Contaminación del aire doméstico y salud: un ensayo de intervención de GLP en varios países (HAPIN)

Participants randomized to the experimental arm will receive a liquefied petroleum gas (LPG) cookstove and 18-month supply of LPG.

The intervention consists of a high-quality locally available liquefied petroleum gas (LPG) stove having at least two burners, a continuous supply of LPG fuel for 18 months, and the promotion of stove use on an exclusive basis for cooking. The intervention will be provided free of charge to all intervention households upon enrollment. On a weekly basis, study staff will examine stove condition, perform any necessary repairs, and measure and record weight of LPG tanks in order to anticipate need for refills.

Participants in the control group will not receive a liquefied petroleum gas (LPG) stove and will continue using traditional cooking methods (open fire or traditional stoves), or the cooking method of their choice. Control households will receive compensation based on a uniform set of trial-wide principles, customized to each site based on formative research.

Birth weight is assessed by a trained nurse or health worker within 24 hours of birth. Infants are weighed naked or in a pre-weighed blanket. Weight is measured to the nearest 10 g using a digital electronic scale, if performed by the study field staff; otherwise, hospital medical records are used.

The incidence of severe pneumonia among offspring during the first year of life is assessed as the number of offspring participants presenting at HAPIN health facilities with severe pneumonia. For this study pneumonia criteria are adapted from the WHO classification of childhood pneumonia (2014) and there are 3 algorithms for case criteria: 1) the presence of cough and/or difficult breathing and at least 1 general danger sign plus evidence of pneumonia on lung imaging (i.e., lung ultrasound or chest x-ray), or 2) the presence of cough and/or difficult breathing and hypoxemia (measured either via pulse oximetry (SpO2), or observing a child requiring advanced respiratory support (i.e., intubation and mechanical ventilation, non-invasive ventilation with continuous or bi-level positive airway pressure support, or high-flow nasal cannula oxygen), or 3) children who die prior to evaluation but their death is attributed to pneumonia by verbal autopsy.

The primary outcome measured is stunting at one year of age, defined as a length-for-age z-score (LAZ) that is 2 standard deviations below the median of the growth standard. Infant length is assessed at birth and quarterly thereafter, until the child is 12 months old. Z-scores are calculated using the 2006 World Health Organization (WHO) Multi-Growth Reference Standard (MGRS).

Systolic blood pressure is assessed in the older adult women in the intervention and control arms using automatic sphygmomanometers (Omron HEM-907XL; Osaka, Japan). The study team used the procedures adapted from previously validated methods and cardiovascular outcome studies, following recommendations for the American Heart Association and the European Society of Hypertension. A systolic blood pressure of less than 120 is considered normal for adults. Systolic blood pressure collected at 3, 6, 9, 12, and 18 months post-randomization time points are averaged together for a single post-randomization value.

Linear growth of children is assessed in centimeters of height.

The CREDI is a population-level measure of early childhood development (ECD) for children from 0-3 years of age assessing 4 domains of child development: 1) motor (fine and gross motor), 2) language (expressive and receptive language), 3) cognitive (executive function, problem solving and reasoning, and pre-academic knowledge), and 4) social-emotional (emotional and behavioral self-regulation, emotional knowledge, and social competence). The CREDI long form consists of up to 108 items and the number of questions answered depends on the age of the child. Responses of "yes" are coded as 1 and "no" is coded as 0; certain items are reverse coded. Total raw scores increase by age (with developmental progression), and higher scores indicate increased development. Both domain-specific and overall z-scores are calculated (mean = 0, standard deviation = 1). Z-scores of 0 mean the child has a similar developmental status to the average child. Scores above 0 are higher than the sample reference.

The MDAT measures gross motor (39 items), fine motor (42 items), language/cognition (40 items) and social skills (36 items). Originally developed and validated in rural Malawi, it has now been used in over 25 countries as both a clinical and research tool. The MDAT is a continuous test with start and stop rules. Most items are administered directly to the child and items that are not easily observed (e.g., child speaks in full sentences; child understands sharing with others; child can dress self) are administered by parent report. Children receive either a pass or fail for each item, and summed pass scores can produce a composite score as well as domain-specific scores. Total scores range from 0 to 157 where higher scores indicate greater neurodevelopment. Both domain-specific and overall z-scores are calculated (mean = 0, standard deviation = 1). Z-scores of 0 mean the child has a similar developmental status to the average child. Scores above 0 are higher than the sample reference.

Blood pressure is assessed in the pregnant women in the intervention and control arms using automatic sphygmomanometers (OMRON HEM-907XL; Osaka, Japan). The study team will use the procedures adapted from previously validated methods and cardiovascular outcome studies, following recommendations for the American Heart Association and the European Society of Hypertension.

Blood pressure is assessed in the pregnant women in the intervention and control arms using automatic sphygmomanometers (OMRON HEM-907XL; Osaka, Japan). The study team will use the procedures adapted from previously validated methods and cardiovascular outcome studies, following recommendations for the American Heart Association and the European Society of Hypertension. Diastolic blood pressure levels of less than 80 are considered normal.

Diastolic blood pressure is assessed in the older adult women in the intervention and control arms using automatic sphygmomanometers (Omron HEM-907XL; Osaka, Japan). The study team uses the procedures adapted from previously validated methods and cardiovascular outcome studies, following recommendations for the American Heart Association and the European Society of Hypertension. Diastolic blood pressure levels of less than 80 are considered normal. Diastolic blood pressure collected at 3, 6, 9, 12, and 18 months post-randomization time points are averaged together for a single post-randomization value.

Mean arterial pressure is assessed in the older adult women in the intervention and control arms using automatic sphygmomanometers (Omron HEM-907XL; Osaka, Japan). Mean arterial pressure is calculated as DBP+(SBP-DBP)/3, where SBP=systolic blood pressure and DBP=diastolic blood pressure. Arterial blood pressure collected at 3, 6, 9, 12, and 18 months post-randomization time points are averaged together for a single post-randomization value.

Pulse pressure is assessed in the older adult women in the intervention and control arms using automatic sphygmomanometers (Omron HEM-907XL; Osaka, Japan). pressure. Pulse pressure is the difference between systolic blood pressure (SBP) and diastolic blood pressure (DBP). A normal pulse pressure is 40 mmHg and pulse pressure tends to increase above age 50 as arteries stiffen. Pulse pressure collected at 3, 6, 9, 12, and 18 months post-randomization time points are averaged together for a single post-randomization value.

Pregnant women have ultrasounds during gestation weeks 24-28 and gestation weeks 32-36 to measure fetal growth. Specifically, the researchers evaluated head circumference (HC), abdominal circumference (AC), femur length (FL) and estimated fetal weight (EFW) during gestation. The researchers calculated z-scores for head circumference, abdominal circumference, femur length and estimated fetal weight at the gestational age using World Health Organization (WHO) INTERGROWTH 21st standards. Z-scores have a mean of 0 and a standard deviation of 1. Z-scores over 0 indicate above average measurements, while a negative z-score indicates measurements are lower than average.

Gestational age at birth is measured in weeks, as a continuous outcome, among all live births.

Preterm birth is defined as delivery of a living infant prior to 37 completed weeks of gestation.

Cumulative incidence of WHO non-severe pneumonia (2014 definition and 2013 definition) during the first year of life. Cases of pneumonia are recorded whenever children present to HAPIN health facilities with respiratory symptoms.

Cumulative incidence of WHO non-severe pneumonia (2014 definition and 2013 definition) during the first year of life. Cases of pneumonia are recorded whenever children present to HAPIN health facilities with respiratory symptoms.

Cumulative incidence of hospitalizations for a respiratory illness during the first year of life.

Cumulative incidence of WHO non-severe pneumonia during the first year of life, as defined in the second edition of the "Pocket book of hospital care for children" (2013). Cases of pneumonia are recorded whenever children present to HAPIN health facilities with respiratory symptoms.

Cumulative incidence of WHO severe pneumonia during the first year of life, as defined in the second edition of the "Pocket book of hospital care for children" (2013). Cases of pneumonia are recorded whenever children present to HAPIN health facilities with respiratory symptoms.

Cumulative incidence of hypoxemic pneumonia during the first year of life. Cases of pneumonia are recorded whenever children present to HAPIN health facilities with respiratory symptoms.

Cumulative incidence of lung ultrasound or chest radiograph pneumonia during the first year of life. Cases of pneumonia are recorded whenever children present to HAPIN health facilities with respiratory symptoms.

Brachial artery reactivity testing (BART) measures endothelial function via flow-mediated dilation (FMD) in response to reactive hyperemia following release of arm blood-flow occlusion. Using ultrasound, the brachial artery is first imaged at rest to establish the baseline (pre-occlusion) diameter. A blood pressure cuff is then inflated to induce distal arm ischemia for 5 minutes. Upon cuff release, the resulting surge in blood flow (reactive hyperemia) stimulates the artery to dilate; the artery is imaged repeatedly during this period and the maximum post-occlusion diameter is identified. The outcome, FMD, is expressed as the maximum percent change in diameter relative to baseline: FMD% = (maximum post-occlusion diameter - baseline diameter) ÷ baseline diameter × 100. Higher values indicate greater dilation and better endothelial function; lower values indicate worse endothelial function.

The carotid intima-media thickness test (CIMT) is used to determine the extent of carotid atherosclerotic vascular disease. The test measures the thickness of the inner two layers (intima and media) of the carotid artery and can detect plaque build-up prior to physical symptoms being experienced. The carotid ultrasound will be performed with a portable ultrasound by trained sonographers. CIMT is a well-established imaging biomarker of atherosclerosis, where higher values indicate greater carotid arterial wall thickness and have been associated with higher cardiovascular disease risk.

Adult respiratory health and well-being is assessed with the St. George Respiratory Questionnaire (SGRQ). The SGRQ measures impaired health and perceived well-being among individuals with chronic airway disease. The SGRQ has sections assessing symptoms, activities that cause breathlessness or are limited because of breathlessness, and the impacts of respiratory problems on employment, sense of control of health, panic, stigmatization, medication use, side effects of therapies, expectations for health and disturbances of daily life. The questionnaire includes multiple choice, true/false and open-ended questions.

The Short Form 36 survey (SF-36) is a standardized, preference-based 36 item questionnaire evaluating quality of life. The survey has 8 sections (vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, and mental health). Possible scores range from 0 (lowest quality of life) to 100 (highest quality of life).

Linear growth of children is assessed in centimeters at birth and quarterly thereafter, until the child is 12 months old. Infant recumbent length was converted to a length-for-age z-score (LAZ) using the WHO Child Growth Standards. Z-scores have a mean of 0 and a standard deviation of 1. Z-scores above 0 indicate above average length-for-age, while a negative z-score indicates lower than average length-for-age.

The Caregiver Reported Early Childhood Development Instrument (CREDI) is a population-level measure of early childhood development (ECD) for children from 0-3 years of age. The CREDI assesses 4 domains of child development: 1) motor (fine and gross motor), 2) language (expressive and receptive language), 3) cognitive (executive function, problem solving and reasoning, and pre-academic knowledge), and 4) socio-emotional (emotional and behavioral self-regulation, emotional knowledge, and social competence). The CREDI long form consists of up to 108 items and the number of questions answered depends on the age of the child. Responses of "yes" are coded as 1 while responses of "no" are coded as 0; certain items are reverse coded. Norm-referenced, age standardized z-scores for overall and domain-specific CREDI scores were calculated. Z-scores have a mean of 0 and standard deviation of 1; values below 0 indicate ECD scores lower than the global CREDI norm-referenced population.

Height is measured in meters. Height in new mothers in Rwanda is measured when the child is 24 months old. For new mothers in Guatemala height is measured when the child is 24 and 36 months old. In older adult women, height is measured when the child is 24-months old.

Weight is measured in kilograms (kg). Weight in new mothers in Rwanda is measured when the child is 24 months old. For new mothers in Guatemala weight is measured when the child is 24 and 36 months old. In older adult women, weight is measured when the child is 24 months old. Weight is measured in children at 24, 36, 48 and 60 months of age.

BMI is calculated as weight in kilograms divided by height in meters (m) squared (kg/m^2). BMI in new mothers in Rwanda is calculated from height and weight measurements obtained when the child is 24 months old. For new mothers in Guatemala BMI is calculated from height and weight measurements obtained when the child is 24 and 36 months old. In older adult women, BMI is calculated from height and weight measurements obtained when the child is 24 months old.

Blood pressure is assessed in the children using automatic sphygmomanometers (OMRON HEM-907XL; Osaka, Japan). The study team uses the procedures adapted from previously validated methods and cardiovascular outcome studies, following recommendations for the American Heart Association and the European Society of Hypertension.

Blood pressure is assessed in the new mothers in the intervention and control arms using automatic sphygmomanometers (OMRON HEM-907XL; Osaka, Japan). The study team will use the procedures adapted from previously validated methods and cardiovascular outcome studies, following recommendations for the American Heart Association and the European Society of Hypertension.

Blood pressure is assessed in the new mothers in the intervention and control arms using automatic sphygmomanometers (OMRON HEM-907XL; Osaka, Japan). The study team will use the procedures adapted from previously validated methods and cardiovascular outcome studies, following recommendations for the American Heart Association and the European Society of Hypertension.

Personal monitoring equipment is used to assess exposure to fine particulate matter (PM2.5) over a 24-hour period in intervention and control participants (pregnant women, older adult women, and children). Exposure for pregnant women is measured at baseline, 24-28 weeks gestation, 32-36 weeks gestation, and in Guatemala and India, when the child is 24 months old. Exposure for the child is measured at 3, 6, 12, 24, 36, 48 and 60 months of age. Exposure for the older adult women is measured at baseline, 3, 6, 12 and 18 months post-randomization, and in Guatemala and India, when the child is 24 months old.

Personal monitoring equipment is used to assess exposure to carbon monoxide (CO) over a 24-hour period in intervention and control participants (pregnant women, older adult women, and children). Exposure for pregnant women is measured at baseline, 24-28 weeks gestation, 32-36 weeks gestation, and in Guatemala and India, when the child is 24 months old. Exposure for the child is measured at 3, 6, 12, 24, 36, 48 and 60 months of age. Exposure for the older adult women is measured at baseline, 3, 6, 12 and 18 months post-randomization, and in Guatemala and India, when the child is 24 months old.

Personal monitoring equipment is used to assess exposure to black carbon (BC) over a 24-hour period in intervention and control participants (pregnant women, older adult women, and children). Exposure for pregnant women is measured at baseline, 24-28 weeks gestation, 32-36 weeks gestation, and in Guatemala and India, when the child is 24 months old. Exposure for the child is measured at 3, 6, 12, 24, 36, 48 and 60 months of age. Exposure for the older adult women is measured at baseline, 3, 6, 12 and 18 months post-randomization, and in Guatemala and India, when the child is 24 months old.

The 10-item Cohen's Perceived Stress Scale (PPS) assesses the way an individual appraises their life events as stressful (e.g., "In the last month, how often have you felt difficulties were piling up so high that you could not overcome them?") (Cohen, 1983). Likert-level responses ranged from 0 (never) to 4 (very often), meaning a high PPS score would result in a high level of perceived stress. A Spanish language PPS created and tested and found to be valid and reliable (Vallijo et al., 2018).

Fetal death before 19 weeks 6 days.

Births at less than 34 weeks completed gestation, among all live births.

Including preterm birth and stillbirth.

Any fetal deaths occurring at or after 20 weeks' gestation OR indicated on Serious Adverse Event form OR on Pregnant Woman Medical History form OR on verbal autopsy form.

Death between birth and 28 days.

Two buccal cell scrapes will be collected by gently scraping the buccal mucosa on both sides of the mouth with a small plastic collection spoon. Nasal turbinate brush samples can be collected using a soft cytobrush on each turbinate. Collection is gentle and causes no discomfort to study participants. Both samples will be processed in the laboratory according to procedures detailed in the protocol. This will occur in the older adult women in an NCI substudy.

For the oral rinse, participants will vigorously rinse their mouth and the rinsates are collected in a centrifuge tube. The tube is centrifuged and the pellet and supernatant are removed to separate cryovials, labeled and frozen. This will occur in the older adult women in an NCI substudy.

Two buccal cell scrapes will be collected by gently scraping the buccal mucosa on both sides of the mouth with a small plastic collection spoon. A 5-mL venous blood sample will be collected in an ethylenediaminetetraacetic acid (EDTA) vacutainer tube by standard clinical venipuncture of a cubital vein. Both samples will be transported and processed in the laboratory according to procedures detailed in the protocol. This will occur in the older adult women in an NCI substudy.

A 5-mL venous blood sample will be collected in an EDTA vacutainer tube by standard clinical venipuncture of a cubital vein. The sample will be transported and processed in the laboratory according to procedures detailed in the protocol. This will occur in the older adult women in an NCI substudy.

Household food insecurity will be measured using the Food Insecurity Experience Scale (FIES), developed and validated by the Food and Agriculture Organization (FAO). The FIES module includes eight questions, each with yes/no response options, on the household's access to adequate food, and is intended to measure three domains of food insecurity: uncertainty/anxiety, food quantity, and food quality. Each question takes values of 0/1, which are summed for a possible total score of 0-8.

Dietary diversity for women will be measured using the Minimum Dietary Diversity - Women (MDD-W) questionnaire from the FAO and FHI 360, which uses an open recall format to collect data on foods and beverages consumed by the respondent during the previous day and night. Responses will be categorized into ten food groups and women who report consuming five or more out of ten food groups will be categorized as achieving minimum dietary diversity.

Minimum dietary diversity for children will be measured using the World Health Organization (WHO) infant and young child feeding questionnaire. The questionnaire uses a combination of open and closed recall and asks caregivers to report on foods and beverages consumed by the infant or young child during the previous day and night. Responses will be categorized into eight food groups and infants who consumed five or more out of ten eight food groups will be categorized as achieving minimum dietary diversity.

Hb will be measured from a single drop of capillary blood obtained via finger prick, using the HemoCue® Hb 201system (HemoCue® AB) point-of-care device

Hb will be measured from a single drop of capillary blood obtained via finger prick, using the HemoCue® Hb 201system (HemoCue® AB) point-of-care device

Lung function measurements will be made using the forced oscillation technique (FOT) with the Tremoflo C-100 device with disposable mouthpieces. FOT is a technique that can identify early changes in the airways. The FOT device measures the relationship between externally applied pressure waves and the resulting air flow to measure respiratory impedance. Values produced at high frequencies correspond to the proximal and large airways, and values produced at low frequencies correspond to distal and small airways. This measurement will be conducted in children in Guatemala.

The carotid intima-media thickness test (CIMT) is used to determine the extent of carotid atherosclerotic vascular disease. The test measures the thickness of the inner two layers of the carotid artery and can detect plaque build up prior to physical symptoms being experienced. The carotid ultrasound will be performed with a portable ultrasound by trained sonographers. This outcome is only assessed in Guatemala during the extended follow-up period (after the birth of the household child).

Multiple exposure biomarkers will be measured: 3-OH Cotinine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), levoglucosan, 8OH-deoxyguanosine (8OHdG), and Volatile Organic Chemicals (VOC) metabolites. Exposure biomarkers (especially for children whose urine may be limited) will be prioritized as follows: polycyclic aromatic hydrocarbon (PAH) biomarkers, levoglucosan, volatile organic chemicals (VOC) biomarkers, heavy metals, and tobacco-related biomarkers. Urinary biomarkers will be measured in pregnant women at baseline, 24-28 weeks gestation, and 32-36 weeks gestation, and in new mothers when the child is 24-months old. Biomarkers will be measured in older adult women at baseline, 3, 6, 9, 12 and 18 months post-randomization. Biomarkers will be measured in children at 3, 6, 12 and 24 months of age.

The main biomarkers to be measured from the dried blood spots is: inflammation markers, endothelial markers of cardiovascular disease, oxidative stress markers, Hb, HbA1C, tumor-associated antigen antibodies, cytochrome P450, p53 tumor-associated antigen (TAA), lipids, metabolomics, MiRNA, heavy metals. DBS biomarkers will be measured in pregnant women at baseline, 24-28 weeks gestation, and 32-36 weeks gestation, and in new mothers when the child is 24-months old. DBS biomarkers will be measured in older adult women at baseline, 3, 6, 9, 12 and 18 months post-randomization. DBS biomarkers will be measured in children at 3, 6, 12 and 24 months of age.

Reported diarrhea will be extracted from the Monthly Child Health Status Visit case report form. Each month, the child's caretaker will be administered a survey to obtain information on whether the child under 1 year of age (the HAPIN study index child) or any other child in the home under 5 has experienced WHO-defined diarrhea (defined as three or more loose stools that can take the shape of a container within a 24-hour period) in the past 7 days. Persistent diarrhea will be defined as 14 or more continuous days of diarrhea. The presence of blood in the stool will also be noted as an indicator of severity.