Gross motor developmental delay in human immunodeficiency virus-infected children under 2 years of age.

Background: Human immunodeficiency virus (HIV) infection has significant effects on child development. We report the outcome of gross motor developmental assessment in HIV-infected children <2 years compared with that of uninfected children. Materials and
Methods: Every child <2 years of age presenting for the first time to the pediatric outpatient department of the hospital over 3 months was studied. Each child had a physical examination with gross motor milestone assessment, as well as initial double rapid HIV antibody tests with confirmatory tests for those with positive or discordant results. Children with evidence of motor delay were booked for reassessment after 1 month. The milestone performance criteria of the Multicenter Growth Reference Study of the World Health Organization were used as a standard.
Results: One hundred and eight children were studied. Male-to-female ratio was 1:1. Fourteen children (13.0%) were HIV infected. Nine children (8.3%) had delayed development of gross motor milestones, of which five were HIV infected and four were uninfected (P = 0.001). Each motor milestone was attained at a significantly later mean age by the HIV-infected children when compared to the uninfected. Evidence of delay in gross motor milestones was apparent by the first 6 months of life. Conclusions: A tendency to poorer motor development is apparent in young children infected by HIV and can manifest as early as the first 6 months of life. Routine HIV screening as well as early developmental assessment of all children should be encouraged.

INTRODUCTION

Nigeria has 220,000 children living with HIV and 1.8 million orphans, the highest number in the world.[1] In children, HIV is characterized by a variety of deficiencies in neurodevelopment, cognition and motor functions, with estimates put between 30% and 90%.[2] Motor deficiencies are apparent during the first 3 months of the life[3] and as the child grows, he is expected to perform increasingly complex and integrated tasks. Thus, delay in motor milestones becomes evident and worsens over time.[34] Gross motor skills require the use of large muscle groups and physical effort. Thus, their deficiencies are more evident than those of fine motor function.[56] The highest incidence of HIV-associated central nervous system (CNS) disease occurs in the first 2 years of life, can occur independently of systemic HIV disease,[7] and may be the first AIDS-defining illness in children.[89]

Reports on the neurological manifestations of HIV disease in children, especially in Africa, are few.[6101112131415] This study assesses the gross motor development of HIV infected children <2 years old and compares it with that of uninfected children.

MATERIALS AND METHODS

All consecutive patients aged 4–24 months, presenting for the first time to the pediatric outpatient department (POPD) of the hospital, and whose caregivers consented to the study were enrolled. Mothers who were known to be HIV-positive and had been on ART during and after pregnancy were excluded from the study. Critically ill children were excluded as this category of children is usually seen at the emergency pediatric unit of the hospital instead. On enrolment, clinical, socioeconomic, and anthropometric data were collected using a study pro forma designed for the study. Information obtained included age, gender, complaints at presentation, orphan status, history of events around the pregnancy, birth and neonatal periods, nutritional history, and history of use of medications in the child. Socioeconomic status was assessed using the method described by Ogunlesi.[16] Anthropometric measurements were carried out using the World Health Organization (WHO) child growth standards and nutritional status for all patients was classified using z scores calculated using the WHO anthropometric calculator.[17]

Six gross motor milestones were assessed. These were sitting without support, hands-and-knees crawling, standing with assistance, walking with assistance, standing alone, and walking alone. These are universal milestones which are fundamental to the acquisition of self-sufficient erect locomotion, and simple to test and evaluate. Information regarding the time of attainment of any or all of the six gross motor milestones was obtained from the caregivers. The performance of the last attained milestone by the child was also observed by the investigator to know if the child could perform it independently, using the criteria set forth in the Multicenter Growth Reference Study (MGRS) of the WHO,[18] or if the child performs it after having been placed into position. A milestone was considered achieved only if all the given criteria were met, as outlined in Table 1.

Table 1

Multicenter Growth Reference Study performance criteria for six gross motor milestones as set forth in the World Health Organization Multicenter Growth Reference Study[18]

Gross motor milestone	MGRS performance criteria
Sitting without support	Child sits up with the head erect for at least 10 s. Child does not use arms or hands to balance body or support position
Hands and knees crawling	Child alternately moves forward or backward on hands and knees. The stomach does not touch the supporting surface. They are continuous and consecutive movements, at least three in a row
Standing with assistance	Child stands in an upright position on both feet, holding onto a stable object (e.g., furniture) with both hands without leaning on it. The body does not touch the stable object, and the legs support most of the body weight. Child thus stands with assistance for at least 10 s
Walking with assistance	Child is in upright position with the back straight. Child makes sideways or forward steps by holding onto a stable object (e.g., furniture) with one or both hands. One leg moves forward while the other supports part of the body weight. Child takes at least five steps in this manner
Standing alone	Child is in upright position on both feet (not on the toes) with the back straight. The legs support 100% of the child’s weight.There is no contact with a person or an object. Child stands alone for at least 10 s
Walking alone	Child takes at least five steps independently in upright position with the back straight. One leg moves forward while the other supports most of the body weight. There is no contact with a person or an object

MGRS=Multicenter Growth Reference Study

All caregivers had a HIV pretest counseling with an option to “opt-out” using the provider-initiated HIV testing and counseling strategy. After general examination and milestone assessment, HIV testing was carried out on participants whose caregivers did not decline testing, and the results were discussed individually with the caregivers. The HIV testing was done using Determine™ (by ABBOTT Japan Co., Ltd., LOT 80610U100) and Unigold™ (by Trinity Biotech Plc., LOT T078027) rapid test kits. Those who tested positive to both test kits had blood drawn for further tests, including HIV DNA polymerase chain reaction, complete blood counts, CD4 counts, and CD4 percentages. Mothers of HIV-infected children were also screened for HIV infection. Every child who exhibited some evidence of gross motor delay was booked for reassessment after 1 month. Every identified HIV-infected child was classified as having advanced HIV disease based on the WHO guidelines for managing advanced HIV disease[19] and referred to the pediatric infectious diseases clinic of the hospital for continued care and treatment. Ethical approval for the study was obtained from the Research Ethics Committee of the hospital.

Data analysis

Data were entered into a spreadsheet and analyzed using the SPSS version 16.0 for Windows (SPSS Inc., Chicago, USA) for Windows. Data from children whose mothers were in labor for >18 h, who did not cry at birth, who were admitted in the 1st month of life with fever and/or jaundice requiring exchange blood transfusion, who were on any anticonvulsant for >1 week and whose milestones could not be assessed were excluded from the analysis. Ratios, percentages, and means were calculated where appropriate. Categorical variables were compared using either the uncorrected Chi-square test or Fisher's exact test. Group means were compared using the t-test. Binary logistic regression was done to obtain the independent predictors of delay in gross motor milestones in HIV-infected children. Statistical significance level was set at P < 0.05.

RESULTS

One hundred and twenty-one children were enrolled, but analysis was carried out on 108 children. This was because 13 children (four HIV-infected and nine uninfected) had findings which caused them to be excluded from the analysis. Of the 108 children studied, 55 (51%) were male. Boys formed a significantly larger proportion (64.3%) of the HIV-infected children. The mean (standard deviation [SD]) age of the study population was 12.4 (6.3) months with no significant difference between both groups. Nine children (8.3%) were orphans with a significantly larger proportion of them being HIV-infected (14.3% vs. 7.4%). Eighty-one (75%) of the children were of the low-socioeconomic class with no significant difference between both groups. Undernutrition, stunting, and microcephaly defined as z scores of <−2 SDs from the mean weight for age, height for age, and head circumference for age, respectively, were significantly more prevalent in the HIV-infected children. The demographic, socioeconomic, and clinical characteristics of the study population are shown in Table 2.

Table 2

Demographic, socioeconomic and clinical characteristics of the study population according to human immunodeficiency virus infection status

Indicator	HIV-infected Group 1, n (%)	HIV-uninfected Group 2, n (%)	P
Total number of children	14	94
Male gender	9 (64.3)	46 (48.9)	0.020
Age (months), mean±SD	13.43±7.25	12.28±6.15	0.524
Orphans	2 (14.3)	7 (7.4)	<0.001
Low SE status	13 (92.8)	68 (72.3)	0.098
WAZ <−2SD	11 (78.6)	50 (53.2)	<0.001
HAZ <−2SD	8 (57.1)	36 (38.3)	<0.001
Microcephaly (HCAZ <−2SD)	7 (50.0)	28 (29.8)	<0.001

SD=Standard deviation, SE=Socioeconomic, WAZ=Weight-for-age Z score, HAZ=Height-for-age Z score, HCAZ=Head circumference-for-age Z score, HIV=Human immunodeficiency virus

All children had more than one complaint on presentation. The most common clinical features on presentation were fever, diarrhea, weight loss, cough, vomiting, and hepatosplenomegaly. The skin lesions seen in the HIV-infected patients were seborrheic dermatitis and extensive tinea corporis, whereas maculopapular rashes, hypopigmented patches, tinea corporis, and pityriasis versicolor were seen in the uninfected children. The various presenting features of the study population are shown in Table 3.

Table 3

Clinical features found in the study population on presentation*

Clinical feature	HIV-infected (n=14), n (%)	HIV-uninfected (n=94), n (%)
Fever	14 (100.0)	90 (95.7)
Hepatomegaly	14 (100.0)	49 (52.1)
Splenomegaly	12 (85.7)	3 (3.2)
Passage of loose stools	11 (78.6)	51 (54.3)
Weight loss/failure to gain weight	11 (78.6)	27 (28.7)
Cough	10 (71.4)	45 (47.9)
Vomiting	9 (64.3)	43 (45.7)
Pallor	6 (42.9)	29 (30.9)
Crepitations	6 (42.9)	12 (12.8)
Skin manifestations	6 (42.9)	22 (23.4)
Parotid fullness	5 (35.7)	2 (2.1)
Oral sores	4 (28.6)	7 (7.4)
Ear discharge	4 (28.6)	1 (1.1)
Eye discharge	1 (7.1)	6 (6.4)
Passage of brownish urine	0 (0.0)	6 (6.4)
Body swelling	0 (0.0)	5 (5.3)

*Most children had multiple complaints on presentation

Five of the 14 HIV-infected children (35.7%) showed evidence of gross motor delay, compared with 4 of 94 (4.3%) uninfected children as depicted in Table 4 (P = 0.002). The HIV-infected children attained each milestone at a significantly later mean age than the uninfected children as shown in Table 5, P < 0.05 at each stage. There was a progressively increasing difference in the mean ages of attainment of motor milestones between both groups.

Table 4

Presence of motor delay in the study population

Motor milestones	HIV-infected (n=14), n (%)	HIV-uninfected (n=94), n (%)	P
Delayed	5 (35.7)	4 (4.3)	0.002
Normal	9 (64.3)	90 (95.7)

HIV=Human immunodeficiency virus

Table 5

Average age of attainment of motor milestones in human immunodeficiency virus-infected and uninfected groups

Milestone	Average age of attainment (months)				P
	HIV-infectedGroup 1		HIV-uninfectedGroup 2
	Age	Percentile	Age	Percentile
Sitting without support	7.8	26th	5.2	75th	0.033
Crawling	9.8	30th	7.8	60th	0.049
Standing with support	9.3	25th	7.5	50th	0.016
Walking with support	12.4	7th	8.2	75th	<0.001
Standing alone	14.9	5th	10.2	60th	<0.001
Walking alone	16.8	2nd	11.9	50th	<0.001

HIV=Human immunodeficiency virus

The differences in the mean (SD) CD4 count and CD4 percentage in the two subgroups of the HIV-infected children, as shown in Table 6, did not attain statistical significance (P > 0.05 in both cases). There was good correlation between the mean CD4 count and CD4% with the WHO clinical stage in HIV-infected children (the WHO clinical stage vs. CD4 count: F = 4.546, P = 0.015; the WHO clinical stage vs. CD4%: F = 23.547, P = 0.001).

Table 6

Comparison of mean CD4 count and percentages with milestones in human immunodeficiency virus-infected children

Motor milestones	Mean±SD CD4 count	Mean±SD CD4%	P
Delayed (n=5)	865.2 (516.2)	16.2 (6.8)	0.241
Normal (n=9)	1337.2 (757.2)	23.6 (6.7)	0.073

SD=Standard deviation

On logistic regression analysis conducted to predict the presence of delay of gross motor milestones in HIV-infected children using sociodemographic and clinical variables as predictors, none of the identified variables was found to be predictive. This is shown in Table 7.

Table 7

Clinical and sociodemographic predictors of delayed gross motor milestones

Predictors	Dependent variable: Gross motor milestones
	β	SE	Wald	OR (95% CI)	P
Gender	−0.624	0.781	0.6	1.9 (0.4-8.6)	0.424
Orphan status	0.283	1.218	0.1	1.3 (0.1-14.4)	0.816
Wasting (WAZ)	1.322	1.191	1.2	3.8 (0.4-38.7)	0.267
Stunting (HAZ)	1.217	0.923	1.7	3.4 (0.6-20.6)	0.187
Microcephaly (HCAZ)	−0.394	0.785	0.3	0.7 (0.1-3.1)	0.616
Constant	−3.715	1.164	10.191		0.001

β=Strength of influence of predictors, Wald=Test of significance for individual regression coefficients, OR=Odds ratio, SE=Standard error, CI=Confidence interval, WAZ=Weight-for-age Z score, HAZ=Height-for-age Z score, HCAZ=Head circumference-for-age Z score

DISCUSSION

About 36% of the HIV-infected children in this study had delayed development of gross motor milestones. This is similar to findings from authors in the United States[3] and other parts of Africa.[61314] However, this figure is much lower than those of Baillieu and Potterton and Ferguson and Jelsma who, in cross-sectional studies in South Africa, found that 85% and 67%, respectively, of HIV-infected children demonstrated gross motor delay.[2021] The study by Baillieu and Potterton[20] was carried out in children between 18 and 30 months most of whom were severely immunocompromised, and this could explain the very high percentage obtained in that study. In the study by Ferguson and Jelsma,[21] two-thirds of the HIV-infected children were already receiving ART. Benki-Nugent et al.[15] in Nairobi also found that most of the HIV-infected infants, all <5 months of age on enrolment, had delayed gross motor milestones even on attainment of the first motor milestone. Hutchings and Potterton[14] in Harare also found significant delays of approximately 2 months in motor development in over half of their HIV-exposed infected infants when compared with HIV-exposed but uninfected infants. These findings are further corroborated by a recent meta-analysis which showed that HIV-infected children had worse motor outcomes compared with HIV-exposed but uninfected children and HIV-unexposed and uninfected children.[22]

The northwestern region is known to have a high level of poverty and undernutrition. This is corroborated in this study by the observation that three-quarters of the children were from a low socioeconomic background while about half of them were undernourished. In the two groups of children, there was no statistically significant difference in socioeconomic status. However, the HIV-infected children had a significantly higher degree of stunting and wasting when compared with the uninfected children and this is known to have synergistic detrimental effects on neurodevelopmental outcomes. This is similar to findings by authors from India[2324] and brings to the fore the need for a holistic, multi-pronged approach to the management of these children. A significant number of the HIV-infected children in this study had microcephaly. This was also the case in the study by Benki-Nugent et al.[15] The importance of this lies in the fact that in children <2 years of age, impaired brain growth manifests as deceleration of head growth or acquired microcephaly. This is an important clinical sign associated with progressive HIV encephalopathy as children with suspected asphyxia, jaundice, and seizures in the neonatal period had been excluded from the analysis. It is, thus, recommended that at clinic visits for HIV-exposed and HIV-infected children, the primary care physician should be particularly vigilant for the appearance of microcephaly.

Among HIV-infected children, factors such as male gender, orphan status, or the presence wasting, stunting, or microcephaly did not predict the presence of delay in gross motor milestones. This highlights the significance of the effects of HIV disease irrespective of these variables, thus strengthening the need for milestones assessment in every HIV-infected child.

The delay in milestone development in this study was apparent as early as the duration of attainment of the first gross motor milestone listed in the MGRS criteria which was sitting without support. Gay et al.[3] in their prospective study in children aged 0–24 months born to HIV-seropositive mothers, found that motor delay becomes apparent as early as 3 months of age and worsens over time. Blanchette et al.[4] had similar findings and also found that abnormalities in the computed tomography scans of the HIV-infected infants were associated with developmental delays, particularly for motor development. Benki-Nugent et al.[15] in their prospective cohort study found that even in infants who had early initiation of ART and who achieved effective responses to ART, there was significant delay in achieving the motor milestones compared to uninfected children. This was attributed to the possibility of early viral infiltration to the CNS or poor clearance from the CNS following ART. Although the studies by Gay et al.[3] and Blanchette et al.[4] used the Bayley Scales of Infant Development, the study by Benki-Nugent et al.[15] used the Denver Development Screening Test, while this study used the MGRS performance criteria for developmental milestone assessment, the findings of significantly delayed gross milestone attainment in HIV-infected children was uniform across the studies. It has been found that early HIV infection may lead to a degree of irreversible damage to the brain even before the initiation of ART, accounting for some of the neurological deficits persisting over time.[25]

The percentile ranking of time of attainment of each motor milestone was poorer in the HIV-infected children with increasing age at the diagnosis of HIV infection. The results showed a progressively increasing difference in the mean ages of attainment of the motor milestones implying that the delay worsens over time, just as Gay et al.[3] found in their study. Baillieu and Potterton also observed that mean motor development was delayed by 9.65 months in their study of mostly severely immunocompromised HIV-infected children.[20] Parks and Danoff had similar findings in a study carried out in HIV-infected older children and preadolescents who were studied over 2 years.[5] This highlights the importance of not only determining the HIV status of children early but also carrying out developmental assessment on children as early as possible and routinely, and hence that ART and other intervention strategies could be immediately instituted as necessary. Neural development is known to continue beyond 2 years of age and as such, more delays would be expected over time if interventions are not done.

In the HIV-infected children, the presenting clinical features and the degree of malnutrition and immunosuppression were further confirmation of advanced HIV disease as defined by the WHO.[19] This is comparable to the finding by Foster et al.[26] that 40% of their study population demonstrated significant developmental delays on assessment. However, Lodha et al.,[27] in India, found that over 75% of the children in their study had moderate-and-severe immunosuppression. This very high figure could be accounted for by the fact that in this study, all the children assessed were <2 years of age and severely ill ones were not assessed for developmental delays as they were not seen at the POPD, whereas in the Indian study, children up to 15 years of age at presentation were studied and the manifestations of disease were already severe.

CONCLUSION

A clear tendency to poorer motor development is apparent in young children infected by HIV. This underscores the need for screening and for the prevention of neurodevelopmental delay at an early age. It further highlights the need for early determination of maternal HIV status, with access to early intervention strategies and improved nutrition in children with HIV. Low-cost strategies for developmental assessment such as that used in this study could be adapted for use by resource-constrained settings such as the location of this study so that proper evaluation of children in the region can still be carried out within the limits of available resources.

This study was limited by the fact that developmental delays in other domains such as cognition, fine motor, and language could not be assessed. This was because of the lack of appropriate tools for their assessment. The sample size was also too small for meaningful generalizations to be made to larger populations.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.