Despite its increasing clinical significance and diagnostic challenges, little is known about functional abdominal pain disorders (FAPDs) in Central-Eastern Europe. In this paper, the prevalence and potential sociodemographic correlates of FAPDs among Hungarian adolescents are explored.N = 267, 51.1% girls, mean age 14.8, SD 2.4 years). The questionnaire included sociodemographic variables , questions regarding self–reported specific learning disorders and the Questionnaire for Paediatric Gastrointestinal Symptoms Rome ΙΙΙ Edition.A cross-sectional, nationwide, questionnaire study in a representative sample of 657 adolescents has been conducted. With a response rate of 80.2%, 522/527 (99.1%) questionnaires were eligible for data analysis (N = 62). FAPDs were significantly associated with female sex. Living in a county town showed a negative correlation with FAPD. Adolescents with self–reported arithmetic learning disorders had an 8.7-fold likelihood of FAPD . Adolescent girls reported pain in all subtypes of FAPDs more frequently than adolescent boys except functional abdominal pain syndrome. The most prevalent FAPD was abdominal migraine , followed by irritable bowel syndrome .The prevalence of FAPDs was 11.9% (The prevalence of FAPDs in Hungary is similar to that reported worldwide, however, contrary to international data, abdominal migraine is the most frequently encountered FAPD in Hungary. In addition to well-known correlates of FAPDs, such as female sex and place of residence, arithmetic learning disorders have also been identified as correlating with the prevalence of FAPDs. Our results suggest culture-specific differences in the distribution of FAPDs, and confirm the significance of school performance indicators such as specific learning disorders as a correlate of FAPDs. The prevalence of functional abdominal pain disorders (FAPDs) ranges between 6.3–27.3% among adolescents as defined by the Rome III criteria, which classify the disorders into 5 subtypes , 2. FAPDThe pathogenesis of the disorder is multifactorial. The biopsychosocial model describes several risk factors  leading to visceral hypersensitivity, altered motility and FAPD , 9. StudDespite the clinical significance of FAPDs and emerging associations with various socio-demographic variables, no information is available about the prevalence and potential risk factors of FAPDs among adolescents in Hungary. The country is undergoing radical societal changes and transformation of the educational system characterised by high psychosocial stress, which has been shown to influence family life as well as the health of adolescents . TherefoN = 602) was determined based on previous epidemiological studies on the topic, which took into consideration a total prevalence of 10%, 95% confidence interval, 5% degree of absolute precision, and 20% attrition [A national cross-sectional study was conducted in April 2016. Adolescent school children in grades 5–12 (every 5th pupil from each class) and their parents from 22 schools in all of the 8 regions nationwide were randomly selected, to obtain a representative cohort for all school grades, sex, and regions. The most recent Hungarian Statistical Yearbook of Education 2013/2014 was used, to ensure that the sample has matching socio-demographic characteristics to those of the normative population . The minAll adolecents who were selected by the randomization process (incl. missing students) were included in the study. The lack of data on sex and answers necessary to diagnose a specific FAPD was excluded from the analysis.Printed questionnaires were mailed to each school. Teachers asked the subjects to complete questionnaires during school-time and at home, within 2 weeks. The questionnaires were anonymous. Consent forms were sent to the parents and only children who obtained informed consent from their parents were allowed to participate in the study.The validated Questionnaire for Paediatric Gastrointestinal Symptoms Rome ΙΙΙ Edition (QPGS-III) was used to assess abdominal pain . The queSubjects were asked about their age, sex, place of residence and region , as well as the marital status of their parents. If the parents were divorced, participants were asked about which parent they lived with. A question relating to participants’ religion was also included: whether they belonged to a church that they regularly visited. In a separate question, the prevalence of previously diagnosed SLDs was asked. If participants answered positively, further questions explored the type of learning disorder, such as writing, arithmetic, reading, or other learning disorders.Additionally, parents were asked about the estimated total monthly income of the family per capita . Parents’ highest attained educational level was also explored on a 5-point scale ; 3: secondary school completion (12 years of education); 4: advanced level grade (13 years of education) 5: higher education degree (14 years or more of education).p < 0.05 was considered as statistically significant.Descriptive statistics for frequency counts were deployed to explore the prevalence of FAPDs and their types; Mann-Whitney U test, χ2 test, and Fisher test were used to evaluate differences in the prevalence of FAPDs between various study groups, and categorical variables. Odds ratios were calculated to assess the strength of the relationships between the variables. Missing data was excluded from the further analyses. Data was analysed by SPSS software version 24.0  and N = 267, 51.1% girls, mean age 14.8, SD 2.4 years).Of the 657 questionnaires distributed to the schools, 527 were returned (response rate of 80.2%). We excluded 5 questionnaires due to missing values, which left 522 questionnaires (79.5%) for data analysis . In our sample, the most prevalent FAPD was abdominal migraine  followed by irritable bowel syndrome (IBS) . Functional abdominal pain syndrome (FAPS) was more prevalent among male adolescents, all other FAPDs were more frequent among females  Table . We founThe relationship between self–reported SLDs, a proxy of performance at school, and FAPDs was also explored. Our results showed that adolescents with previously diagnosed SLDs have a 2.2-fold likelihood of having FAPD, which is significantly higher than subjects without FAPD. In our study, SLD with impaired arithmetic skills was the most prevalent learning disorder, and it was associated with an 8.7-fold likelihood of FAPDs Table .Table 4In this community based representative study among Hungarian adolescents, we identified a prevalence of 11.9% for FAPDs. Our results are in line with those reported by a number of epidemiological studies, which demonstrated a mean total prevalence of FAPDs of 12.48% (range of 6.3–27.3%) . Two stuIn almost all studies, IBS has been shown to be the most prevalent FAPD in the adolescent age group followed by FAP , 11–23. On the other hand, it is well-accepted that the prevalence of AM is overestimated using the Rome III criteria vs the Rome IV or Rome II criteria. This might have led to the overestimation of the prevalence of AM in our sample .We found a higher prevalence of FAPDs among female vs. male adolescents. Our findings confirm results from previous research on the relationship between FAPDs and sex. Our finding of sex differences in the prevalence of FAPDs could be explained by sex differences in pain perception and processing. Evidence suggests that female adolescents exhibit enhanced central pain sensitivity possibly also due to sex hormonal effects .FAPD was more prevalent among female adolescents in all subtypes except FAPS. This supports our clinical impression that the most disabling cases of FAP are among adolescent boys. In a study from Sri Lanka, FAP was also found to be more prevalent in boys, but the authors did not publish any data about the prevalence of FAPS . StudiesWe found no differences in the prevalence of FAPDs among various age cohorts in this study. These results are in line with those of the Mediterranean–European Area project on functional gastrointestinal disorders (MEAP) . SimilarOur findings demonstrated that living in towns  had an inverse relationship with FAPDs. Our findings add further data to a very small body of evidence presented only in three studies on non-representative samples, about the associations between the type of the settlements and FAPDs , 13, 19.We found no difference in the prevalence of FAPDs among geographical areas with low and high economic status, despite the fact that there is more than a two–fold difference between the poorest and the richest part of the country according to data on gross domestic product per capita, as reported by the National Statistical Agency on 2015 .We expected a lower prevalence of FAPDs in higher income families and in families where parents had higher educational levels, however, we could not confirm our hypothesis. To our knowledge, our study is one of the first to explore the relationship between different geographical areas, family income, educational level of the parents and FAPD, according to Rome III. The studies assessing socio–economic status by other methodologies demonstrated either no difference, or a higher probability of any FGID  with lower socioeconomic status , 13, 19.Membership of a religious community did not significantly influence the prevalence of FAPDs in our sample. To our knowledge, no other studies have examined religiosity in connection with FAPDs. Research by German scientists about chronic pain among patients in adult out–patient setting identified associations between spirituality/religiosity, positive appraisals and internal adaptive coping strategies with pain . FurtherSLDs were identified as a new possible correlate of FAPDs. The role of learning disorders in the pathogenesis of FAPDs has not been studied before. It may be suggested that this relationship can be explained by higher school stress and emotional burden due to SLDs, which in turn may support the development of FAPDs. Indeed, school stress and emotional burden have been implicated in the maintenance of FAPDs .In our evaluation, the present study has several strengths. This is the first survey that reports epidemiological data about FAPDs from Central and Eastern Europe using the Hungarian version of Rome III questionnaires, which allows for more appropriate cross–cultural comparison. In addition, our study used a representative sample for various socio-economic variables to explore probable correlates of FPADs. Finally, this is the first study that explored the possible association between SLDs and FAPDs. Another of our study is the use of the child–report methodology, as parental reports often underestimate the prevalence of these disorders. Our methodology allows for a more accurate assessment of the prevalence of FAPDs .Our study also has some limitations. The cross-sectional setting does not allow for cause–and–effect conclusions. We did not include all school-types from all regions and did not perform a detailed work–up regarding specific learning disorders, which further limits interpretation of our results. Participants did not receive physical examinations, which may distort some of our findings.Our results provide important insights into potential risk factors of FAPDs and uncover likely associations between FAPDs and SLDs, an indicator of school performance. These results may add further impetus to cross-cultural clinical research in the field, and aid clinical decision-making and diagnosis. Further research is needed to explore the role of sex, place of residence and SLDs in the pathogenesis and evolution of abdominal pain among adolescents.


Pteris cretica var. Albo-lineata (Pc-Al). We assume difference in physiological parameters and level of DNA methylation in young and old fronds as symptoms of As toxicity.Arsenic toxicity induces a range of metabolic responses in plants, including DNA methylation. The focus of this paper was on the relationship between As-induced stress and plant senescence in the hyperaccumulator Pc-Al fronds, grown in pots of haplic chernozem contaminated with 100 mg As kg− 1 for 122 days, decreased with age. Content of As was higher in young than old fronds for variants with 100 mg As kg− 1 . The highest As content was determined in old fronds of Pc-Al grown in pots with 250 mg As kg− 1. The increase with age was confirmed for determined nutrients – Cu, Mg, Mn, S and Zn. A significant elevation of all analysed nutrients was showed in old fronds. Arsenic accumulation affected DNA methylation status in fronds, but content of 5-methylcytosine (5mC) decreased only in old fronds of Pc-Al (from 25 to 12%). Determined photosynthetic processes showed a decrease of fluorescence, photosynthetic rate and chlorophylls of As treatments in young and old fronds. Water potential was decreased by As in both fronds. Thinning of the sclerenchymatous inner cortex and a reduction in average tracheid metaxylem in the vascular cylinder was showed in roots of As treatment. Irrespective to fronds age, physiological parameters positively correlated with a 5mC while negatively with direct As toxicity. Opposite results were found for contents of Cu, Mg, Mn, S and Zn.The As accumulation of Pc-Al, upon low and high exposure to As contamination. The significant impact of As on DNA methylation was found in old fronds. Irrespective to fronds age, significant correlations were confirmed for 5mC and As toxicity. Our analysis of the very low water potential values and lignification of cell walls in roots showed that transports of assimilated metabolites and water between roots and fronds were reduced. As was showed by our results, epigenetic changes could affect studied parameters of the As hyperaccumulator plant Pc-Al, especially in old fronds.The results of this paper point to changes in the metabolism of the hyperaccumulator plant  Arsenate (AsV) taken up by roots of P. vittata from the soil was reduced to arsenite (AsIII), which was rapidly transported to the vacuoles of the upper and lower epidermal cells and trichomes of the fronds [P. vittata was primarily contained as inorganic arsenite (average of 94%). According to these authors arsenite re-oxidation to arsenate occurred more often with senescence of fronds. Koller et al. [Pteris umbrosa on As content. The senesced fronds had a significantly lower As content in contrast to green fronds while expanding fronds had the highest As content. The different result - increase in As concentration from young to mature and old fronds was shown in P. vittata [Environmental pollution with arsenic (As) poses a risk to plant, animal and human health. Uptake and accumulation of this element by plants vary according to plant species. For most plants, significantly reduced growth and fitness is evident at soil arsenic concentrations of 25.0–85.0 mg kgy weight . The culo et al. , who repe fronds . Tu and r et al.  confirmeArsenic stress can provoke numerous toxic effects in plants. As is widely reported to inhibit the rate of photosynthesis in plants and to reduce chlorophyll concentration . AgnihotStudies have also revealed that stress-inducing abiotic factors, including As, can trigger epigenetic changes (in particular DNA methylation/demethylation), which may contribute to the regulation of gene expression in chronic stress conditions . PhenotyV to AsIII and the formation of AsIII-glutathione or AsIII-phytochelatin complexes, which are eventually transported to the vacuole. Disturbances in cellular processes, caused by a toxic excess of As, induce oxidative stress responses [P. cretica [Pteris cretica var. Albo-lineata. In addition, we examined related changes in selected physiological parameters and DNA methylation status as potentially indicative of epigenetic modification. The degree of senescence was evaluated with respect to different changes found in young and old fronds of P. cretica var. Albo-lineata.The primary detoxification of As in the cells of terrestrial plants relies on rapid reduction of Asesponses –17, meth cretica , and epi cretica . In this100 soil was observed only on young fronds. The dry biomass of Pc-Al young fronds was decreased by 43%  and old fronds (by 100%), respectively. The increases in S (59%) and Zn (86%) concentration were only observed in old fronds. When grown in As100 and As250 soils, the concentrations of Mg and Mn increased in old fronds of Pc-Al (Mg by 60% and Mn by 66%) but decreased in young fronds (Mg by 6% and Mn by 18%).The analysis of the concentration of elements in dried fronds of ds Table . In the p < 0.01): a, b comparison between the treatments of young fronds (control and As100) and old fronds ; A, B comparison between young and old fronds for control and As100 treatment. Results for comparison between control and As100 of young and old fronds are in Additional File Values with the same letter were not statistically significant at the 0.01 level by the Kruskal-Wallis test. Different letters indicate significantly different values  of ed Figs.  and 3. C100 and As250 soil resulted in a decrease of chlorophyll contents  of Pc-Al . While the average value of Chl A and Chl B ratio remained unaffected by As in old fronds, it increased in young fronds of ferns grown in As100 soils (Table Growth in As− 2 s− 1) responded to the quantum yield of photosystem II. During As100 stress Fv/Fm of fronds decreased compared with controls (by 12.5% in young fronds and 14% in old fronds). Also As250 stress decreased Fv/Fm of old fronds – by 29% (Table 250 conditions in old fronds. Observed declines in pigment content and Fv/Fm in old leaves of fern in As100 and As250 soils indicated a faster progression of senescence.Chlorophyll fluorescence (Fv/Fm), as an indicator of plant photosynthetic activity, was lower in old fronds than in young fronds. The value of Fv/Fm for young fronds from control plants . Higher values of WP were observed in young fronds, irrespective of added As. To explore potential changes in roots, cross-section analysis through adventitious roots was performed. The roots of As treated plants showed thinning of the sclerenchymatous inner cortex and a reduction in average tracheid metaxylem in the vascular cylinder, compared to controls  was decreased in young and old fronds of the plants grown in Asols Fig. .Fig. 4CN/E). Values with the same letter were not statistically significant at the 0.01 level by the Kruskal-Wallis test. Different letters indicate significantly different values (p < 0.01): a, b comparison between the treatments of young fronds (control and As100) and old fronds ; A, B comparison between young and old fronds for control and As100 treatment. Results for comparison between control and As100 of young and old fronds are in Additional File From these data, the water-use efficiency was estimated (WUE = PN and the rate of transpiration (E) were determined to gain further insight into the photosynthetic performance in Pc-Al fronds  were located in the different parts of the diagram, which indicated a high effect of the treatments on all the recorded data. As observed with primary data, PCA confirmed that the accumulation of Cu, S, Zn, Mg and Mn was more pronounced in old fronds of Pc-Al grown in As100 and As250 soils and that Chl B, PN, WP, E, Fv/Fm, as well as 5mC were higher in young fronds of control plants. Arsenic content was negatively correlated with relative 5mC content of DNA as the angle between the vectors for As and 5mC was > 90°. Relationships visualised in the PCA diagram were confirmed by linear correlations  is showed in Additional File The first axis of the PCA analysis explained 81% of the variability of all analysed data, the first two axes explained 90% of the variability, and the first four axes together explained 99% of the variability. Diagramming PCA analysis was used for visualisation of all relationships between ns Table . The resns Table . The con−1, As could accumulate in the fronds of P. cretica var. Albo-lineata to > 2000 mg As kg− 1 dry mass. These data confirmed the As hyperaccumulation status of Pc-Al and were consistent with results reported by Zhao et al. [P. vittata. The As content in young fronds of control and As100 variants was higher than in old fronds. Effect of the development stage of fronds on As content was determined in Pteris umbrosa by Koller et al. [P. umbrosa exposed to 100 and 600 mg As L− 1 declined. This finding is consistent with our results for control and As100 variants.Our results show that when grown in chernozem soils spiked with 100 and 250 mg As kgo et al.  for thisr et al. . During Pc-Al showed that As reduced the extent of DNA methylation. Similar results for heavy metals were published by Aina et al. [Arsenic stress induces epigenetic changes in organisms, resulting in a decrease or increase in DNA methylation . Analysia et al. . The fira et al. . Their rPc-Al young fronds was decreased by 43% . As revealed by PCA and correlations, physiological parameters of the Pteris cretica var. Albo-lineata are strongly affected by the methylation status of DNA and by direct As toxicity. Increased accumulation of tested nutrients  or decreased chlorophylls, Fv/Fm, PN and WP could be affected by epigenetic changes as was showed by our results.The results of this paper point to changes in the metabolism of the As-hyperaccumulator plant N and E, indicated reversible senescence in As plants. Based on our determination of very low values for WP (from − 1.4 to − 3.7) and morphological changes in the roots  we proposed that transport of assimilated metabolites between roots and fronds might be reduced.Accumulation of As in plants affected photosynthetic processes and the content of pigments in fronds. There was a decrease of chlorophylls (ΣChl by 69%) and Fv/Fm (by 29%) in old fronds of As treatment, indicating a faster progression of senescence. These changes together with values of PPteris cretica (L.) var. Albo-lineata (Pc-Al) were obtained from the garden centre Tulipa Praha (Czech Republic). Ferns at the 10–15 fronds stage were planted in 5 L pots (1 fern for pot) under greenhouse conditions  for 122 days. Each pot contained 5 kg of haplic chernozem mixed with 0.5 g N, 0.16 g P and 0.4 g K per 1 kg of soil (supplemented as NH4NO3 and K2HPO4). The soil used in this experiment (Table 100) and 250 mg As per kg soil (As250). Arsenic was added as a solution of Na2HAsO4 and was thoroughly mixed with the soil; maturation period of spiked soil was ten days. Each treatment was replicated three times. Above-ground biomass of control and As100 variants were separated to young and old fronds. The young and old fronds were separated according to their location in plant habit and their size. The young fronds were located lower ground of fern and their area did not exceed to 5 × 10 cm. The larger fronds from full habit were indicated as old fronds. Growth of new fronds were not found at As250 variants and senescent fronds were indicate as old fronds. After being harvested, the fronds were treated as described below. Cross-sections through an adventitious root were inspected using a Nikon E 200 microscope equipped with DS camera head and the NIS-Elements application .Plants of 3 and H2O2  in an Ethos 1 device . Contents of As, Cu, Mg, Mn, and Zn were determined using inductively coupled plasma-optical emission spectrometry . Certified reference material  was mineralized under the same conditions for quality assurance.Fronds were oven-dried for three days at 40 °C. Homogenised material (0.5 ± 0.05 g) was digested with a mixture of HNOThe fronds were weighed, frozen in liquid nitrogen and stored at − 80 °C prior to DNA methylation analysis. To isolate total DNA, the fronds (1 g fresh weight) were ground to a fine powder in liquid nitrogen by mortar and pestle. DNA was extracted from 100 mg of powdered tissue using a NucleoSpin Plant II molecular kit , as instructed in the user manual. The global DNA methylation status of DNA was determined using 100 ng of isolated DNA and a MethylFlash Methylated DNA Quantification Kit  according to the manufacturer’s instructions. A SpectraMax MiniMax 300 Imaging Cytometer  with excitation at 530 nm was used to measure the fluorescence at 590 nm.2) excised from a freshly separated frond was incubated in the dark in 1 ml dimethylformamide with shaking for 24 h. The absorbance of the extract was measured at wavelengths 480, 646.8, and 663.8 nm. Absorbance values at 710 nm were subtracted from these measurements. Data pigment contents were calculated from these data:Pigment content in the leaves was measured photometrically with an Evolution 2000 UV-Vis . A vessel-free leaf segment (0.5 cm− 1): Chl A = 12.0 × A663.8–3.11 × A646.8.Chlorophyll A : Chl B = 20.78 × A646.8–4.88 × A663.8.Chlorophyll B: : Chl A + Chl B = 7.12 × A663.8 + 17.67 × A646.8.Total chlorophyll : Crtx + c = (1000 × A480–1.12 Chl A – 34.07 Chl B) / 245.Carotenoids . The fresh leaf was obscured by clipping after 20 min to set up a dark-adapted state. Chlorophyll fluorescence was excited by a 660 nm solid-state light source, with filters blocking radiation longer than 690 nm. Saturation of the photosystem being measured was achieved by using a filtered 35 W halogen lamp (350–690 nm) with a pulse of 15,000 μmol m− 2 s− 1 during 0.8 s.The chlorophyll fluorescence [variable fluorescence (Fv)/maximal fluorescence (Fm); μmol mWater potential , a measure of the energy status of the water in a system, was measured using a dew point PotentiaMeter . The leaves of the plants were placed in a disposable syringe, the air was drawn off from the syringe, and the syringe was tightly closed with parafilm. The specimen was frozen at − 18 °C, then thawed, and the sap flow was pushed out into the measuring chamber of the PotentiaMeter.N; μmol CO2 m−2 s−1) and the rate of transpiration  were determined with the portable gas exchange system LCpro+ . The water-use efficiency parameter (WUE) was calculated from these determined values (WUE = PN/E). Values of PN and E were determined between 8:00 and 11:30 Central European Time (CET) and conditions of measurement chamber were described previously [The net photosynthetic rate  by Statistica 12.0.All data were checked for homogeneity of variance and normality by Levene and Shapiro-Wilk tests. Collected data did not meet the conditions for the use of analysis of variance (ANOVA) and were thus evaluated by non-parametric Kruskal-Wallis test in the Statistica 12.0 program . Significant differences were assessed as effect of i) treatment on physiological parameters and ii) age of fronds on physiological parameters. A principal component analysis (PCA), in the CANOCO 4.5 program, was applied to all collected data as a single set. We used standardisation of species because data of different characters were analysed together. PCA was used to draw correlations from the complex data set. The results were visualised in the form of bi-plot ordination diagrams using the CanoDraw program . CorrelaAdditional file 1. Table S1. Content of elements and physiological parameters in young and old fronds of P. cretica var. Albo-lineata growing on low As dose – As100.Additional file 2. Table S2. Coefficients of variation  for the content of elements, DNA methylation and physiological parameters in P. cretica var. Albo-lineata.Additional file 3. Figure S1. Ordination diagram showing the results of PCA analysis with selected parameters in fronds of P. cretica var. Albo-lineata growing on low As dose – As100. Treatment abbreviations: control, treated with 0 mg As kg− 1 soil; As100, treated with 100 mg As kg− 1 soil. Parameter abbreviations: Crt, carotenoids; Chl A, chlorophyll a; Chl B, chlorophyll b; Σ Chl, total chlorophyll; WP, water potential; PN, net photosynthetic rate; E, transpiration rate; Fv/Fm, fluorescence; 5mC, 5-methylcytosine; As, Cu, Mg, Mn, S and Zn; total content of elements. The first axis of the PCA analysis explained 74% of the variability of all analysed data, the first two axes explained 94% of the variability, and the first four axes together explained 99% of the variability.Additional file 4. Table S3. Linear correlation of As and 5mC with selected parameters of P. cretica var. Albo-lineata growing on low As dose – As100.


Infants born to HIV-infected mothers are more likely to be low birthweight (LBW) than other infants, a condition that is stigmatized in many settings worldwide, including sub-Saharan Africa. Few studies have characterized the social-cultural context and response to LBW stigma among mothers in sub-Saharan Africa or explored the views of women living with HIV (WLHIV) on the causes of LBW. We purposively sampled thirty postpartum WLHIV, who had given birth to either LBW or normal birthweight infants, from two tertiary hospitals in Accra, Ghana. Using semi-structured interviews, we explored women’s understanding of the etiology of LBW, and their experiences of caring for a LBW infant. Interviews were analyzed using interpretive phenomenology. Mothers assessed their babies' smallness based on the baby's size, not hospital-recorded birthweight. Several participants explained that severe depression and a loss of appetite, linked to stigma following an HIV diagnosis during pregnancy, contributed to infants being born LBW. Women with small babies also experienced stigma due to the newborns' "undesirable" physical features and other people's unfamiliarity with their size. Consequently, mothers experienced blame, reluctance showing the baby to others, and social gossip. As a result of this stigma, women reported self-isolation and depressive symptoms. These experiences were layered on the burden of healthcare and infant feeding costs for LBW infants. LBW stigma appeared to attenuate with increased infant weight gain. A few of the women also did not breastfeed because they thought their baby's small size indicated pediatric HIV infection. Among WLHIV in urban areas in Ghana, mother and LBW infants may experience LBW-related stigma. A multi-component intervention that includes reducing LBW incidence, treating antenatal depression, providing psychosocial support after a LBW birth, and increasing LBW infants’ weight gain are critically needed. Low birth weight (defined as weighing <2500g at birth), caused by preterm birth <37weeks) or intrauterine growth restriction , is a le7weeks orLBW can have significant negative effects on child development, caregiver’s health, and family socioeconomic wellbeing. Short- and long-term mild to severe morbidity and disability, including growth failure, stunting, respiratory problems, and mental illness, are more prevalent among LBW compared to normal birthweight (NBW) –8 infantHIV significantly increases the risk of LBW in sub-Saharan Africa . In a meDeath Without Weeping, in northeast Brazil  . Adwen adwen, or its derivative, dwen dwen, is a common idiom used in Ghana by clinically depressed patients , which greatly affected me. I lost the desire to eat. I was filled with adwen adwen. I think my lack of eating and the adwen adwen had an impact on my baby… When you hear that you are infected for the first time, it is not easy because you think about what may have went wrong…I am a wedded wife, too. I wanted to abort the baby because I was afraid that I might infect the baby.” [P31]“asram , and inadequate nutrition (e.g. We concluded that the woman and the baby were not well fed that is why the baby’s weight was low.” [P11]) as causal factors. Participants also observed that not all of the babies they saw at the NICU were born to WLHIV. As one mother stated: “Some of the mothers at the NICU were not infected with this illness, but they also gave birth to small babies. What about that?" [P32]. Maternal illness, particularly excessive vomiting during pregnancy, and preterm birth were the most common non-HIV factor discussed.Several mothers did not believe that HIV contributed to having a LBW birth, citing instead causes including birth history, maternal illness during pregnancy , prematurity, infant illness at birth, Na wosa paa" , 2) "Na wo ye ketewoa bi" (the child was tiny), and 3) Na wo ye kete kete (the child was tiny tiny)." Some babies were LBW, but their mothers did not consider them kete kete. Other names included the English word “premature (the most common),” "aketew" (the tiny one), "obumpa" ," "kukuba"  and “Asram kotrɛ” . Designation as being small did not always occur at the time of birth. Some participants with NBW babies indicated that their babies were born “normal” or “big” but became small later because they lost weight.Participants based their assessments of their babies' smallness not on the hospital-recorded weight but rather on the baby's appearance. Mothers commonly used three phrases to describe the size of their babies at birth: 1) "“Any time I went to the NICU, I did not feel good. Sometimes, I felt they would tell me the child has died.” [P32]).None of the mothers with small babies, except one, associated a baby’s size with a long-term disability; however, the majority seemed to be aware of the poor chances for survival of LBW infants. Mothers who described their babies as small, compared to those who did not, reported more fear and uncertainty about their infants' survival because of their size, particularly among those who were hospitalized at the NICU. As one stated: Fig 1. It is important to emphasize that several participants did not report experiencing negative treatment from individuals within their family and social circles. Among these participants, many said their family members or friends had seen a small baby before. One stated: “Most of them had seen a premature baby before and had positive views about their future outcomes. [P33]” Some did not let others see their baby to avoid social stigma. One group that mothers felt did not stigmatize them were healthcare workers at the NICU. All the participants who had children admitted to the NICU praised the healthcare staff. They felt that the staff made them feel "like human beings" and did not "shout or yell" at them. They also called their "baby by their [mother’s] name " and treated the babies "as if they were adults."While none of the WLHIV with NBW babies reported experiences or expectations of stigma relating to their baby’s size, about half of the participants with LBW infants did. Relying on the women’s accounts, we describe the sources, spectrum of experiences, effects, and management of LBW stigma below. We illustrate the relationships between these dimensions of stigma in Most participant narratives indicated that stigma toward small babies and their mothers was closely connected to the babies' 'undesirable' physical features and people's unfamiliarity with the baby's size. These two factors led to what Goffman has called a "spoiled" identity . SeveralI said 'No—that could not be my baby, and that it was an animal, and I cannot believe that I have given birth to such a baby.'…There were some of the mothers sitting outside, and they were talking about me." [P08]"fatter" or "stronger" over time, if they are well-nurtured.Despite this negative characterization, in a few cases, there were also positive reactions—that LBW infants are resilient and could overcome their low weight and reduced chances of survival and become "Some mothers reported that the attributes of their baby resulted in negative social interactions toward them and their child. A wide spectrum of reactions discussed ranged from an expression of surprise to overt restriction of social support to the mother-infant dyad. Women seemed to feel that society saw them as responsible for the birth of such a small child, as illustrated in this quote:She [my sister] asked me, 'Why have you brought such a small into this house? You are always pointing out the flaws in others' children and insulting them, have you seen what you have given birth to? Is this what you have given birth to?'… I told her to leave me alone." [P06]" In this modern Ghana, when you have such a child, people would not to come around you and your child. [P01]” Gossip, name-calling, and unwelcomed stares were experienced by some of the participants. For example, one woman described how people close to her home would call her “kangaroo” (a reference to the well-known “kangaroo mother care (skin-to-skin)” method for caring for LBW infants) as an insult: "When I used to go to the NICU, I would tie her [the small baby] on my back, and so when people saw us coming, they would yell: "kangaroo" is coming." [P19]Women also said that their friends or neighbors sometimes refused to visit mothers with small babies. For example, "Another example of social stigmatization is the experience of maternal blame perpetuated by other mothers or non-NICU healthcare workers:Oh! They [women at the postnatal clinic] also stare. It's not different. They really stare at you!…when I [also] went there [postnatal clinic], they [nurses] blamed me that I was not giving the child breast milk [and] that is why the baby looked the way it did." [P25]"One participant’s secondary account suggests that expectations from family members, along with stigma from others, constrained the choices of mothers of very small babies and contributed to child abandonment, although mothers resisted this pressure.Stigmatization goes with preterm delivery… Some people can advise the mother to terminate the child's life… Some people, if they do not terminate the child's life, they will abandon the child…Some cannot withstand the social pressure. For example, a teenage girl had this preterm baby, and her sister advised her that she should strangle her, but the mother did not have the courage to do so. They then quietly abandoned the baby [at the hospital]. People can say: "Go and dump the baby in the bush or by the riverside because the baby is too tiny…They are afraid. They feel they have invested so much into the pregnancy—the time, the stress, and the resources. The expectations they have, you know, have been interrupted… Some of them are afraid of the stigmatization—If I send this child home, what will my mother- or father-in-law say? What will society say? Will they accept the baby? Will my husband understand the situation?" [P11]"adwen adwen I told the nurse that this animal was not my baby because when I give birth, my babies are beautiful—and why is this one like this? I told them to look for my baby.” [P08]Another effect was self-imposed social isolation of the mother-infant dyad that emanated from the reluctance to show the baby to others (described earlier), which also limited the child’s interaction with others. In contrast, interviews with mothers with NBW babies suggest that infants had more family members and neighbors interact with their children. Moreover, the social pressure some mothers faced (discussed earlier) unduly contributed to child abandonment. Maternal rejection of the infant was observed in one interview: “It is essential to point out that, the emotional, social, and psychological effects were similar to those that many women described they faced at the NICU, because of the poor survival chances of LBW infants and the limited control they had over their child’s care at the NICU.Oh!, she was very small. I did not even know she would live. [It] made me unhappy because I wondered if she would make it.” [P18]“They do not allow you to come close [to some of the babies]. Every day, the baby would cry [at the NICU] and you could not do anything. [Sometimes] you just went there and watched [through the doors] because you [generally] heard a baby cry. As a mother, you feel something, like a sting, inside of you, but you cannot do anything… Sometimes you do not see your child with your own eyes. You feel unhappy. You feel dull. You feel fear…You do not want the baby to die!” [P27]“Mothers with NBW infants did not report emotional and psychological difficulties based on their infants’ size.Most mothers with small babies were very reluctant to show the baby to others. In contrast to mothers with NBW infants, mothers with LBW infants reported using various strategies to prevent others from seeing their infants because of their size and appearance. These strategies included making excuses to prevent others from visiting them, hiding their babies before a visit, avoiding public transportation or covering the babies, and delaying the “outdooring” of the infant, a naming ceremony in which the child is symbolically given an identity as a human being . The parOne day, we were outside of the room to get some fresh air, and I didn't know that she [a family friend] was coming to visit me. When she made it closer to the house, I quickly took the baby inside. I told her that she could not visit because we had not officially "outdoored" the baby…It was not until we did the outdooring that we let our neighbors see the baby. We were able to bring him out because he looked much better than when he was born.” [P25]“…I waited until no one was around before I bathed her…[because] they would have said that the child was small and all that" [P18]. One mother who did not want to keep her baby in-doors or regulate her childcare practices in her compound house suffered the worst social mistreatment of all the participants in the study. She was labeled a witch, experienced withdrawal of social support, gossip, and pressure to leave her home. She also felt her neighbors might have known her HIV status.One emerging theme was that women's socioeconomic status strongly influenced their ability to regulate people's exposure to their child. Mothers who lived in a single-family housing (such as their own home or apartment) were able to control when and how others saw their child more so than women who lived in a multi-family compound house, which has a shared courtyard and amenities . A compoThey said the child was too small and that I should take her to my mom [which she later did]…The child cried very loudly too often, so when I bathed her [in the compound], people would approach, and see how tiny she was. They thought I was a witch… The child was small [so] they used to whisper among themselves… They might have heard that I had gotten this illness [HIV]…[because] the person who was supposed to help me bathe the baby was later reluctant to do so… As for my child, I brought her outside early since she did not like to stay indoors…” [P17]“The strategies used to endure stigma and manage the broader psychosocial challenges associated with the care for LBW infants varied across participants. These strategies included regulating visitations, seeking social support for feeding and encouragement from others, disregarding negative comments, resisting maternal blame, and recognizing that there were others with LBW babies facing similar or even more difficult challenges. For example,At that place (NICU), when you see other people's babies, you will be thankful for your baby; even those parents [with smaller and sicker children] …are [finding reasons to be] thankful, how much more me?” [P30]“You cannot question me! I did not hide the baby because the baby was full term. He was nine months old when he came out. I cannot throw the baby away, so why would I be worried about what people think about his smallness?… Is it compulsory that the baby has to be healthy?… Other kids are big, but they are not healthy.” [P27]“adwen adwen described her daughter who weighed 1.2kg at birth:One observation from the data was that the negative psychosocial effects related to LBW infant care and stigma were attenuated with adequate infant weight gain, an outcome that consistently resulted in relief and pride. One of the participants who had experienced severe She had really put on weight by the fourth month… When we go to the clinic now, the doctors and nurses all run to receive her because they know she was a premature baby. They all get excited because they know I have taken good care of her [participant smiles and shows interviewer her baby's picture].” [P31]“At Korle Bu, even if you have health insurance, after you are discharged, they will give you a bill to pay." [P09]. The NICU also did not have space for mothers to stay overnight with their babies. Consequently, some mothers with financial means paid for accommodation and food on-site. Others went home and paid for the commute. As one mother pointed out, some of those who could not afford their hospital costs do not return. Moreover, the two hospitals also did not have a pharmacy at the NICU, so mothers had to locate and purchase prescribed medications elsewhere.Stigma was not the only lived experience of WLHIV with LBW infants. Care of LBW infants also required financial investments from families. Hospital admission-related costs were the major, but not the only, source of economic strain. Limited resources at the NICU compounded the burden. Mothers said that they paid for the number of days the baby stayed in the NICU or general pediatric wards. One woman explained: “The children of some of the mothers are admitted to the NICU for a long time… [but] they do not have a place to sleep. Some [women], too, prefer to go home and come back [the next day] since they are unable to pay the ward bills…Some [who are unable to pay] even do not come back because the NICU will still take good care of the baby if they do not…The food I bought from the NICU was quite expensive. It was 40 Ghana Cedi (~ U.S. $10) [a day]…The place [NICU] also does not have a pharmacy…I had to go the suburbs of Accra to find some of the prescribed medications. It is not good for a mother who has just given birth to roam in search of a medication. Women who have had a cesarean section, upon their return, sometimes collapse at the NICU because of the stress they had to go through.” [P23]“Another source of economic stress was buying infant formula. Desire to prevent mother to child transmission of HIV was the most common reason for needing formula, but a few of the women also did not breastfeed or weaned early because they thought their baby's small size suggested that the child was already infected with HIV.It was there [at the hospital] that I decided not to breastfeed, but use baby formula instead…I did not want her to be infected through the breastmilk since the virus may be in my blood… Every nursing mother would testify that it [the cost] is a problem. I just even called someone for money to buy food for her because she will be running out of food soon. Just one can of baby food costs GHC 25 (~$5).” [P19]“I initially wanted to breastfeed him, but because of his small size, I thought he was infected [with HIV]; I weaned him from breastfeeding as a result [in order not to give him more of the virus]…My other children even breastfed for more than a year.” [P05]“This study is the first to examine lived experiences of WLHIV with LBW infants in a sub-Saharan African context. Their experiences and perceptions of LBW reveal the sociocultural context of stigma toward LBW babies, the structural context that shapes it, and the burden that stigma places on individual mothers and their infants. Collectively, mothers attributed LBW to varied and nuanced causes or influences, including maternal , infant , and social (HIV stigma) factors. Participants reported significant negative consequences of LBW for both maternal and infant wellbeing, including maternal depression and isolation, which compounded the economic and psychological difficulties associated with NICU care. Women in the study demonstrated agency by resisting blame and leveraging social and cultural norms to avoid enacted stigma.Both Lupton and Merleu-Ponty's discourse on interembodiment, the idea that primary caregivers (such as a mother) and their infants' bodies are intertwined, argue that through pregnancy and childcare practices, the experience of a mother is inseparable from that of the infant , 45. AltBased on our findings, the nature of social stigma towards small babies in Ghana appears to be distinct from other settings, in that it is not tied to their future capabilities and productivity. In contrast, a Korean study found that the source of stigma toward LBW infants was more related to children's potential future mental disability than appearance . HoweverStigma is inherently connected to structural violence, or the disadvantages and harm that social, economic and political systems place on certain groups , 48. LBWWhile other studies have reported psychological and emotional stress mothers bear due to fear that their baby may not survive, our work suggests that the conditions of urban WLHIV may exacerbate and prolong maternal mental health concerns. Previous studies of the experiences of LBW and preterm babies have mostly focused on HIV-uninfected mothers' experiences, particularly in the NICU , 33, 35.The results have implications for public health and clinical practice. As part of efforts to reduce the prevalence of LBW and preterm birth, pregnant women should be screened and treated for depression. One meta-analysis with 25,663 women found that untreated antenatal depression increased the odds of LBW and preterm birth by 96% and 56%, respectively . A critiEfforts should also be made to reduce stigma related to preterm birth and low birthweight, especially targeting WLHIV. Depressive symptoms and social pressure the study participants faced calls for NICU teams in Ghana to include mental health practitioners. Moreover, linking women to existing mother-to-mother support groups could leverage the experience of mothers who have lived through these challenges to support newer mothers. Finally, LBW stigma and psychological difficulties related to LBW infants’ care among WLHIV in urban areas of Ghana appear to diminish with an infant’s increased weight gain. Thus, nutritional and nurturing care interventions that increase weight gain in LBW infants are recommended.Our study has several limitations. First, our participants included only women living in an urban area. Further, because all women in our study had HIV, we do not know if these women were also different from the general population in other ways, thus the transferability of our findings to different parts of Ghana is unknown. Future studies should include rural women, relatives of mothers with small babies, and health workers to give a holistic picture of women’s experiences. A strength of our study is that it is one of the few investigations in sub-Saharan Africa that has used qualitative methods to get an in-depth understanding of newborn size as a stigmatized condition. Furthermore, the development of a conceptual model around stigma towards the mother-infant dyad in this setting could serve as a framework for measuring and evaluating the effects of this stigma in Ghana and other similar sub-Saharan Africa settings.Being born small at birth is a cause of stigma against mother-infant dyad among WLHIV in urban areas of Ghana. Our findings suggest that LBW stigma in the short term may contribute to poor maternal mental health outcomes and maternal-infant isolation. The findings support a multi-pronged approach, including prevention of LBW, sensitization, counseling, and a multi-disciplinary health care team to address this stigma and its consequences.


O-methyltransferase (COMT) 158MetVal genotype and early-life environmental adversity involved in the risk of inattention and hyperactivity/impulsivity symptoms. In this prospective longitudinal study, we examined for the first time the impact of proximal and distal early-life family adversity and 158MetCOMT Val polymorphism gene – both the direct and the interactive effects, on children’s ADHD symptoms across childhood. Data came from the Family Life Project, a prospective longitudinal study of 1,292 children and families in high poverty from birth to 11 years. In infancy, data regarding socioeconomic (SES)-risk-factors, observed-caregiving behaviors, and DNA genotyping were collected. In early and middle childhood teachers rated the occurrence and severity of the child’s ADHD symptoms. Multilevel growth curve models revealed independent effects of COMT, early-life SES-risk and negative caregiving on ADHD symptoms in early and middle childhood. Significant gene-environment interactions were found, indicating that overall, carriers of at least one 158MetCOMT allele were more sensitive to early-life adversity, showing higher inattention and hyperactivity/impulsivity symptoms severity in childhood when exposed to high SES-risk factors in infancy, compared to Val-Val carriers. Findings provide new insights into the complex etiology of ADHD and underline the need for further investigation of the neuronal mechanisms underlying gene-environment interactions. Findings might have implications for prevention and intervention strategies with a focus on early-life family relationships in genetically at-risk children.Attention-deficit hyperactivity disorder (ADHD) is among the most commonly diagnosed psychiatric disorders of childhood. The dopaminergic system has been shown to have substantial effects on its etiology, with both functional Catechol- Attention-deficit hyperactivity disorder (ADHD) is one of the most prevalent childhood-onset neurodevelopmental disorders, affecting approximately 7% of children and adolescents . ADHD isADHD is a complex and heterogeneous disorder, and its etiology is not yet completely understood . Both geO-methyltransferase (COMT) 158MetVal (rs4680) polymorphism  substitution at codon 158. The Val158COMT enzyme is thermally more stable than the Met158 version, and catecholamine breakdown is about 40% more efficient in Val-homozygotes, thus conferring lower synaptic DA levels in PFC . We would not expect to find such differences between groups under low levels of early-life adversity. Second, we expected that children with Met allele would be more sensitive to early adverse environments (show a steeper positive slope) and would exhibit a significant increase in ADHD symptom severity as a function of early-life adversity.Several studies have supported such GxE interactive pattern by showing that under high psychosocial stress, Met-carriers, compared to Val-homozygotes, showed greater impairments, such as reward hypersensitivity , slower N = 1,292) living in two rural areas of high poverty: three counties in North Carolina and three in Pennsylvania (The Family Life Project (FLP) was designed to study families  coding system . To crealack of positive caregiving. Therefore, we include positive caregiving as a control in our model.Global ratings of primary-caregiver behavior were made based on a scale adapted by Cox and Crnic (1999) from the NICHD Early Child Care Research Network (1999) . Videos p < 0.001, missingness by marker <5%, missingness by sample <5%, affirmative relationship checking in PEDCHECK, and Mendelian inconsistency caused genotypes to be dropped at that locus. In the current study, the sample was divided according to the presence or absence of the rare Met allele, by comparing rs4680 Val/Val homozygotes with pooled heterozygote and homozygote carriers of the Met allele . This approach was based on the dominant genetic model, as recommended by previous studies . Forty nanograms of DNA were combined in a volume of 5 ml with 2X Universal PCR Mix (Applied Biosystems) and 1/20 the volume of the Taqman SNP assay in a 384 well plate. A Pre-Read was performed and then PCR as follows: a 10 min hold at 95°C, followed by 40–45 cycles of 15 s at 92°C and then 1 min at 60°C in a 7900HT PCR System. After amplification, a Post-Read was performed to analyze. Automatic and manual calls were made . SNPs wees e.g., , and was(I)Compared with the Val/Val homozygotes, the Met-allele carriers  tend to have one-fourth less COMT enzymatic activity  and are (II)Met-carriers exhibited smaller striatal GMV than the Val-Val genotype , p. 2, w(III)Distinct associations between Met-carriers and Val-Val-carriers and social impairment, ADHD and other psychiatric disorders e.g., .(IV)ADHD children who were Val-Val-carriers had significantly better sustained attention  and cognDSM-IV ADHD symptom severity over the last 6 months. The instructions were as following: “We would like some information about this child over the course of the LAST 6 MONTHS. Please tell us how often this child does the following:”. All 18 DSM- IV symptoms for ADHD were rated on a 4-point Likert-like scale . In this study, we focused on separate inattentive and hyperactive/impulsive ADHD factors scores. A mean of inattention ADHD score and a mean of hyperactivity/impulsivity ADHD scores were created separately. Teacher’s inattention and hyperactivity-impulsivity ADHD scores served as the two primary outcomes  to 3 (very much). The instructions were: “Read each statement and rate how much it described your behavior when you were between 5 and 12 years of age:”. A mean of retrospective report of inattentive behaviors, and a mean retrospective report of hyperactive-impulsive behaviors were created separately. Primary-caregivers’ inattentive and hyperactive/impulsive ADHD scores served as covariates in the current study  and early environmental risk factors , along with interactions capturing the moderation of each environment variable with the gene were evaluated. Controls for: race, sex, state, age, the primary-caregiver’s ADHD symptoms, and the positive caregiving composite were included in all models. It may well be that primary-caregivers with a specific genetic variant of COMT have an increased probability to use maladaptive caregiving strategies or of being exposed to unstable and risky environment because they have a genetic disposition toward inattention and/or impulsivity, and in such a way transmit a genetic risk for ADHD on to their children . Since primary-caregivers’ genotype might affect the relation between early-life family environment and children’s ADHD symptoms  to construct standard errors and P-values.In these multilevel models, growth was modeled as a quadratic in age. Random effects for the intercept, linear slope and quadratic change over time were chosen in models for both outcomes using the AIC . All thrCOMT genotype was missing on about 30% of children in our study. Instead of deleting cases, we used a Chained Equations . Note that both FIML and MI-based approaches relied on the assumption that missingness is “at random” , missing subjects scored lower on key variables such as ADHD symptoms and environmental risks . However, after imputation, all the analysis samples had means much more closely aligned with the available case means.To control for potential bias due to missing data, we use multiple imputation MI;  methods,ns MICE;  approachom” MAR; . For exaCOMT data due to loss of follow-up/those with data and categorical variables  and slightly lower, but not significant positive caregiving scores . When we observed outcomes, we saw no difference in the distribution of ADHD symptoms for those missing COMT or not. We performed a further set of robustness checks. While it is common procedure to multiply impute all missing predictors and all outcomes of interest  in the eight reported effects using the work of COMT genotype) and outcome variable (ADHD symptom severity) are significantly related (at a 0.05 level). The range presented covers 95% of the observed environmental factor (±2 SD). In Following X2 statistics were used to analyze the association between child COMT genotype and other categorical variables (race and sex), and multiple regression analyses were used to examine the association between genotype and continuous variables (SES-risk and negative caregiving). Frequencies for 158MetCOMT Val genotype are reported in COMT genotype was unrelated to sex, X2(df = 1) = 0.065, P = 0.798, but was associated with race, X2(df = 1) = 56.007, P < 0.001. African American race was associated with greater odds of having Val-Val genotype, OR = 2.92, 95% CI .Pearson COMT as a predictor of SES-risk scores and negative caregiving scores using multiple regression analysis with controls for race, state and sex. There was no overall association between COMT genotype and SES-risk, beta = −0.05, P = 0.23, and no overall association between COMT genotype and early negative caregiving, beta = −0.06, P = 0.11. Descriptive statistics for primary study variables and corresponding bivariate associations appear in To test for the presence of Gene–Environment correlation (rGE), we examined COMT was not significant in either period. The main effect for negative caregiving was significant for both early and middle childhood, with higher levels of negative caregiving during infancy predicting greater hyperactivity/impulsivity symptom severity. The main effects for SES-risk were not significant in either period. The interactions between COMT and SES-risk were significant in both early and middle childhood. The interaction between COMT and negative caregiving was significant only in middle childhood but not in early childhood. However, this effect was not identified in our preliminary listwise-deletion-based model and isolated to specific levels of SES-risk identified in exploratory analyses. We took this to indicate that it was not robustly supported in our data.As seen in COMT was not significant in early childhood but significant in middle childhood, showing that children carrying Met allele had higher levels of inattention severity symptoms compared to Val-Val carriers. The main effect sizes for negative caregiving in both early and middle childhood were significant, with higher levels of negative caregiving during infancy predicting higher inattention symptom severity. The main effect sizes for SES-risk were significant in early and middle childhood, suggesting that higher SES-risk during infancy predicted greater inattention symptom severity. The interactions between COMT and negative caregiving were found non-significant in both time-periods. The interaction between COMT and SES-risk was found significant only in middle childhood but not significant in early childhood, even though a similar pattern of interaction was found.As seen in To illuminate the nature of the four significant GxE interactions, we plotted regression slopes of early-life adversity (SES-risk and negative caregiving) on ADHD symptom severity separately for children with Val-Val genotype and at least one Met allele . Next, wP = 0.13), and Val-Val carriers (P = 0.08). In Panel B, the effects of SES-risk on ADHD-Inattention in middle childhood was significant only for Met carriers (P = 0.003) but not for Val-Val carriers (P = 0.26) In panel C, the effects of SES-risk on ADHD-Hyperactivity/impulsivity in middle childhood was significant only for Met carriers (P = 0.007) but not for Val-Val carriers (P = 0.49).In addition, we conducted simple slopes analysis. In COMT gene 158MetVal polymorphism on ADHD symptoms across childhood in population sample of low-income children. Our findings show that both proximal factors, such as the quality of caregiving, and more distal ones, such as family income, caregivers’ education, neighborhood safety and household density, are related to developing childhood ADHD symptoms, as reported by child’s teachers. Previous studies have shown that teacher rating made a stronger contribution to the prediction of ADHD dimentions than parent ratings , and minor(s)’ legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this manuscript.EA and CB contributed to the conception and design of the study. EA and MS organized the database and performed the statistical analysis. EA wrote the first draft of the manuscript. MS and CB wrote sections of the manuscript. All the authors contributed to the manuscript revision, read and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


To evaluate the differences of ocular abnormalities between children with attention deficit hyperactivity disorder and non-attention deficit hyperactivity disorder children using siblings of cases in Jordan.A case–control study of 55 children with attention deficit hyperactivity disorder, and 55 children without the disorder as a control group using siblings of cases. Examination included visual acuity, motility, anterior and posterior segments, convergence, optical coherence tomography and corneal topography.Thirty-eight patients from the attention deficit hyperactivity disorder group had visual acuity better than 0.8 in both eyes; 36.4% had normal cyclorefraction, while 54.5% had mild hyperopia. Most of them did not need glasses. Tomography showed normal values with no statistically significant differences between the two groups. The near point of convergence showed significantly abnormal values in 41.9% of children with attention deficit hyperactivity disorder. Pentacam measurements showed normal values with no statistically significant differences between the two groups.Children with attention deficit hyperactivity disorder show significant low near point convergence compared with the study control group. •ADHD is one of the most common neurodevelopmental disorders of childhood.•It is important to rule out underlying ocular conditions.•Children with ADHD show significant low near point convergence.•All children with ADHD should undergo an ophthalmological assessment. The repTwo studies were performed in Jordan to determine the prevalence of ADHD with differing results. The first was conducted in the north of the country and found that the prevalence was high compared to other countries with prevalence rates of combined type ADHD of 20.21%, hyperactivity–impulsivity of 9.58% and inattention of 10.83% . The secThe emotional and behavioral problems associated with ADHD may interfere with nearly every aspect of a child's life, including family and sibling relationships, peer relationships, academic performance, planning, and task completion ,9,10.While it is definitely common practice to rule out any underlying neurological condition that might cause behavioral aberrations in children, it is still uncommon to refer these children to an ophthalmologist to rule out underlying ocular conditions that might interfere with the child's attention .Various ocular conditions can be identified by simple screening. One of those that might have an influence on the child's behavior or his attention span during various activities like studying and reading is convergence insufficiency (CI), which was found to be significantly higher in our study group. CI can have a high impact on the patient during near viewing causing diplopia, blurred vision, asthenopia (eye strain) and slow reading . This caThis study aims to identify the ocular disease in children with ADHD, and to identify whether any specific ocular abnormality would be linked to their lack of attention. Also, this study evaluates the differences of ocular problems between children with attention deficit hyperactivity disorder and non-attention deficit hyperactivity disorder children using siblings of ADHD children in Jordan.2Fifty-five children diagnosed with ADHD from pediatric psychiatry clinic at KAUH were enrolled in this study as a case group, and 55 siblings of case group as a control group. All participants were assessed for all tests related to the study. ADHD was assessed using DSM-5 diagnostic criteria for cases. All ADHD cases who met the DSM-5 diagnostic criteria and checked by pediatric psychiatry consultant were eligible to participate in the study. Siblings of cases were eligible to put as control group and were confirmed not to be ADHD using the same DSM-5 diagnostic criteria and checked by same pediatric psychiatry consultant. Any participant in both groups with any comorbid psychiatric disorders, missing data and incomplete examinations were excluded.The parents were asked to enroll their children in this study and a written consent forms were obtained from the parents. The study was approved by the Institutional Review Board Committee at our institution before data collection. It was conducted over a period of 18 months, from October 2017 until April 2019. As summarized by the Centers for Disease Control, the diagnosis of attention disorders requires six criteria to be present in a child under the age of 17 years . Those iMethylphenidate  was prescribed according to weight and response for ADHD group. Arrangements were made to attend the pediatric ophthalmology clinic for cases and their siblings.Visual acuity was measured in all participants in the study group. Different methods were used according to the patient's age and cooperation. In 46 patients in the ADHD group, visual acuity was obtained using a Snellen chart , E letters and pictures, while in nine patients, vision was measured by the central, steady maintained (CSM) method because they were uncooperative and lost attention during the exam.The anterior segments of both eyes were examined using a slit lamp . Ocular alignment and extraocular motility examinations were performed in all children. Hirschberg's test, cover-uncover, and alternate cover tests were performed. The near point of accommodation (NPA), and near point of convergence (NPC) were measured using an RAF binocular gauge rule .Cycloplegic refraction was performed in all children, 30–45 min after the last instillation of 1% cyclopentolate eye drops  at 10-min intervals. A Welch Allyn Retinoscope  was used by trained senior ophthalmology residents or by the pediatric ophthalmologist. Detailed fundus examinations were performed. Corneal topography using an Oculus Pentacam Type 70,700  and optical coherence tomography of the macula  were conducted.Glasses were prescribed when appropriate, giving either the full correction to patients found to have strabismus, or according to the post-mydriatic test for subjective refraction. Patients who had ocular findings, who required glasses, or who needed another intervention including strabismus correction surgery were followed up.t-test and ANOVA were applied to examine the significance level for continuous normally distributed variables.Data were analyzed using SPSS software, version 20 . Data were presented as frequency distributions for categorical variables and mean ± standard error of the mean for continuous variables. Data was tested at a significance level of 0.05%. Pearson χ2 test was used to investigate the significance of association between categorical variables, while student's The work has been reported in line with the STROCSS criteria . The wor3A total of 110 children were included, 55 children in the ADHD group, and 55 in the control group. Also, Values for near point of convergence (NPC) are summarized in It was found that 16.4% of children with ADHD group have reduced NPC compared to 3.6% in the control group. In addition, 25.5% of the ADHD children had abnormal NPC results compared to only 1.8% in the control group.4Recently, an increase numbers of children are being diagnosed with ADHD worldwide. This study aims to evaluate the differences of ocular problems between children with attention deficit hyperactivity disorder and non-attention deficit hyperactivity disorder children using siblings of ADHD children in Jordan. It was found that ADHD children show significant low near point convergence compared with the control group. Many centers consider a complete ophthalmological exam mandatory for children diagnosed with ADHD. However, this is not a worldwide regular practice.This study showed that there was no statistically significant difference in visual acuity, motility and ocular balance, fundus exam, OCT of the macula, and in Pentacam values between the ADHD group and controls. On the other hand, the near point of convergence (NPC) was significantly different between the groups. This confirms the results obtained in a study by Granet et al. in which the charts of 266 patients with CI were reviewed retrospectively, and in whom 9.8% were diagnosed with ADHD at some point.  The inciIn a case-control study of Fabian et al, a possible relationship between ADHD and undiagnosed refractive errors, concluded that both groups were comparable with regard to visual acuity at near and far distances, cycloplegic refraction and binocular function.  It showeMartin et al. compared the results of visual fields of children with ADHD before and after treatment with stimulants and showed a significant improvement from a subnormal visual field pretreatment to results comparable to the control group after treatment. .The fundus images obtained by Martin et al. showed subtle morphological changes to the optic nerve and retinal vasculature, with a small disc and rim compared to controls, which indicated early disturbance of the development of neural and vascular tissue in the CNS.  The presThis study, along with other studies, showed no statistically significant differences in the presence of refractive errors or strabismus amongst children with ADHD compared with controls.  The authThe parents of the child who underwent bilateral medial rectus recession for the correction of esotropia, reported that the child had become “quieter” and “more attentive”.This study has some limitations, first of all we have lost some cases and their siblings to do the ocular examinations because of different schedules time of ophthalmology clinic and psychiatric clinic, which resulted in a lack of a complete dataset of the visual field tests, therefore, no firm conclusions could be drawn. The second one that this study was conducted only at single hospital in Irbid; however, it is a referral tertiary teaching hospital receiving cases from all over the country. The third one that, we faced uncooperative cases whom ocular examination was not possible to be performed. It is suggested that future research should study the effect of ADHD on the visual field on a larger group and to do it on multi hospitals that is more amenable to follow-up.5This study concluded that children with ADHD show significant low near point convergence compared with the control group. This may prompt a policy where all children with ADHD should undergo an ophthalmological assessment.All authors  made substantial contributions to the conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.Not commissioned, externally peer reviewed.Institutional approval was obtained from the Institutional Review Board at Jordan University of Science and Technology. Written informed consent was obtained from the participants. This study was conducted in accordance with the Declaration of Helsinki.Written informed consent was obtained from the patient's parents for publication.The datasets generated and analyzed during the current study are available from the corresponding author.The authors declare that they have no competing interests.10.13039/501100004035Jordan University of Science and Technology to recruit the participants and investigate them ta (Grant number: 20170233).This article was funded by the Deanship of Research at


Attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders in children. Its occurrence and pattern of presentation are unknown in Botswana.To determine the prevalence of attention-deficit hyperactivity disorder (ADHD), associated comorbid conditions and risk factors amongst school-age children in Botswana.Primary schools in Gaborone, Botswana.This study used a cross-sectional design. A two-stage random sampling technique was utilised to select learners from 25 out of the 29 public schools in the city. The Vanderbilt ADHD Diagnostic Rating Scale (VADRS), teacher and parent versions, was administered.n = 884) were male, and their mean age was 9.53 years (s.d. = 1.97). The prevalence of ADHD was 12.3% (n = 213). The most prevalent presentation was the predominantly inattentive, 7.2% (n = 125). A family history of mental illness  and perinatal complications  emerged as the independent predictors of ADHD.Of the 1737 children, 50.9% (The prevalence of ADHD in Botswana is slightly higher than that reported in the literature, but the pattern of presentations and comorbidities is similar. A positive family history of mental illness and perinatal complications independently predicted ADHD. Mental health screening amongst families of the affected individuals and improved perinatal care should be considered as health care priorities in Botswana. It also exacts a huge psychosocial and economic burden on the family and the community.2Attention-deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders in childhood and affects 3% – 12% of primary school children.5It is associated with an increased risk of low self-esteem, poor interpersonal relationships, poor school performance, conduct problems, criminality, substance abuse and sexual promiscuity, which may increase the risk of human immunodeficiency virus (HIV) transmission.6 Symptoms include behaviours such as excessive talking, difficulty in paying close attention to details, difficulty in organising tasks and activities, fidgeting and an inability to remain settled in appropriate situations amongst others.6 According to the Diagnostic and Statistics Manual-5 (DSM-5) criteria, this pattern of behaviours should be present in at least two settings (such as school and home). It must also result in impaired performance in social, educational or work settings.6 Three presentations have been described in the DSM-5, and these include the inattention, hyperactivity and the combined.6Attention-deficit hyperactivity disorder is characterised by a pattern of reduced sustained attention and a higher level of activity in children or adolescents than expected for someone of that age and developmental level.8 No single factor has been identified or sufficient to cause the development of ADHD, but a composite interaction of nature and nurture had been shown to be contributory.9 It is commonly associated with other psychiatric disorders such as oppositional defiant disorder (ODD), conduct disorder (CD), anxiety disorder, mood disorders and psychosis.10 These associations are possibly because of shared genetic and environmental factors, including maternal illness, obstetric complications, exposure to heavy metals such as lead, substance abuse and head injury.11Attention-deficit hyperactivity disorder is more common in males, but the rate varies amongst the presentations.13 A prevalence rate of 11% was found amongst children and adolescents in the United States of America14 and 0.5% in the United Kingdom.12 Data from Africa found prevalence rates of 6% in the Democratic Republic of Congo,15 8.7% in Nigeria8 and 23.7% amongst medical students in Kenya.16 Anecdotal reports from private and public health facilities had confirmed that ADHD exists in Botswana as elsewhere. Previously, a 25% prevalence of ADHD was reported amongst children from the only tertiary psychiatry hospital,17 but the prevalence of ADHD in the community is yet to be ascertained. Furthermore, the youthful population profile in Botswana (Botswana Population Census Atlas 2011) makes this research relevant, as ADHD is predominantly a disorder of youth.1 Hence, this study aimed to determine the prevalence of ADHD, the presentations and associated comorbid conditions in a community sample of school children in Gaborone, Botswana. The study also explored the associated factors of ADHD, based on the findings from the parents’ interview. The present study hoped to add to the existing knowledge on the geographical variation and cultural disparities in rates of ADHD and its presentations. It additionally hoped to lay a foundation for further research and mental healthcare formulation for the affected children, who are yet to be identified in the community in Botswana.Epidemiological studies had reported varying prevalence rates across cultures and geographical regions of the world, with worldwide prevalence rates of as low as 0.5% to 20%.This was a cross-sectional study, which involved parent and teacher survey of primary school pupils, aged 6–12 years. The study was conducted in Gaborone, the capital city of Botswana. Gaborone is the most densely populated city, accounting for approximately 10% of Botswana’s total population (Botswana Population Census Atlas 2011). It is also representative of the reference population regarding the number of primary schools and ethnic distribution.Two hundred pupils were selected from seven regions in Gaborone to constitute 1400 participants, by using a two-stage sampling technique. Nonetheless, we increased the sample by 30%, anticipating a 30% attrition rate, which was calculated from a pilot study conducted earlier. A sample size of 1820 pupils was thus targeted.The data collection was carried out in two phases. The teachers were instructed on how to administer the Vanderbilt ADHD Diagnostic Rating Scale-Teacher Version (VADRS-TV) on the pupils whose parents or guardians provided written consent. Only the teachers who have been with the pupils for a minimum of 6 months were interviewed. The research assistants then followed up with parent interviews only for those who met the criteria for ADHD on the teacher version. The parents were instructed on how to rate their children on the parent version of the Vanderbilt ADHD Diagnostic Rating Scale-Parent Version (VADRS-PV). The research assistants helped those unable to read or write by reading out the questions and filling their responses on the empty questionnaires. Only the agreement between the two ratings was regarded as diagnostic of ADHD in this study based on DSM-5 diagnostic criteria of symptoms in two settings.18 is available in two versions, namely the parent version and the teacher version. These two versions are quite similar and are designed to assess disruptive problems modelled on DSM-IV criteria amongst children aged 6–12 years of age. The teacher version comprises 35 items, whereas the parent version has 47 items. The items represent DSM-IV criteria for ADHD predominantly but include items on the DSM-criteria for the ODD, CD, anxiety and depression. The items are rated on a 4-point scale with responses: ‘never’, ‘occasionally’, ‘often’ and ‘very often’. Only the symptoms that happen ‘often’ or ‘very often’ are regarded as present. The scale also includes eight items on classroom performance, peer relations and organisational skills, which are rated on a 5-point scale, but grouped into three labels, namely problematic, average and above average. Scores of ‘2’ on at least two, or ‘1’ on at least one of the performance questions, that is ‘problematic’ indicates dysfunction. To meet the criteria for the ADHD diagnosis, which is the outcome measure, pupils must have at least six positive responses to either the inattentive or hyperactive nine core symptoms, or both, plus a score that indicates ‘problematic’ in the performance section. These instruments had been used previously in African settings with comparable results.15 In addition to the questions on the VADRS-PV, some essential socio-demographic questions were asked of the parents. These included age, occupation, educational level, history of any mental illness in the family, history of perinatal complication, maternal illness or use of any substance in pregnancy and the number of children. Questions on the children’s age and gender were also included. The occupation was classified based on the 2008 Botswana Standard Classification of Occupations. It was classified into the upper occupational group , lower occupational group  and the unemployed. The parent version was translated to Setswana, by using the procedure of iterative back-translation by a panel of bilingual experts.Vanderbilt ADHD Diagnostic Rating Scalep-value of less than 0.05 was accepted as the level of statistical significance.Data were analysed by using the Statistical Package for Social Sciences (SPSS) for Windows, version 16.0. The descriptive statistical tools such as frequencies (%), mean and s.d. were used to present the prevalence of ADHD and other demographics. Continuous variables such as age were dichotomised by using the calculated mean as the cut-off. Pearson’s Chi-square tests were used to calculate differences between groups, such as the presence of ADHD, the outcome variable and gender. The relationship between ADHD and comorbid disorders, such as ODD and CD, was also tested by using Chi-square tests. A post hoc analysis was performed on those who were positive by the teachers’ rating. The relationship between identified socio-demographic risk factors and ADHD was explored using Chi-square tests and logistic regression. All tests were two-tailed, and a Permission to embark on the study was obtained from the Ethics and Research Committee of the University of Botswana (UBR/RES/IRB/BIO/016) and the Ministry of Basic Education (DPRS 7/1/5 XXX (18) PAO-Research). Letters were sent to the schools to inform the teachers and parents or guardians about the study. Their consents to participate were also sought in writing.Of the 1820 VADRS-TV distributed to the teachers who consented, 1799 (98.8%) were retrieved after the first phase of the study, and 420 (23.3%) children met the criteria for ADHD. The parents of these 420 participants were subsequently interviewed with VADRS-PV, and 402 parents returned the questionnaires. The questionnaires of those whose parents refused to participate and those with incomplete responses in the variables of interest were excluded. Hence, 1737 (92.4%) questionnaires were finally analysed.There were slightly more male children than female children (50.9% vs. 49.1%), and the mean age of the participants was 9.53 (s.d. = 1.97) years, with a range from 6 to 12 years.n = 402), by parents’ rating was 13.2% (n = 229) and by combined parents’ and teachers’ reports was 12.3% (n = 213). The distribution of ADHD presentations was the predominantly hyperactive/impulsive , the predominantly inattentive  and the combined . The male-to-female ratio for the 213 children with ADHD in this study was 2.2:1. Across the presentations, the male : female gender ratios were predominantly inattentive: 2.4:1, hyperactive/impulsive 1.2:1 and combined 3:1. A statistically significant gender difference was observed in the rate of ADHD , the predominantly inattentive presentation  and the combined χ2 = 16.4, p < 0.01) with male predominance. There was no gender difference in the predominantly hyperactive presentation .The prevalence of ADHD amongst 1737 school-age children according to the teachers’ rating was 23.1% , especially in the hyperactive-impulsive and combined subgroup. The externalising disorders, ODD  and CD , were more associated with the hyperactive and the combined presentation, whereas the internalising disorders  more associated with the inattentive presentation.Of the 213 patients who met the criteria for ADHD on the teacher and parent scales, 113 (53.1%) had at least one comorbid psychiatric disorder. The most common psychiatric disorder amongst those who met the criteria was ODD  and history of perinatal complications  emerged as the independent predictors of ADHD .The main finding of this study was the 12.2% prevalence of ADHD based on the agreement between teachers and parents on the Vanderbilt Rating Scale. Other key findings in this study included male predominance in those who met the criteria for ADHD and the independent association between ADHD and clinical variables such as a positive family history of mental illness as well as history of perinatal complications at birth.19 and 13% in some non-western cultures such as Iran20 and 12% in Ghana.21 The rate is nonetheless higher than 0.5% found in a study in Europe12 and other African countries such as Nigeria8 and Congo,15 where 8.7% and 6%, respectively, were reported. Methodological differences, which include sample size, the nature of the sample and criteria used in the definition of the disorder, have been identified for these disparities.22The ADHD prevalence rate in this current study is comparable with 11% reported in a study in the USA,23 These findings may explain the lower rates reported in the United Kingdom compared with the United States of America. Likewise, the nature of the sample used  and the small sample size may have contributed to the higher rate (25%) of ADHD reported from an earlier study in Botswana.17In the United Kingdom, more stringent ICD-10 criteria are often preferred to DSM criteria, and doctors working in the United Kingdom are less likely to make a diagnosis of ADHD compared with those in the United States of America.22 it is noteworthy to find that our rate differs from that of Adewuya and Famuyiwa,8 who also used the VADRS and a similar methodology in an African setting. Perhaps, geographical location and local culture similarly play a significant role in the epidemiology, and varying rates of ADHD symptoms reported despite the argument to the contrary. Families, teachers and even clinicians from different cultures around the world vary in their expectations and tolerance of children’s behaviours.24 Varying attitudes towards acceptable behaviour and cultural interpretation of symptoms may influence the diagnosis of ADHD, particularly in Africa, where some still attribute mental illness to supernatural affliction. In the current study, the perceptions of parents were different from those of the teachers, which explained the disparity in their ratings. It is possible that parents who spend more time with their children have grown to accept some of the behaviours and, consequently, more tolerable than the teachers who barely know them or spend less time with them. Moreover, it has been suggested that the disparities would be more prominent when a rating scale is used as in this study rather than diagnostic criteria such as DSM, which may be more resistant to cultural influence.25 Thus, whilst controlling for the influence of different designs on the varying rates of ADHD, the role of cultural differences and geographical location should also not be overlooked, especially in the African setting. Nevertheless, the relatively higher rate from the current study calls for immediate intervention and further research with a diagnostic assessment of children in Botswana.Even though the variations in rates across nations have mainly been attributed to methodological differences,7 the pattern of presentation in the current study followed the popular trend, internationally.27 The inattentive type was the commonest, followed by the combined presentation. This finding contrasts with a study from Korea,28 which reported different patterns of presentation. The influence of culture on the interpretation and appreciation of symptoms of ADHD may also contribute to the variation in the prevalence of ADHD presentations.Notwithstanding that the rate of ADHD in Botswana is slightly higher than reports from most literature,10 Similarly, the present study revealed that 53.1% of those who met the criteria for ADHD according to the rating scales had at least one comorbid psychiatric condition. The most frequently observed comorbid psychiatric disorder was ODD, which occurred in 32.9% of those who met the criteria for ADHD. Furthermore, our study showed that the externalising disorders, ODD and CD, were more associated with the hyperactive and combined presentations, whereas internalising disorders such as anxiety and depression were more associated with the inattentive subgroup. These findings have been replicated by previous literature,29 which suggested that externalising disorders are more associated with the hyperactive-impulsive presentation of ADHD, whereas the internalising disorders are more associated with the inattentive presentation.Evidence suggests that more than 50% of those who have ADHD have a comorbid psychiatric disorder.7 This study did not find any gender difference in the hyperactive presentation as in previous studies with similar designs.7 Ramtekkar and colleagues30 suggested that the gender difference in the hyperactive/impulsive presentation of ADHD reduces or becomes insignificant as children approach adolescence or adulthood. The fact that more than half  of those who had hyperactive/impulsive presentations were 10 years and older may have contributed to the insignificant gender difference observed in the present study.A gender difference was observed in the prevalence of ADHD in the present study. Boys were 2.2 times more likely to have rated positive for ADHD than girls, and this is comparable with the pooled prevalence of 2.45 for boys from a systematic review.31 Nonetheless, gender roles in the development of ADHD should be further explored.The post hoc analysis revealed a significant association between gender and ADHD in this study. Whilst the initial analysis suggested that gender plays a role in the development of this disorder, the logistic regression analysis proved otherwise. The influence of other variables such as a history of mental illness in the family included in the analysis may have accounted for the significant relationship on bivariate analysis. For instance, gender-specific vulnerability to non-familial risk factors has been shown to mediate the onset of ADHD in males.32 Authors have also suggested that ADHD symptoms in childhood may be predictors of adult schizophrenia and mood disorders.33 The co-occurrence of ADHD, schizophrenia, depression, and bipolar disorder suggests that they may not entirely be aetiologically distinct sub-syndromes, but disorders with shared genetic factors. Therefore, it is not surprising that we found six times the risk of ADHD amongst those who have a family history of mental disorder.In the present study, a positive family history of mental illness was associated with ADHD on logistic regression analysis. The fact that ADHD coexists with other psychiatric disorders, as shown in this study, is not a coincidence. Attention-deficit hyperactivity disorder has been genetically linked to various psychiatric disorders. High proportions of psychiatric disorders such as ADHD and CD have been found amongst relatives of individuals with schizophrenia and schizotypal personality disorder.32 and greater mental health awareness from previous mental healthcare contact. Further studies may be needed to clarify these. Nevertheless, whilst the present study did not investigate the type of mental disorders, it highlights the need to see childhood disorders such as ADHD as a pointer to adult or other psychiatric disorders. Screening for them in other members of the family or the children with a behavioural disorder may help in early detection and better quality of life.34Other possible reasons for this association include a lower threshold for behavioural problems in children with ill family membersThe complexity observed in the inheritance of ADHD and that it does not follow the Mendelian law of segregation imply an interaction between multiple genes and environmental risk factors as alluded to previously.35 Getahun and colleagues36 suggested that the adverse effect of ischemic-hypoxic conditions due to birth asphyxia and respiratory distress syndrome on prenatal brain development may lead to functional problems, including ADHD. After controlling for the genetic relatedness of behavioural disorder between parent and child, Wiggs and colleagues11 also opined that birth injury and early developmental health hazards might have a significant influence on the ‘neuropsychological processes underpinning’ externalising disorders such as ADHD.In this study, the identified environmental factor associated with ADHD was a history of perinatal complications. This variable was not only found to be associated with ADHD but also suggested that those exposed to perinatal complications have two times the risk of developing ADHD. The current finding is consistent with a previous work, linking perinatal complication with later development of externalising disorders such as ADHD and CD.17The need to improve on perinatal care and discourage unplanned home delivery cannot be overstressed in this community, especially that an earlier study in Botswana had suggested a link between perinatal complications and childhood mental disorders.The present study was conducted in one of the 17 districts in Botswana; thus, generalising the findings to other parts of the country remains hypothetical and should be interpreted with caution. However, the study location has the densest population and is representative of the reference population regarding ethnic distribution.The present study is limited by the use of parents’ and teachers’ ratings without a clinical diagnostic interview or a direct assessment of the children, to confirm the diagnosis. Nonetheless, the tool used was based on DSM IV-TR criteria and remains valid as DSM-5 still uses the same criteria, except that the symptoms must be present before age 12 years. The use of a sub-sample to explore the risk factors of ADHD also limits our findings.The strength of the study lies in the use of information by both the teachers and parents to control for over-reporting. Adherence to the DSM-5 diagnostic criteria, one of which emphasises the need for symptoms in two different settings, adds to the strength of this study. Furthermore, it is essential to note that this was the first study to assess the community prevalence of ADHD in Botswana with relatively modest sample size.The prevalence rate of ADHD in Botswana is slightly higher than reports from the literature, possibly because of the nature of the instrument used in the present study. The pattern of presentation is nonetheless like the earlier reports, with the predominantly inattentive presentations as the most prevalent and ODD as the commonest comorbid condition. The role of cultural differences in the varying rates of ADHD, especially in the African setting, should be further explored.Having a positive family history of mental illness and perinatal complications remained the independent predictors of ADHD in the subsample of children with teacher and parent surveys. Hence, mental health screening amongst families of the affected individuals and improved perinatal care should be considered as healthcare priorities in Botswana and other sub-Saharan countries.