Determinants of early-life lung function in African infants

Background Low lung function in early life is associated with later respiratory illness. There is limited data on lung function in African infants despite a high prevalence of respiratory disease. Aim To assess the determinants of early lung function in African infants. Method Infants enrolled in a South African birth cohort, the Drakenstein child health study, had lung function measured at 6-10 weeks of age. Measurements, made with the infant breathing via a facemask during natural sleep, included tidal breathing, sulfur hexafluoride multiple breath washout and the forced oscillation technique. Information on antenatal and early postnatal exposures was collected using questionnaires and urine cotinine. Household benzene exposure was measured antenatally. Results Successful tests were obtained in 645/675 (95%) infants, median (IQR) age of 51 (46-58) days. Infant size, age and male gender were associated with larger tidal volume. Infants whose mothers smoked had lower tidal volumes (-1.6 mL (95% CI -3.0 to -0.1), p=0.04) and higher lung clearance index (0.1 turnovers (95% CI 0.01 to 0.3), p=0.03) compared with infants unexposed to tobacco smoke. Infants exposed to alcohol in utero or household benzene had lower time to peak tidal expiratory flow over total expiratory time ratios, 10% (95% CI -15.4% to -3.7%), p=0.002) and 3.0% (95% CI -5.2% to -0.7%, p=0.01) lower respectively compared with unexposed infants. HIVexposed infants had higher tidal volumes (1.7 mL (95% CI 0.06 to 3.3) p=0.04) compared with infants whose mothers were HIV negative. Conclusion We identified several factors including infant size, sex, maternal smoking, maternal alcohol, maternal HIV and household benzene associated with altered early lung function, many of which are factors amenable to public health interventions. Long-term study of lung function and respiratory disease in these children is a priority to develop strategies to strengthen child health. Infants enrolled in a birth cohort study, the Drakenstein Child Health study,10 had lung function tested. This study, set in a periurban, low socioeconomic community in South Africa, aims to investigate the epidemiology and aetiology of childhood respiratory illness and the determinants of child health. Participants were enrolled at two primary care clinics, Mbekweni, serving a predominantly black African population and Newman, serving a predominantly mixed ancestry population. Lung function testing was undertaken at the local hospital. Infants underwent testing at 5–11 weeks of age corrected for prematurity (37 weeks). Infants born <32 weeks gestation or with congenital anomalies were excluded from this analysis. Mothers had spirometric lung function (Jaeger Masterscope, CareFusion, Switzerland) at the same visit, provided they had not had a respiratory infection within the last 2 weeks. Information regarding antenatal, birth and early-life exposures and events were collected by questionnaire at scheduled antenatal and study visits. These are comprehensively defined in online supplementary table S1. The socioeconomic status (SES) was defined in quartiles from lowest to highest status. This score was derived from employment status and standardised scores of educational attainment, household income, assets and market access (bank accounts, shops accessed, retail accounts); this methodology has been validated for capturing SES variation within an LMIC setting.11 LRTI was defined according to WHO criteria,12 and based on confirmatory examination by trained study staff (professional nurse and/or doctor). thoraxjnl-2015-207401supp001.pdf Maternal recurrent respiratory symptoms or low lung function was defined as at least one of doctor diagnosed asthma, chronic cough or recurrent wheeze in previous 12 months and/or low FEV1, defined as FEV1 < −1.64 SDs, predicted using the Global Lung Initiative multiethnic equations.13 Maternal distress and alcohol use during pregnancy were assessed using the self reporting questionnaire (SRQ) −20 and Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) self-reported questionnaires completed at 28–32 weeks gestation.14 The SRQ-20 is a widely used WHO-endorsed measure of psychological distress.15 We used a dichotomous score of ‘high risk’ versus ‘low risk’, with ‘high risk’ defined as a score of ≥8.15 Infants were classified as alcohol-exposed in utero if their mother reported ASSIST scored heavy exposure with high risk for alcohol related problems: daily and/or weekly use of alcohol during at least 3 months of pregnancy. Maternal smoking history was corroborated on a quantitative analysis of maternal urine cotinine (IMMULITE 1000 Nicotine Metabolite Kit; Siemens Medical Solutions Diagnostics, Glyn Rhonwy, UK) collected antenatally and at birth. Smoking exposure based on urine cotinine was defined as follows: active smoker if urine cotinine >500 ng/mL, passive smoker if urine cotinine 10–500 ng/mL and non-smoker if urine cotinine <10 ng/mL.16 Maternal urine was collected for cotinine testing at the second antenatal study visit (28–32 weeks gestation) and at birth, with the higher result used to classify smoking levels. Benzene, a household air pollutant, was measured at an antenatal home visit using a Markes thermal desorption tube left in the home for 2 weeks.17 The South African National Ambient Air Quality standard of 5 μg/m3 was used to define above and below threshold values for benzene.17 Lung function measurements included tidal breathing and flow volume loops (TBFVL), sulfur hexafluoride (SF6) multiple breath washout (MBW) and the forced oscillation technique (FOT). Infants were tested from July 2012 to December 2014 for TBFVL and MBW and, for operational reasons, from October 2012 to December 2014 for FOT. Lung function was measured in unsedated infants during quiet sleep and conformed to American Thoracic society/European Thoracic society (ATS/ERS) guidelines,18 19 as previously published.20 21 Tidal breathing measures of tidal volume (VT), respiratory rate and expiratory flow ratios were collected using the Exhalyser D with ultrasonic flow metre (Ecomedics, Duernton, Switzerland) and analysed using analysis software (WBreath V.3.28.0; Ndd Medizintechnik, Zurich, Switzerland), as described previously.20 MBWs measuring the functional residual capacity (FRC) and lung clearance index (LCI) were performed using 4% SF6 as a tracer gas and ultrasonic flow metre (Spirison, Ecomedics) with acquisition and analysis software (WBreath V3.28.0, Ndd Medizintechnik) as reported previously.22 Measurements of respiratory system resistance (RRS) and compliance (CRS) with the FOT were made with purpose built equipment (University of Szeged, Hungary) using a medium frequency signal, as previously reported.21 23 The study was approved by the Faculty of Health Sciences, Human Research Ethics Committee, University of Cape Town (401/2009) and by the Western Cape Provincial Health Research Committee. Mothers gave written informed consent in their first language for participation. Lung function outcomes were modelled using multiple linear regression to assess the impact of different antenatal and early-life exposures on lung function at 6–10 weeks. A base model was constructed using Directed Acyclic Graph (DAG) for confounder selection using graphical interface software DAGitty (http://www.dagitty.net V.2.2, 2014), (see online supplementary figure S2).24 DAG minimal adjusted set of variables were selected using a step-by-step approach.25 Interactions were then explored between infant growth and lung maturation (weight for age z score, gestation, birth weight z score), sex, ethnicity, environmental and socioeconomic factors (tobacco smoke exposure, high household benzene, SES), maternal factors (maternal stress score, infant feeding, maternal respiratory health, maternal HIV, antenatal alcohol) and previous LRTI, for each lung function outcome separately. Confounders and interactions were included in the final model for each outcome if they were associated with p value of <0.5 and/or the association had biological plausibility based on previous literature, as shown in online supplementary tables S2–S10. Statistical analyses were performed using STATA V.13 for windows (STATA, College Station, Texas, USA). Data are presented as mean and SD for normally distributed variables and median and IQR for non-normally distributed variables. Weight (WAZ) and height (HAZ) for age z scores were calculated using the WHO Child Growth Standards ‘I grow up’ STATA package.26