Developmental Delay and its Predictors among Under-Five Uncomplicated Severe Acute Malnourished Children: A Cross-Sectional Study in Rural Areas of Pakistan

Background: In developing countries, malnutrition in children and developmental delays are two major challenges for public health. To achieve the vision of the Sustainable Development Goals in the broader perspective of child health, an early identication of developmental delays and timely intervention is crucial. The aim of this study is to assess the prevalence of suspected developmental delay and their predictors in under-ve uncomplicated severe acute malnourished children in rural areas of Pakistan. Methods: A multicentre cross-sectional study has been conducted among 185 uncomplicated severe acute malnourished children. We screened 6–59 months aged children for their nutritional status and clinical complications. Children fullling the inclusion criteria underwent the Denver Development Screening Tool II (DDSTII). The global developmental prole of children was calculated according to established protocols of DDSTII based on four important domains of development: personal and social behaviour, language, gross motor adaptive and ne motor adaptive skills. A pretested structured questionnaire on socio-demographic and nutritional factors was used for assessing predictors of developmental delay, which were analysed in a multivariate logistic regression model. Results: Out of 177 severe acute malnourished children, 69 (38.9%) had normal global development and 108 (61.1%) had delayed global development. Signicant associations with global development delay were found for lower aged children (6-24 months vs. 25-59 month; AOR=4.53, 95% CI: 1.56–13.10, p<0.01), not exclusively breastfeed children (AOR=3.07, 95% CI: 1.24–7.56, p=0.01), and a history of contact with tuberculosis smear positive adult (AOR=2.67, 95% CI: 1.30–5.49, p<0.01). Conclusion: With about two thirds of study participants showing delayed or unstable global development, there is a high prevalence of suspected developmental delay among under-ve uncomplicated severe acute malnourished children in rural areas Pakistan. Particularly children in their rst two years of life with insucient breastfeeding are at high risk. This emphasizes the need for providing adequate infrastructure and information to parents in remote areas.


Background
Developmental delay indicates extensive de cits and lack of developmental skills that would be appropriate for children of their respective age. It may exhibit in different domains, including motor adaptive skills, language as well as personal and social behaviour [, ]. Grantham et al. [] suggested that globally approximately more than 200 million children under-ve are unable to attain their developmental potential due to poverty, malnutrition, inappropriate child care, and child abuse. Most of them belong to South Asia and sub-Saharan Africa.
Severe acute malnutrition (SAM), also known as severe wasting, represents the most critical form of undernutrition. It is further classi ed as complicated and uncomplicated SAM based on the presence of medical complications []. Children with medically complicated SAM will mostly be treated as inpatients in a facility, but children with uncomplicated severe acute malnutrition are advised to be nursed at home with high calorie, micronutrient enriched food []. SAM is responsible for a large part of global disease burden among children and has a high lethality (10-30%). Those children who survive have compromised physical and cognitive development, which could deteriorate economic productivity in adulthood [, , ].
Early childhood, known as the rst 5 years of life, is the fastest and most sensitive period of child growth and brain development. This period is easily in uenced by poverty, biological and psychosocial risk factors [ 1 , ]. The link between nutritional status of children and developmental pro le in this period cannot be overstated, particularly in developing countries, as numerous studies have proven strong acquaintances among them [, , ]. Malnutrition and scarce stimulus have the potential to ru e the progression of rapid brain development by adversely affecting the structural and functional capacity of the brain resulting in developmental de cits of children in all domains [3, ]. The unconstructive society or child external environment also has a negative impact on a child's ability to accomplish his or her full social and developmental skills [ 11 ]. Therefore, several social, biological and psychological factors might contribute to developmental delay in children [ 1 ]. Despite the already available data on the nutritional pro le of under ve children in Pakistan, there is still a scarcity of data to depict how malnutrition correlates to developmental potentials of children. Moreover, the factors in uencing delays in child development, the associations between these factors, as well as their direct and indirect relationship with developmental outcome in severe acute malnourished children have been seldomly examined. For that reason, the objective of this study is to assess the prevalence of developmental delay and its predictors among under-ve uncomplicated severe acute malnourished children in rural regions of Pakistan.

Study area, design and population
A multicentre cross-sectional study was conducted during the period of one year at the end of 2016 at four Outpatient Therapeutic Programme (OTP) Centre's in the District Dera Ghazi Khan of Southern Punjab, Pakistan. Dera Ghazi Khan has the worst indicators of malnutrition (stunting and wasting) in Punjab. This socio-economically underprivileged district has the highest prevalence of illiteracy and overcrowding and is frequently affected by oods [ 16 ,].
Overall 185 children, aged 6 to 59 months, were selected to participate in the study in case of their parents' written informed consent. At enrolment, these children had severe acute malnutrition (SAM) without complications according to World Health Organization (WHO) criteria (mid-upper arm circumference [MUAC] < 115 mm and a weight-for-height [Z score]<-3), were clinically well, alert and had good appetite. Severe acute malnourished children with complications were not included in the study on baseline assessment. Complications, as de ned by WHO, were hypoglycaemia, hypothermia (axillary temperature < 35 °C), hyperpyrexia (axillary temperature > 39 °C), anorexia, severe dehydration, grade three pitting oedema, severe anemia and acute lower respiratory tract infection [ 5 ].

Sample size
For sample size calculation, WHO Sample Size 2.0 and the following formula have been used: with a level of signi cance of 95% (Z = 1.96), an expected proportion of wasting (P) of 11% [ 17 ], and an expected error (d) of 5%. This leads to a sample size of 151, which was in ated to a total of 185 to enhance study precision, strength, and accuracy. The eligibility to participate in the study was assessed among 252 children; 67 were excluded, because they either did not meet the inclusion criteria (n = 52) or parents refused to participate (n = 15) ( Fig. 1).

Data collection and exclusion criteria
A structured and pretested questionnaire was used for face-to-face interviews with parents to assess data on socio-demographic characteristics and nutritional consumption. Interviews with parents and child physical examination were conducted at OTP centers.
Gestational age of mothers was taken from antenatal records in case of hospital delivery or was based on maternal recall if the birth has been conducted at home. The age of children ≤ 24 months and born before 37 weeks of gestation was adjusted by deducting the number of weeks of missed gestation from the present age.
Medical history was obtained for symptoms of acute diarrhea, high grade fever, lethargy, cough, shortness of breath, seizures, neurological de cit and anorexia. All of these symptoms were indications for a child being clinically ill. In physical examination, severe dehydration, palmar pallor (as an indication for anemia), and severe pitting edema was assessed in children [ 4 , 5 ]. Children's vital signs were assessed for hypothermia/hyperpyrexia and respiratory rate. For assessment of hypoglycemia, a heel-prick was done and children with glucose concentration of < 3 mmol/L based on the Dextrostix reagent strip were deemed to be hypoglycemic. Appetite test was conducted by giving the child a small amount of ready-touse therapeutic food (RUTF) to eat. The child who did not consume a minimum one third of a packet (three teaspoons, which is 30 g) of RUTF after three tries were labeled as poor appetite [ 4 , 5 , 6 ]. Children evaluated as being clinically ill due to the aforementioned symptoms and classi ed as having poor appetite were not included in the study. Instead they were referred to an inpatient facility.

Measurements
Anthropometric measurements Anthropometric assessments were conducted by trained staff that. Assessments were made twice by a study team to avoid potential bias. In case both measurements differed, further assessments were done till a precise value was obtained. The repeated value was then documented. The mid upper arm circumference was assessed to the proximate 0.1 cm with color-labeled MUAC tape at the midpoint among the olecranon and the acromion process.
Child weight was measured with UNISCALE, close to 10 g undressed or in a light dress. If children and infants were not able to stand by themselves, UNISCALE was utilized to determine only mothers' weight. Afterwards, the infant/child was handed over to the mother while she was standing on the scale and the collective infant and mother weight was assessed. The calculation of infant/child weight was made as the difference among these two readings. UNISCALE was calibrated for standard weight and adjusted to zero prior to all measurements. The recumbent length of child who were less than or equal to 87 cm in height was assessed to the proximate 0.1 cm with the help of a length-measuring board with a xed headrest and a mobile foot piece ("SECA GmbH & Co. KG, Hamburg, Germany"), laid on a smooth surface. Children larger than 87 cm in height were assessed in the stand-up position after removing shoes and with heels together on a horizontal at plate attached to the base of the measuring board []. Standard protocols for child growth were applied for calculating the weight-for-height Z-score with WHO ANTHRO version 3.2.2.

Developmental screening
Study participants underwent the Denver Development Screening Tool II (DDST II) [] for assessing the development pro le. This tool measures the children's pro ciency, under the age of six years to do a range of different tasks and make comparisons with a standardized population of same age children. It measures the four parameters of development that is personal-social behavior development, ne motor development, language, and gross motor development. This tool was executed by a physician trained in conducting DDST II for child development assessment. The average screening time for DDST II was about 30 minutes. If the child was uncooperative and untestable at the rst screening for global developmental status, a follow up rescreen visit has been conducted after two days. If the child was still untestable, the screening was repeated again after two days. The tool was translated into the native language for elimination of communication barrier. The owchart of developmental screening is presented in Fig. 1.
Following a standardized algorithm, child's development was categorized as "normal (if child performs the items, on the left of age line completely), caution an intermediate classi cation (if child is unsuccessful or say no on an item on which age line falls on or between the 75th and 90th percentiles), or delay (if child isn't passing an item that 90% of children in the standardization passed at an earlier and item on which age line falls completely to the left of the age line)" [ 19 ]. These category measurements were then applied to grade global developmental status as "normal" (no category delayed and no more than one category classi ed as caution), "suspect" (≥ 2 cautions or ≥ 1 delay), or "untestable" (based on a speci c pattern of refusals) [ 19 ].

Statistical analyses
Data was analysed using SPSS version 23. Simple logistic regression was applied to assess the bivariate relationship through unadjusted Odds Ratios (OR) between the dependent and independent variables. The p-value was relaxed up to 0.20 in order to take all signi cant variables as confounding variables in the multivariate analysis []. Hence, multivariate logistic regression was run to measure the dynamics among the potential predictors for the delayed development among children and present results in terms of Adjusted Odds Ratios (AOR) with 95% con dence intervals (95% CI).
The outcome variable was the children's developmental status as a binary variable (delayed development vs. normal development). Socio-demographic characteristics, medical history and dietary practices are included as independent variables, because they can theoretically affect development delay (Fig. 2). The reporting follows the STROBE statement for cross-sectional studies (see Supplementary Appendix 1).

Developmental status
Out of the total 185 children, 8 children (4.3%) were untestable for developmental status even after rescreening. Therefore, the analysis is based on 177 children. Result of prevalence of suspected Global development delays based on developmental milestones in all domains and separated for each domain are presented in Table 1. According to this, 61.1% (n = 108) showed a suspected delay at the global level. The delay was most pronounced in personal and social behaviour (62,1%, n = 110), whereas for language 70.6% (n = 125) showed a normal development.

Socio-demographic characteristics and developmental status
Comparisons of socio-demographic characteristics between children having normal development and suspected developmental delay are presented in Table 2. The comparison revealed that age (p < 0.01), monthly income (p = 0.04), mother's (p = 0.01) as well as father's education (p = 0.04), and family size were (p = 0.01) are signi cantly related with suspected developmental delay. All other socio-demographic factors did not show any signi cant association with developmental status. Medical history, dietary practices and developmental status A signi cant association with delayed development was found for the frequency of hospital visits (p = 0.03), which are visits to hospital in the past six months due to diarrhoea, respiratory infections, or because of any other illness con rmed from their medical record to avoid any recall bias, history of tuberculosis (TB) contact (p = 0.01), which is a child with close contact to a TB smear positive adult patient at home or in the near surroundings, and breastfeeding practices (p = 0.01). Furthermore, history of worm infestation (p = 0.14) was included in the multivariate analysis as the level of signi cance was relaxed for this analysis (p < 0.20). All other variables, such as complementary feeding practices (complementary food was probed in detail from mothers according to WHO recommendations by showing them different utensils and food charts to assess quantity, variety and frequency of food), hygienic practices, vaccination, and history of measles, were not related to delayed development among children (Table 3).

Multivariate logistic regression
All variables which were found signi cant (p ≤ 0.20) in the simple logistic regression models (Tables 2  and 3) were included in the multivariate logistic regression analysis. As multicollinearity was found between mother's education and father's education, we only kept mother's education in the analysis to account for the fact that mother's education was found to be a signi cant predictor of child development in previous studies [].
In the multivariate logistic regression model, only a younger age (6-24 months vs. 25-59 months) of the child (AOR = 4.53, 95% CI: 1.56-13.10, p < 0.01), history of TB contact (AOR = 2.67, 95% CI: 1.30-5.49, p < 0.01), and mixed breastfeeding practices (AOR = 3.07, 95% CI: 1.24-7.56, p = 0.01) remained signi cantly associated with developmental delays (Table 4). Children in our study were also found to be affected in language and motor adaptive skills. Previous research explained that due to malnutrition children are suffering from multiple micronutrient de ciencies (like calcium and vitamin D), which are important for skeletal muscle function. For that reason, a de ciency of these micronutrients affects motor skills [ 6 ]. Nutritional insu ciencies even in acute stage may damage the cognitive pro le and entire auditory system in children resulting in verbal and written language problems. It has already been proved that height, weight and head circumferences are directly related to high incidence of delays in motor skills and the language domain [, ].
Child development proceeds through a gradual multifaceted interaction, probably by the parents or caregiver's education level, living and working conditions, social circumstances, availability of health facilities, and the physical environment. An unconstructive social or external environment in early life years is mostly linked to compromised development. Every region or community has their own circumstances. For that reason, locally targeted research and interventions are needed to go forward [ 26 ].
In the present study, mother's education, monthly income of a family, frequent hospital visits due to repeated illness, and family size were signi cantly linked to developmental delays in the bivariate analysis. This has also been shown in previous studies [ 1 , 3 , 10 , 26 ]. Comparable research in the Indonesian slum area and in the United States revealed that low maternal education and low family income, is strongly associated with delayed development in young children [ 1 , , ]. This is due to the fact that maternal education has a direct effect on proper medical follow-up in the antenatal period, effective family planning, optimal nutrition and child health care [ 22 ].
In our study, exclusive breastfeeding was signi cantly associated with normal child development. In addition, a strong correlation between breastfeeding and progressive developmental outcomes in children was proven previously. This can be explained by the nutritive value of breast milk and the strong emotional bonding between mother and child. Studies also relate breastfeeding with high score achievements in cognitive tests and in motor and mental development [, ]. A cluster-randomized trial did intervene for breastfeeding promotion and found signi cant results for children long-term outcomes in health and neuro-development [].
The risk of developmental delay was found to be increased in the rst two years of age. It was also observed previously, that if an infant is suffering from malnutrition in early childhood the risk of developmental delay is enhanced. Furthermore, this is an indication of serious physical or psycho-social problems. Development in infancy and toddler period is fast and easily in uenced by environmental and social-demographic variables [ 1 , 30 , 32 ].
In contrary to other studies, the history of a child's close contact with a TB smear positive adult patient at home or in near surroundings is signi cant in the present study. For understanding this phenomenon, more in-depth research is required. One explanation might be that these children could have had an undiagnosed latent or active TB because of malnutrition, low immune status [ 2 , 10 ], or the contact with smear positive TB patients. Therefore, a complete physical examination along with laboratory investigations is required for the diagnosis of TB in these children.

Strengths and limitations
Besides the missing information on TB status of the children within this study, another major limitation is the cross-sectional design. Monitoring the child's developmental and nutritional status over a longer time period would impart a better perceptiveness because of the dynamic nature of growth and development.
The strength of our study is that we have used the Denver Developmental Screening Test II, which is a validated scale for developmental assessment of children. Furthermore, this assessment has been conducted by well-trained medical staff using established protocols. Moreover, to our knowledge, this is the rst study in rural areas of Punjab, Pakistan, to investigate the loss of developmental potential in children with severe acute malnutrition.

Conclusion
Severe acute malnourished children have a high prevalence of suspected global developmental delay.
Developmental delay and malnutrition are two major interrelated public health problems, hindering the achievement of SDGs in children of low-resource countries. Thus, timely identi cation and proper management of developmental delays in children should be reinforced to meet enduring growth and developmental needs. The results of this study will be helpful for policy makers to develop strategies for prevention and treatment of growth failure and developmental delay in these vulnerable malnourished children.  Flowchart of sample selection and developmental screening Figure 2