.8%–15.2% pooled prevalence of HIV among people who used substances.² A United Nations and Drug and Crime report in 2023 showed a rising trend of injecting drug use (IDU) (ie, 13.2 million in 2021 and 11.2 million in 2020). The IDUs face a 35 times higher risk of acquiring HIV than the general population (ie, about one in eight IDUs is living with HIV/AIDS).³ A study conducted in Canada showed that women with HIV/AIDS are at a greater risk of substance use disorders. For example, when HIV-positive women compared with their counterparts tobacco use (41% vs 14%), marijuana use (15% vs 7%), cocaine and crack use (17% vs 0.1%), amphetamine use (3% vs 0.1%), heroin (11% vs 0.1%) and lower alcohol and binge drinking than their counterparts in the general population.⁴

Another epidemiological trend analysis in the USA showed a dramatically increasing trend of substance use among women of childbearing age, and substance use during pregnancy is becoming a public health issue.⁵ This is fueled by the presence of HIV/AIDS and associated health, social and economic complications. A study conducted to evaluate the effect of illness burden and pain on illicit drug use among people living with HIV/AIDS including 2267 participants showed HIV-associated/AIDS-associated pain as a major predictor of substance use.⁶ A demographic survey database analysis to estimate tobacco use among people living with HIV from 28 low-income and middle-income countries showed an increased risk of tobacco use among HIV-positive participants⁷, that is, 24.4% vs 1.3%, 3.4% vs 2.1%, and 27.1% vs 3.6% prevalence among men versus women for tobacco smoking, smokeless tobacco use and any tobacco use.⁷ A cohort that evaluated 480 HIV-infected pregnant women revealed 29% self-reported prevalence of substance use. The commonly used substances were tobacco (18%), alcohol 10%, marijuana 7.2% and <4%. The substance use was more common in the first trimester (25%) followed by second (17%) and third (15%) (p<0.01). This could lead to an increased risk of teratogenic effect since the first trimester is the period of organogenesis.⁸

Different studies showed the effect of HIV/AIDS and its treatment on placental, fetal and maternal outcomes.⁹ Both HIV/AIDS and its treatment affect the placental and fetal growth and development.¹⁰ Studies indicated that maternal vascular malformation, chorioamnionitis and decreased placental weight are associated with HIV/AIDS.¹¹ Effects of HIV infection on maternal and neonatal health among 1183 uninfected and 561 HIV-positive pregnant women in southern Mozambique showed that HIV-infected women were more likely to have anaemia, increased incidence of hospital admissions, double risk of stillbirths and fetal anaemia.¹² A prospective cohort study conducted in South Africa to evaluate the impact of HIV and antiretroviral therapy (ART) treatment during pregnancy on fetal growth involving 122 cases and 250 controls showed lower placental weight and shorter umbilical cord length among pregnant women with HIV.¹³ The effect was specific to the newborn sex (short cord length, lower abdominal circumference and increased femur length in males and lower placental weight, birth weight and head circumference in female newborns).¹³ A similar study among 122 Brazilian HIV-infected pregnant women and their newborns showed higher small-for-gestational-age (SGA) placental area, SGA placental weight, SGA fetal weight, preterm birth (PTB), perinatal death and HIV vertical transmission among HIV-infected pregnant women than reference values.¹⁴

A cross-sectional study conducted to evaluate the impact of maternal HIV infection on pregnancy outcomes among 4397 mothers in China showed that maternal HIV infection, rural residence and pregnancy history were associated with adverse pregnancy outcomes (low birth weight, preterm delivery and low Apgar score).¹⁵ Another study showed an association of HIV/AIDS with acute chorioamnionitis, low placental weight and maternal vascular malperfusion, with a tendency towards lower rates of chronic villitis.¹⁶ Exploring the impact of HIV infection and antiretroviral therapy on placenta morphology among 40 Canadian women living with HIV on ART and 54 counterparts showed lower placenta weight and smaller placenta area in the HIV⁺ group, SGA births, lower cord marginality, abnormal placenta cord insertion and non-circular placentas (with protease inhibitor exposure).¹⁷ Pregnancy outcomes among HIV-infected women from Africa showed 52% PTBs, 4% stillbirths, 20% spontaneous abortions, 11% elective terminations and 1% ectopic pregnancies. Women conceiving on ART had high rates of PTB and other adverse pregnancy outcomes.¹⁸ A systematic review of the literature and meta-analysis on the association between maternal HIV infection and perinatal outcomes showed an association between HIV infection and spontaneous abortion, stillbirth, fetal abnormality, perinatal mortality, neonatal mortality, infant mortality, intrauterine growth retardation, low birth weight and preterm delivery.¹⁹

In addition to the effect of HIV/AIDS on placental, fetal and maternal outcomes, the disease associated with an increase in substance use disorders is also contributing to adverse placental, fetal and maternal outcomes. The developmental effects of HIV and alcohol among 667 mother-infant dyads in South African communities showed an association between alcohol use and low birth weight, shorter infant length, smaller head length, smaller head circumference and early gestational age.²⁰ Another study also indicated the presence of unintended pregnancy or miscarriage and high HIV-positive women.²¹ Substance use disorders and HIV have a bidirectional relationship (ie, the presence of one can pull the other). People who use illicit drugs are at increased risk of contracting HIV/AIDS,²² and people living with HIV/AIDS are at increased risk of using substances due to disease-related complications like depression and HIV-associated dementia.^{23 24} The effect of HIV/AIDS on pregnant women as well as fetal growth is well studied.²⁵ The problem of substance use disorders and HIV/AIDS in pregnancy is a major public health dilemma requiring better understanding and care models to improve fetal, maternal and neonatal outcomes.²⁶ There is a lack of research on health services and placental, fetal, maternal and neonatal outcomes of pregnant women with HIV/AIDS and substance use disorders globally. Therefore, this systematic review and meta-analysis will be conducted to fill this gap.

Methods

Search strategy

We will search articles written in the English language since 1985 until 30 January 2024, from PubMed/Medline, Cochrane Library, Embase, Scopus, Web of Sciences, SUMsearch2, Turning Research Into Practice database and Google Scholar. A systematic search strategy involving AND/OR Boolean Operators will retrieve information from these databases and search engines. The search keywords will be HIV/AIDS, Substance use disorders, Placenta and Fetal growth, fetal development, pregnant women, fetal outcomes, and maternal outcomes. The search strategy will involve (((((((HIV/AIDS) AND (Substance use disorders)) AND (Pregnancy outcomes)) OR (Fetal outcomes)) OR (Placenta growth or development)) OR (Fetal outcomes)) OR (Neonatal outcomes)) OR (Maternal outcomes) (available in online supplemental file). We registered the systematic review title in Prospero with registration number CRD42023478360 at https://www.crd.york.ac.uk/PROSPERO.

PICO Criteria

Problem: pregnancy among women with HIV/AIDS and substance use disorder comorbidity

Intervention: HIV/AIDS treatment and prevention and substance use disorder prevention

Comparison: pregnancy without HIV/AIDS and substance use disorders

Outcome: placental, fetal, maternal and neonatal outcomes

Study types

Clinical trials, cohort studies and case-control studies written in the English language, evaluating the effect of HIV/AIDS and substance use disorder on placental, fetal and maternal outcomes and fulfilling inclusion criteria will be included, whereas cross-sectional studies, case reports, conference reports, books, guidelines, letters to editors and articles written in other languages will be excluded.

Context

Substance use disorders and HIV have a bidirectional relationship (ie, the presence of one can pull the other). People who use illicit drugs are at increased risk of contracting HIV/AIDS, and people living with HIV/AIDS are at increased risk of using substances due to disease-related complications like depression and HIV-associated dementia. The effect of HIV/AIDS on pregnant women as well as fetal growth is well studied. However, there is no adequate evidence of HIV/AIDS and substance use disorder comorbidity-related effects on placental, fetal and maternal outcomes globally.

Data extraction, selection and coding

Study selection and identification of potentially relevant articles will be made based on the prespecified search and retrieval strategy listed above. Two investigators will independently review each study’s abstract against prespecified inclusion and exclusion criteria. After retrieving articles by the literature search, potentially relevant articles will be abstracted by applying the inclusion-exclusion criteria listed above to select relevant articles. The article selection process will be drawn in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow chart. Two investigators will independently review each study’s abstracted data on the effect of HIV/AIDS and substance use disorder on placental, fetal and maternal outcomes. In case of disagreement on the quality of the article, two authors discussed in the presence of the third and fourth authors.

Risk of bias assessment

A risk of bias assessment will be done based on validated tools for each included study. A revised Cochrane risk-of-bias tool will be used for randomised trials,²⁷ and the Risk Of Bias In Non-randomised Studies of Interventions will be used for non-randomised clinical trials.²⁸ Newcastle-Ottawa Scale tool will be used for assessing the risk of bias in cohort and case-control studies.²⁹ In addition to this, the assessment of meta-bias like publication bias, missing data and selective reporting will be handled based on Cochrane Library a framework for assessing the risk of bias due to missing results^{30 31} and extensive searching of available literature with our review team with expertise in medical literature searching and retrieval process will be considered to minimise meta-bias.

Definitions of main outcomes

This review has placental, fetal and maternal outcomes. The outcomes are further classified as primary and secondary or additional outcomes. The primary outcomes include placental and fetal growth and development, abortion, stillbirth and HIV transmission and composite maternal outcomes (maternal mortality and viral load). Secondary/additional outcomes include fetal outcomes: fetal abnormality, perinatal mortality, neonatal mortality, infant mortality, intrauterine growth retardation, preterm delivery, low birth weight, metabolic disorders, cardiovascular diseases and mental disorders. Placental growth factor (PlGF) is important for angiogenesis and placental development during pregnancy. Placental expression of PlGF dominates from the second trimester when the uteroplacental circulation is advancing, with myometrial spiral arteries remodelling in a ‘second wave’ of invasion beginning at 16–18 weeks of gestation (23 pg/mL at term to 141 pg/mL at around 30 weeks of gestation). The reduced level of PlGF factor is associated with low birth weight and pre-eclampsia.³² Fetal growth and development are usually monitored by SGA, fetal growth restriction (FGR) or individualised growth monitoring models. To enhance the accuracy of defining FGR, antenatal testing modalities for fetal health (fetal heart rate analysis, amniotic fluid volume assessment and biophysical profile) and Doppler fetal and maternal vessel evaluation of placental function will be used.³³ SGA is a birth weight of <10th percentile for gestational age by considering all growth curves. Since SGA cannot be used as a marker for FGR, for this review, fetal growth and development abnormality is defined if the infants have SGA secondary to FGR.³⁴ Abortion is a pregnancy termination before 22 weeks of gestation or a fetus born weighing <500 g,³⁵ while stillbirth is the death of a fetus that has reached a birth weight of 500 g or, if birth weight is unavailable, gestational age of 22 weeks or crown-to-heel length of 25 cm.³⁶ Mother-to-child HIV transmission is defined as the transmission of HIV from mother to fetus during pregnancy, delivery or breastfeeding.³⁷

For composite maternal outcomes (maternal mortality, low birth weight, antiretroviral drug regimen, viral load, metabolic disorder and cardiovascular diseases), the following definitions will be used. Maternal mortality is defined as the death of a woman while pregnant or within 42 days of termination of pregnancy irrespective of the duration and the site of the pregnancy, from any cause related to or aggravated by the pregnancy or its management but not from accidental or incidental causes.^{38 39} Viral load is a measure of treatment success (persistently detectable level exceeding 1000 copies/mL in two consecutive measurements within 3-month intervals with adherence support after 6 months of treatment indicates virologic failure).⁴⁰ The viral load is also a predictor of transmissibility of the virus (ie, undetectable is equal to untransmissible).⁴¹ We will consider the last term viral load since the presence of detectable viral load at term indicates a need of caesarean section delivery.⁴²

Cardiovascular diseases are a group of disorders of the heart and blood vessels. They include coronary heart disease, cerebrovascular disease, peripheral arterial disease, rheumatic heart disease, congenital heart disease and deep vein thrombosis and pulmonary embolism.⁴³ Metabolic syndrome is a cluster of interconnected factors that directly increase the risk of coronary heart disease, other forms of cardiovascular atherosclerotic diseases and diabetes mellitus type 2. It is defined as any three of the following: elevated waist circumference (according to population and country-specific definitions), triglycerides 150 mg/dL or greater, HDL-cholesterol <40 mg/dL in men and <50 mg/dL in women, blood pressure 130/85 mm Hg or greater and fasting glucose 100 mg/dL or greater.⁴⁴

Substance use disorders are defined based on the Diagnostic and Statistical Manual, Fifth Edition (DSM-V), criteria as follows: three or more dependence criteria (withdrawal, tolerance, used larger amounts/longer, repeated attempt to quit/control use, much time spent on using, physical/psychological problems related to the use and activities given up to use) within 12 months.⁴⁵ For this review, DSM-V criteria will be used for the diagnosis of substance use disorders.

Effect measurement

The effect is measured by using a two-step process. Initially, individual study effects will be measured and reported along with their OR, relative risk and risk difference at a 95% CI. Second is an overall treatment effect as the weighted average of individual treatment effects. Greater weights will be given to the results of the studies that will provide more information as they are closer to the estimated true effect. They are inverse of the square of standard error (variance) and related to sample size. Forest plots will be used to report the estimates of overall studies included and the degree of heterogeneity among studies.⁴⁶

Data synthesis

Qualitative and quantitative analysis methods will be used to report the effect of HIV/AIDS and substance use disorders on placental, fetal and maternal composite outcomes. Descriptive statistics like pooled prevalence mean and SD will be used for qualitative analysis. However, quantitative analysis outcomes will be done by using Comprehensive Meta-Analysis Software for studies that are combinable. The individual study effects and the weighted mean differences at 95% CI will be reported in a forest plot. Heterogeneity across studies will be assessed with Higgins’s I² test.⁴⁷ I²>75% will be considered indicative of high statistical heterogeneity, >50% of moderate and <25% of low statistical heterogeneity across studies.

Subgroup analysis

The presence of multiple morbidities like diabetes, chronic kidney disease and maternal haemoglobin level could affect placental and fetal growth and development, abortion, stillbirth, HIV transmission and composite maternal outcomes.^{36 48 49} Therefore, subgroup analysis or meta-regression (if more or equal to 10 studies) will be performed for crude and adjusted estimates of diabetes, chronic kidney disease and maternal haemoglobin level could affect placental growth, fetal growth and development, abortion, stillbirth, HIV transmission and composite maternal outcomes to see their contribution to effect sizes.

Confidence in pooled evidence

This study will assess the available evidence on the effect of HIV/AIDS and substance use disorders on placental, fetal, maternal and neonatal outcomes by involving clinical trials and observational studies. As per our protocol, we are selecting robust study designs with clear causal inferences, that is, randomised controlled trials, prospective cohort studies, case-control studies with baseline HIV viral load and substance use disorder assessments which will enhance pooled study quality. In addition, the risk of bias assessment based on standard tools and strategies that we will use to minimise bias can further improve the quality of pooled data. The inclusion of articles published in English language could be considered limitation of this review.

Ethics statements

Patient consent for publication

Not applicable.