ARTMOMSBABES: Cardiometabolic Health of Children Exposed to Anti-retroviral Therapy (ART) in Utero

Sponsor

Walter Sisulu University (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT04763668

Collaborator

Nelson Mandela Academic Hospital (Other), Umtata General Hospital (Other), Medical University of Graz (Other)

320

Enrollment

Location

31.4

Anticipated Duration (Months)

10.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The Human Immunodeficiency Virus (HIV) has been recently linked to increased risk for cardiovascular diseases (CVDs). The prevalence of cardiovascular diseases and its risk factor, hypertension, are very high in African communities especially in the working age group which also happens to have the bulk of young female adults in the reproductive age. Hypertension in African children is becoming a real cause for concern though its etiology remains elusive. Thanks to antiretroviral therapy (ART) use, many more infected persons live long enough to reproduce, consequently, an increasing number of children are being born to mothers who are infected with HIV. Could it be that in utero exposure of these children to HIV/ART contribute in programming them for increased risk for cardiovascular diseases thus making them more vulnerable to hypertension in childhood and adulthood? This study is aimed at exploring the possible association of in utero exposure to the HIV/ART environment and an increased risk for cardiovascular disease.

Condition or Disease	Intervention/Treatment	Phase
In Utero Drug Exposure	Other: Pregnant HIV positive women on ARTs Other: Babies born to HIV positive mothers on ARTs

Detailed Description

Sample size calculation The number of participants required to show statistical significance is based on previously published studies in which vascular function was assessed in HIV patients (Agu et al., 2019). An error probability (α) of 0.05, and power (1- β) of 0.80 and an average effect size (d) of 0.5 were used to calculate the sample size (n= 64 persons). Assuming a 25% drop out rate, we will use N = (64 + (64*25)/100) = 80 mothers/group to ensure that we will have enough sample size/group to show statistical significance. Total number of participating mothers will therefore be 160 (80 cases and 80 controls) and their offspring - 160.
Ethical approval Ethical consent and permission to carry out the research project will be obtained from the Faculty of Health Sciences Research and Ethics Committee (HRSEC) at Walter Sisulu University (WSU). The purpose of the study will be explained to women attending the antenatal clinic in the Umtata General and Nelson Mandela Academic Hospitals, Mthatha, Eastern Cape Province. Pregnant women who will be willing to participate will be required to sign informed consent forms to participate in the study and to allow their children to participate in the study from birth.
Study design A prospective case control study design will be used in this study.
Selection criteria Sub-Saharan women with singleton uncomplicated 11-14 week old pregnancies, be HIV positive for the case group and HIV negative for the control group. Pregnant women with type 2 diabetes, gestational diabetes, renal and cardiovascular diseases or any critical health condition will be excluded from the study
Experimental Plan

Work Package 1 (Pregnant women):

Three antenatal visits will be recorded for this study - These visits will be done during the first, second and third trimesters of gestation.

The following information and parameters will be assessed during each antenatal visit:

Baseline information: Maternal demographic, obstetric and family history of cardiovascular diseases during the first visit using a questionnaire - once off at the start of the study.
Anthropometric measurements: Height and weight will be determined as per recommendations of the NHANES, 2009 recommendations. BMI will be calculated using the formula weight/(height (m) x height (m)).
Blood pressure measurements: Office blood pressure will be measured as described by Muntner et al., (2019) in triplicates at three minutes intervals after 10 minutes of rest in the seated position. This will be followed by 24 h ambulatory blood pressure measurement for determination of day time/night time blood pressure and dipping phenotype.
Placental morphometry, architecture and vascularization: Uterine arteries, umbilical artery and middle cerebral artery and uterine artery mean pulsating index will be determined by ultrasound. Foetal cerebroplacental ratio will be calculated when possible.
Endothelial function tests: Carotid intima media thickness, pulse wave velocity and flow mediated slowing and retinal artery assessment will be measured using ultrasonography and Vicorder (Ellins, 2017). Retinal microvasculature will be studied to determine endothelial function.
Markers of endothelial function: Endocan, asymmetric dimethyl arginine (ADMA) and nitric oxide (NO) will be assayed using ELISA kits as per manufacturers' instructions.
Markers of oxidative stress: Lipid peroxidation, total antioxidant capacity and 8-hydoxyl-2-deoxyguanine (8-OHdG) will be determined using ELISA kits as per manufacturer's protocols.
Lipid profile indices: Total cholesterol, triglyceride, LDL cholesterol and HDL cholesterol, and oxidized LDL-cholesterol will be measured as per manufacturer's protocol.
Insulin Resistance: Fasting glucose, glycated haemoglobin and insulin concentrations will be determined using kits as per manufacturer's methods. The HOMA-IR formula will be used to calculate insulin resistance from fast glucose and insulin.
Renal function indices: glomerular filtration rate (GFR), creatinine and albumin will be determined and albumin to creatinine ratio computed.

Work Package 2 (Neonates):

During delivery, cord blood will be collected for assessment of markers of oxidative stress and endothelial function and epigenetic markers in the foetus. The following data will be collected:

Anthropometric measurements: The weight, length, cranial circumference of the child will be measured.
Blood pressure measurements: Casual blood pressure will be measured by oscillometry using disposable arm-size appropriate cuffs. Blood pressure will be measure in triplicates with five minutes intervals at least one hour after baby's meal and when baby is sleeping (Samantha et al, 2015).
Markers of endothelial function: Endocan, asymmetric dimethyl arginine (ADMA) and nitric oxide (NO) will be assayed using ELISA kits as per manufacturers' instructions.
Markers of oxidative stress: Lipid peroxidation, total antioxidant capacity and 8-hydoxyl-2-deoxyguanine (8-OHdG) will be determined using ELISA kits as per manufacturer's protocols.
Lipid profile indices: Total cholesterol, triglyceride, LDL cholesterol and HDL cholesterol, and oxidized LDL-cholesterol will be measured as per manufacturers protocol.
Insulin Resistance: cord blood glucose and insulin concentrations will be determined as per manufacturer's methods. The HOMA-IR formula will be used to calculate insulin resistance.
Renal function indices: glomerular filtration rate (GFR), creatinine and albumin will be determined. The Albumin to creatinine ratio will also be determined.
Epigenetic markers: Urine concentrations of 5-methyl-2-deoxycytidine and trimethyl histone H3K9 using Elisa kit as per manufacturer's methods.

Work Package 3 (Mothers at 3 months post-natal follow-up)

Mothers will followed up three months after delivery. During this visit no blood nor will urine samples be collected from the mothers. Urine samples will be collected from babies for measurement of CVD risk makers. The following data will be collected:

Anthropometric measurements: Height and weight will be determined as per recommendations of the NHANES, 2009 recommendations. BMI will be calculated using the formula weight/(height (m) x height (m)) for both mother and baby.
Blood pressure measurements: Office blood pressure will be measured as described by Puntner et al., (2019) in triplicates at three minutes intervals after 10 minutes of rest in the seated position. This will be followed by 24 h ambulatory blood pressure measurement for determination of day time/night time blood pressure and dipping phenotype - mother
Blood pressure will be measured in the baby in the supine position.
Endothelial function tests: Carotid intima media thickness, pulse wave velocity and flow mediated slowing and retinal artery assessment will be measured using ultrasonography and Vicorder (Ellins, 2017). Retinal microvasculature will be studied to determine endothelial function in the mother.
Endothelial function tests: pulse wave velocity and flow mediated slowing using the Vicorder in the baby (Ng et al, 2018).

Work Package 4 (Child):

Data will be collected from children at three, twelve and twenty four months after birth as follows:

Anthropometric measurements: The weight, length, cranial circumference of the child will be measured.
Blood pressure measurements: Casual blood pressure will be measured by oscillometry using disposable arm-size appropriate cuffs. Blood pressure will be measure in triplicates with five minutes intervals at least one hour after baby's meal and when baby is sleeping (Samantha et al, 2015).
Endothelial function tests: pulse wave velocity and flow mediated slowing using the Vicorder (Ng et al, 2018).
Markers of endothelial function: Urine samples will be collected for Endocan, asymmetric dimethyl arginine (ADMA) and nitric oxide (NO) assays using ELISA kits as per manufacturers' instructions.
Markers of oxidative stress: Lipid peroxidation, total antioxidant capacity and 8-hydoxyl-2-deoxyguanine (8-OHdG) will be determined in urine samples using ELISA kits as per manufacturer's protocols.
Renal function indices: Urine creatinine and albumin will be determined. The Albumin to creatinine ratio will also be determined.
Epigenetic markers: Urine concentrations of 5-methyl-2-deoxycytidine and trimethyl Histone H3K9 using elisa kit as per manufacturer's methods.
Endothelial function tests: pulse wave velocity and flow mediated slowing using the Vicorder (Ng et al, 2018).

Study Design

Study Type:

Observational [Patient Registry]

Anticipated Enrollment :

320 participants

Observational Model:

Case-Control

Time Perspective:

Prospective

Official Title:

Assessment of the Impact of HIV Infection an Anti-retroviral Therapy (ART) on the Cardiometabolic Health of Pregnant Mothers and Their Offspring

Anticipated Study Start Date :

May 20, 2021

Anticipated Primary Completion Date :

Dec 31, 2021

Anticipated Study Completion Date :

Dec 31, 2023

Arms and Interventions

Arm	Intervention/Treatment
Pregnant HIV positive women on ART Sub-Saharan women with singleton uncomplicated 11-14 week old pregnancies at recruitment, HIV positive and have been on ARTs for at least four months before pregnancy. Participants must not have type 2 diabetes, gestational diabetes, renal / cardiovascular diseases or any critical health condition.	Other: Pregnant HIV positive women on ARTs Cardiovascular disease risk in pregnant HIV positive women on ARTs
Pregnant HIV negative women Sub-Saharan women with singleton uncomplicated 11-14 week old pregnancies at recruitment, HIV negative. Participants must not have type 2 diabetes, gestational diabetes, renal / cardiovascular diseases or any critical health condition.	Other: Pregnant HIV positive women on ARTs Cardiovascular disease risk in pregnant HIV positive women on ARTs
Babies born to HIV positive mothers on ARTs All babies born to pregnant HIV positive women on ARTs who were in the first arm of the study	Other: Babies born to HIV positive mothers on ARTs cardiovascular disease risk in the offspring of HIV positive mothers on ARTs
Babies born to HIV negative mothers All babies born to pregnant HIV negative women who were in the first arm of the study.	Other: Babies born to HIV positive mothers on ARTs cardiovascular disease risk in the offspring of HIV positive mothers on ARTs

Outcome Measures

Primary Outcome Measures

Assessment of changes in cardiovascular risk profile during pregnancy in pregnant HIV positive women on ARTs [March 2021 to March 2022]
Cardiovascular risk will be assessed in pregnant
Assessment of of CVD risk in offspring of HIV positive mothers on ARTs [March 2021 to March 2022]
Cardiovascular risk will be assessed in the offspring of HIV positive mothers on ART at three time point: at birth, three, twelve and twenty months after birth.

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Cases: sub-Saharan women with singleton uncomplicated 11-14 week old pregnancies, be HIV positive and have been on ARTs for at least four months before pregnancy.

Controls: 11-14 week old pregnant HIV negative women.