Cohort Profile: São Paulo Western Region Birth Cohort (ROC)

Despite major progress over the past several decades to address early adversity,1 young children in low- and middle-income countries continue to be exposed to a high degree of adversity, undermining their ability to reach their full developmental potential.1–3 As highlighted in both the 2007 and 2016 Lancet ‘Early Childhood Development’series, more than 200 million children under the age of 5 are at risk of delays in their physical, cognitive and socioemotional development.1,4 Such delays that occur in early development are consistently associated with lower adult educational achievement and lower adult wages, reducing human capital across future generations.4–6 Exposure to adversity is particularly common in low- and middle-income settings, where children continue to face high exposure to infectious disease as well as environmental and social risks.1,4 The complex interaction between genes, individual experiences and the environment shape the developing brain throughout childhood and adolescence.4 A growing body of evidence suggests that brain development is modifiable by external influences. Exposure to early adversity, especially accompanied by problematic caregiver interactions or other developmental insults, is likely to undermine psychological and cognitive development in the short run, and to impede long-term well-being.4,7,8 An increasing number of developmental studies have explored the relationship between DNA methylation and isolated prenatal stress factors. Relatively little evidence is available today linking social and environmental factors to these processes. The (São Paulo) Western Region Birth Cohort (ROC) was launched in 2012 as a longitudinal and observational study to better understand the relationship between early life risk exposure, early life adversity and long-term outcomes in a modern, poor urban context. Compared with other low-income settings, the setting studied has substantially better access to food, water and sanitation, but is characterized by both under- and overnutrition as well as extreme income inequalities. Primary risk factors for children are external and domestic violence, air pollution, traffic and caregiver mental health, as well as general exposure to drugs and crime. Such characteristics lead to challenges in the enrolment and retention of birth cohort studies within low-income settings. The health disparities faced by women and children from this region, and the need to understand the relations between adversity and early development, served as an impetus for establishing this cohort. To date, the cohort has also been used as a platform for randomized control trials to develop and test interventions and strategies for improving well-being in the short and long run. The primary objective of the ROC study is to assess the impact of social and environmental factors on early childhood development in the modern urban low-income setting of São Paulo. Secondary objectives are: (i) to identify potential epigenetic changes due to toxic stress exposure and its impact on child development; (ii) to understand the influence of antenatal and post-natal toxic stress exposures on child development; and (iii) to assess potential interventions designed to improve well-being through case-control and randomized controlled trials. The ROC comprises all children from the Butantã/Jaguaré Region born at São Paulo’s University Hospital (HU USP) between 1 April 2012 and 31 March 2014. HU USP is the largest public hospital in the Western Region of São Paulo. During the recruitment period, approximately 300 births per month took place at the hospital, accounting for about 40% of all deliveries in the Butantã/Jaguaré Region, and for about 80% of deliveries by Western Region mothers exclusively covered by Brazil's public health care system, the Sistema Único de Saúde (SUS). A total of 7066 deliveries were recorded at HU USP during the recruitment period; 859 births were excluded because the mother’s primary residence was outside the Butanta-Jaguaré Region; And 45 children were stillbirths; resulting in a final cohort sample size of 6162 children born alive. Figure 1 shows the spatial distribution of study households in the Butanta-Jaguaré area. Spatial Location of the São Paulo Western Region Birth Cohort households within the Butanta-Jaguaré area Spatial Location of the São Paulo Western Region Birth Cohort households within the Butanta-Jaguaré area Overall 61% of mothers in the sample identified themselves as White, 35% as mixed race and 4% as Black. Among the children, 48% were born by vaginal delivery, 37% by caesarean section and 15% by forceps, 7.7% of babies being preterm and only 0.2% post-term. Of the newborns, 86% had weight adequate for gestational age, 4.1% were large for gestational age and 10.0% were small for gestational age. Fifty-six children (0.9%) were twins. Only 24% of mothers were married at the time of birth; more than 50% were in informal and often unstable relationships;and 20% of children were born to adolescent mothers. Table 1 compares basic birth outcomes of children in the cohort with children in Brazil, as well as with children from São Paulo state and the São Paulo municipality. Compared with the surrounding municipality and state, a higher proportion of children were born to adolescent mothers and a lower proportion to mothers aged 35 and older—the overall age distribution of mothers looks similar to the Brazilian national average. In terms of birth outcomes, children born at the University Hospital fared better than the state or municipality average both in terms of the low birthweight and in terms of preterm deliveries, which is likely due to the relatively easy access to quality care in the study setting. The primary challenges for families in the sample include having poor housing conditions, poor air quality and exposure to violence and drug-related crime. Among the partners, 30% have children from previous relationships and substance use among the partners is common (58% use tobacco, 30% use alcohol and 7% other drugs). Another critical challenge for children growing up in poor urban environments is the increasing prevalence of maternal depression. Recent evidence from the area suggests that more than one-quarter of women suffer from depression during the postpartum period9; 32% of mothers report family conflicts and lack of support; and maternal depression rates during pregnancy are close to 20%. Families delivering at the hospital are generally from lower-income segments: 78% of children in the cohort come from low-income families (monthly incomes less than R$1245). In the 2010 Census, average income at the national level was R$2298.00 [https://www.ibge.gov.br/indicadores.html]. Comparison by basic birth characteristics (n): Brazil, São Paulo State, São Paulo Municipality and the São Paulo Western Region Birth Cohort—ROC Comparison by basic birth characteristics (n): Brazil, São Paulo State, São Paulo Municipality and the São Paulo Western Region Birth Cohort—ROC Electronic medical records from the university hospital were used to extract information on weight, length, gestational length, type of delivery and Apgar scores of all children born between 1 April 2012 and 31 March 2014. During the postpartum period at the hospital, 6162 mothers were invited to complete a short questionnaire on socioeconomic status and family background to complement the clinical information obtained from the hospital’s system. Of these, 448 mothers were too young to provide consent to the interview in the absence of their parents and were thus excluded from this interview; eight children died in the first 2 days; and 217 mothers refused to participate in the survey. An additional 1682 mothers left the hospital before the postpartum interview could be completed and 3807 interviews were successfully completed. With the exception of those whose children subsequently died, all caregivers of children in the original cohort (n = 6162) were re-invited for interviews in the later rounds. At 6 months of age, children and their caregivers (who were not always the children’s mothers) were invited by phone to attend a free paediatric consultation and assessment at the hospital. Health-related information such as growth, immunization, breastfeeding, food introduction, sleep hours and other health information was collected by the paediatrician. A total of 1696 dyads accepted this offer and completed the 6-month assessment; 15 children died between the postpartum period and the 6-month follow up. All surviving children and their caregivers remained eligible for subsequent rounds. A first round of home visits was implemented when children reached 12 months of age. The primary goal of this follow-up was to verify survival of all children and to assess their overall development, measured by the Brazilian Ministry of Health Child Development form (Ficha de Desenvolvimento da Criança). A total of 3222 caregiver-child dyads completed the 12-month assessment. An additional 11 children passed away between the 6-month and the 12-month assessments; 58 caregivers refused to participate in this survey round; and 2848 dyads could not be reached due to a variety of administrative challenges including funding delays, local strikes, high staff turnover and difficulty in finding families. At 36 months, a new follow-up round at the children’s homes was launched. The primary subjects of this assessment round were child development, stress exposure and parental lifestyle. In total, 3619 children and their caregivers completed the 36-month assessment. A total of 83 children (1.3%) had died between birth and age three and 35 caregivers refused to complete the 3-year interview. In total, 2470 study participants could not be reached within the foreseen assessment period. Figure 2 summarizes participant flows over time. Table 2 compares characteristics of the caregiver-child dyads assessed in each round. Women and children interviewed postpartum were overall very similar to the full sample with the exception for age—as explained above, very young women could not be consented for this interview in the absence of parents. This age selection is also reflected in the 6-month survey. For the 12-month survey, consent was directly obtained at the child’s home, which resulted in a more balanced maternal age distribution. Follow-up rates were marginally lower for White mothers, as well as for children with a low initial Apgar score (Apgar 0 <7). Survey respondents in the 36-month round were overall also very similar to the full sample, with marginally lower prevalence of children with low birthweight as well as children with low initial Apgar score. Consort diagram Consort diagram Sample characteristic comparison by follow-up round p < 0.05 for H0: mean of population followed-up = mean of population not followed up. Sample characteristic comparison by follow-up round p < 0.05 for H0: mean of population followed-up = mean of population not followed up. Figure 3 shows the overlap in survey completion rates for the three main home survey rounds. Participating subjects varied substantially across survey rounds. From the 3809 caregivers participating in the postpartum interview, 3076 appeared in at least one of the two following survey rounds; 1362 women completed all survey rounds. Venn diagram Venn diagram As of the writing of this manuscript, a 72-month (age 6) assessment is in progress. This follow-up round once again targets all the 6124 families whose child is still alive and assesses child development and school readiness, mental health, health behaviours (exercise, screen time, activities) and general living conditions. The main objective of the cohort is to measure the impact of environmental and social determinants of health on child development. Table 3 displays each of the measures for children’s home environment and development at each follow-up wave. Summary of measurements Self-reported major diseases and treatment Self-reported major behavioural risk factors Self-reported socioeconomic and education status Self-reported family history of education and disease Antenatal care 6 months 2012–14 Linear growth, hospitalizations in the postnatal period, immunization, feeding habits, sleep habits, clinical assessment Self-reported major disease, examinations and treatment Self-reported major behavioural risk factors 12 months 2013–15 Survival status Self-reported child development milestones Ages and Stages Questionnaire for a subsample (700 children) 36 months 2015–17 Household characteristics Child anthropometrics Mother height and weight Self-reported depression, conflicts and violence in the environment Paternal information Observed parenting style and discipline Parental knowledge Caregiver-reported child development: Caregiver Reported Early Development Index (CREDI) Child development assessment: the Regional Project on Child Development Indicators (PRIDI) Pre-school arrangements Self-reported food insecurity 72 months Ongoing Height and weight of child and mother Self-reported family social economic status Self-reported parenting style School arrangements Observed child development: the International Development and Early Learning Assessment (IDELA) Behaviour checklist (caregiver report): Child Behavior Check List (CBCL) Self-reported major diseases and treatment (allergy and other respiratory problems) Self-reported major behavioural risk factors Nutrition Screen time Self-reported major diseases and treatment Self-reported major behavioural risk factors Self-reported socioeconomic and education status Self-reported family history of education and disease Antenatal care 6 months 2012–14 Linear growth, hospitalizations in the postnatal period, immunization, feeding habits, sleep habits, clinical assessment Self-reported major disease, examinations and treatment Self-reported major behavioural risk factors 12 months 2013–15 Survival status Self-reported child development milestones Ages and Stages Questionnaire for a subsample (700 children) 36 months 2015–17 Household characteristics Child anthropometrics Mother height and weight Self-reported depression, conflicts and violence in the environment Paternal information Observed parenting style and discipline Parental knowledge Caregiver-reported child development: Caregiver Reported Early Development Index (CREDI) Child development assessment: the Regional Project on Child Development Indicators (PRIDI) Pre-school arrangements Self-reported food insecurity 72 months Ongoing Height and weight of child and mother Self-reported family social economic status Self-reported parenting style School arrangements Observed child development: the International Development and Early Learning Assessment (IDELA) Behaviour checklist (caregiver report): Child Behavior Check List (CBCL) Self-reported major diseases and treatment (allergy and other respiratory problems) Self-reported major behavioural risk factors Nutrition Screen time Summary of measurements Self-reported major diseases and treatment Self-reported major behavioural risk factors Self-reported socioeconomic and education status Self-reported family history of education and disease Antenatal care 6 months 2012–14 Linear growth, hospitalizations in the postnatal period, immunization, feeding habits, sleep habits, clinical assessment Self-reported major disease, examinations and treatment Self-reported major behavioural risk factors 12 months 2013–15 Survival status Self-reported child development milestones Ages and Stages Questionnaire for a subsample (700 children) 36 months 2015–17 Household characteristics Child anthropometrics Mother height and weight Self-reported depression, conflicts and violence in the environment Paternal information Observed parenting style and discipline Parental knowledge Caregiver-reported child development: Caregiver Reported Early Development Index (CREDI) Child development assessment: the Regional Project on Child Development Indicators (PRIDI) Pre-school arrangements Self-reported food insecurity 72 months Ongoing Height and weight of child and mother Self-reported family social economic status Self-reported parenting style School arrangements Observed child development: the International Development and Early Learning Assessment (IDELA) Behaviour checklist (caregiver report): Child Behavior Check List (CBCL) Self-reported major diseases and treatment (allergy and other respiratory problems) Self-reported major behavioural risk factors Nutrition Screen time Self-reported major diseases and treatment Self-reported major behavioural risk factors Self-reported socioeconomic and education status Self-reported family history of education and disease Antenatal care 6 months 2012–14 Linear growth, hospitalizations in the postnatal period, immunization, feeding habits, sleep habits, clinical assessment Self-reported major disease, examinations and treatment Self-reported major behavioural risk factors 12 months 2013–15 Survival status Self-reported child development milestones Ages and Stages Questionnaire for a subsample (700 children) 36 months 2015–17 Household characteristics Child anthropometrics Mother height and weight Self-reported depression, conflicts and violence in the environment Paternal information Observed parenting style and discipline Parental knowledge Caregiver-reported child development: Caregiver Reported Early Development Index (CREDI) Child development assessment: the Regional Project on Child Development Indicators (PRIDI) Pre-school arrangements Self-reported food insecurity 72 months Ongoing Height and weight of child and mother Self-reported family social economic status Self-reported parenting style School arrangements Observed child development: the International Development and Early Learning Assessment (IDELA) Behaviour checklist (caregiver report): Child Behavior Check List (CBCL) Self-reported major diseases and treatment (allergy and other respiratory problems) Self-reported major behavioural risk factors Nutrition Screen time All residential addresses have been geocoded and can be linked to publicly available spatial layers with information on violent crime, altitude, green space and air pollution. Detailed measurements on local nitrogen oxides (NOx) and noise exposure are in progress at the time of the submission of this manuscript. In all, 1619 births were considered high risk by the medical staff. For these high-risk births (preterm or small for gestational age deliveries, mother with known medical conditions or drug use history), placenta samples were collected, as part of routine hospital services during delivery, for further investigation in the hospital’s laboratory. Fragments of 1.0 × 1.0 × 0.4 cm from two collection points (mother and child placenta) were collected and subjected to routine histological processing. The samples were stored in paraffin blocks at the Pathology Sector at the University Hospital. The consent terms signed by pregnant women before delivery include the authorization to use information, regarding all procedures during labour and delivery received at the hospital, for research. For maternal and cord blood collection, 96 women were randomly selected. Separate consent forms were used for this biomarker selection; no refusals were observed. DNA was extracted from 89 umbilical cord blood samples. Bisulphite-converted DNA was hybridized to the Human Methylation 450 BeadChip microarrays (HM450K, Illumina) as previously described.10 Briefly, raw data were extracted by iScan SQ scanner (Illumina) with GenomeStudio software (v.2011.1) the methylation All samples passed quality control data were and for a cord blood as implemented in The which was also collected as of toxic stress A first of samples from dyads was collected at the 6-month hospital consultation and at the 12-month home were collected on interviews the was was collected through of the 3 months sample 58 children not have for this assessment. samples were long least 6 a sample from the was to assess over time. A collection = was in 2016 as part of the 3-year follow-up for children again samples were collected as part of All samples were to a in São Paulo for on these samples were and have been The primary objective of the cohort is to assess the impact of adversity and toxic stress on child development. have a between and being small for gestational age and development at 12 months, with in ability to with have also in DNA early life that can be critical for later life and between maternal and child were during the first data on child development measured at 12 months, also the relationship between maternal depression and child development at age 1 finding to these with the more developmental in the assessment round. The data on child development were also used to new to assess child development in and As a study the ROC a home early childhood randomized controlled The main that home visits can child development in this such have to be with by the The ROC was the first cohort up in the environment of São Paulo. The ROC comprises information from a large of children living in of which are as The main of the is that birth records as well as data on antenatal care collected through The also education and the study of stress factors exposures and their impact on of development, including growth, development and and as well as mental parenting information also the study of such behaviours and their impact on child development, as a or In the cohort a of for including cord placenta samples and the of a randomized controlled on early childhood development the also have in early development that can be studied in future addresses also to a variety of other such as altitude, and crime. The main of the ROC are the rates that across rounds. households in with and address changes and to other are In the early of the also to mothers to come to the University Hospital to complete interviews in a setting. mothers free and a free consultation with a very mothers were to participate in such settings. for mothers to come to be a potential to this but also in this poor were collected to and to interview mothers, but these to be very in because mothers to phone The only to reach mothers in this setting have been home The also a with administrative such as funding which in and resulted in a relatively large number of interviews not being completed. in are particularly for on child development because are designed for relatively age a developmental designed for a child to a not also faced challenges with high staff in the by this cohort is had only one of a being is a in and with is by lack of local in the data could the or The ROC is a birth cohort of 6162 children born between April 2012 and March to assess primary risk factors as well as interventions to improve child health and development in a modern of São Paulo. The comprises and environmental information for children and to health and administrative hospital trials have been implemented in the including a randomized on home and a at in with caregivers have been birth and at 12 and 36 months of children’s 72-month assessment of the 6124 eligible children cohort is under birth outcomes, each follow-up round data on maternal and child health, child and child development as well as data on children’s home residential addresses were linked to publicly available spatial layers with information on violent crime, altitude, green space and air pollution. Detailed measurements on local nitrogen oxides (NOx) and noise exposure are in progress at the time of the submission of this manuscript. The cohort has been by the São Paulo Health the de de São Paulo the for at the and the at the and Health

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