In this study, children with ZIKV-related microcephaly differed from children without microcephaly in terms of weight and prematurity and presented deficits in the growth process during the study period. The frequency of birth weight of less than 2500g, of weight-for-age z-score indicating low weight, of length/height-for-age z-score indicating very short stature, and of weight-for-length/height z-score indicating thinness was higher in children with Zika-related microcephaly. The growth curves were different between the groups with and without microcephaly, with significant deficits in the first group. The frequency of prematurity also differed between groups, and was higher among children with microcephaly.
The frequency of prematurity in children with microcephaly was 20.63%, while in children without microcephaly it was 8.78% (p = 0.001). A higher frequency of prematurity in children with microcephaly (27%) was also observed in another study conducted by our group15. In children without microcephaly, the frequency of prematurity was similar to the general population of Brazil (7.2%)16.
The occurrence of low birth weight in children without microcephaly (8.99%) was similar to that described by the Brazilian Ministry of Health (8%)16. In children with microcephaly, this frequency was 31.43%, which could be related to intrauterine growth retardation, as suggested by Brasil et al17.
The frequency of breastfeeding was high both in children with microcephaly (86.96%) and in children without microcephaly (92.5%), as was the duration of breastfeeding, which continued until the sixth month and beyond. The breastfeeding rate in Brazil, in August 2020, was 54%18. Although some studies have indicated the presence of the Zika virus in breast milk, the Brazilian Ministry of Health has recommended that breastfeeding should continue for mothers with ZIKV infection, taking into account that the studies have not indicated transmissibility via this route19. The protocols and guidelines for the care of these children may justify the high rate of breastfeeding in this population. In addition, the children received long-term medical follow-up, during which breastfeeding was encouraged. This justifies the fact that the breastfeeding rate of mothers who gave birth to children with microcephaly and of those who had Zika during pregnancy and had children without microcephaly was higher than the national rate19.
With regard to the feeding route of children after being discharged from the maternity hospital, we observed that most children from both groups left the maternity hospital receiving exclusive breastfeeding. It is important to mention that the Global Strategy for Infant and Young Child Feeding, created in 2002 by the United Nations Children's Fund (Unicef) and the World Health Organization (WHO), in addition to the creation of the strategy for the Hospital Amigo da Criança (Friends of Children Hospitals), by the Brazilian Ministry of Health, may have generated positive results for initiating and continuing with breastfeeding in general20.
In terms of requiring an alternative feeding route on discharge from the maternity hospital, we observed that the frequency in both groups was less than 5%, i.e., despite the brain damage of children with microcephaly, their swallowing function was normal during the neonatal period.
In our study, the frequency of food allergy and intolerance was low in the assessments of both groups throughout the period. This result is consistent with studies that suggest an association between a high frequency of breastfeeding and a reduction in allergies and intolerance21.
In later assessments, especially after 12 months of age, children with microcephaly in the study required the use of an alternative feeding route more often than children without microcephaly. We also observed that 16 to 18% of these children with microcephaly progressed from a temporary alternative route to a definitive alternative route (GTT). The use of an alternative feeding route may be directly linked to the need for adequate nutritional support and/or difficulties in food intake. The NET is indicated for short periods of up to six weeks and after this period, if there is no improvement, a route which is considered definitive should be chosen, which is gastrostomy21.
The use of an alternative feeding route is directly related to the presence of dysphagia. Dysphagia occurs at a frequency that varies between 48 and 88.9% in children with microcephaly, resulting from neurological alterations that cause swallowing difficulties14,22,23. Swallowing in the first weeks of life, even in children with severe brain damage, occurs reflexively, which is why the onset of dysphagia occurs later, when the swallowing process would be governed by the cerebral cortex28,29.
In our study, we observed that in the second assessment, when children were aged between 1 and 12 months, 50% of those with microcephaly presented dysphagia, as opposed to 8.7% of those without microcephaly. In the following periods, the frequency of dysphagia increased in children with microcephaly (59.4%, 62.2% and 66.7%) while in the group without microcephaly there was a reduction. We found no studies that describe the findings of dysphagia over time, although other studies have suggested that the presence of dysphagia in children with microcephaly has a frequency greater than 50%22,23,24.
The results on the growth trajectory of the children assessed in this study demonstrated that children with microcephaly, when compared to children without microcephaly, in the assessment through the z-score in successive cross-sections, presented a higher frequency of very low weight and low weight in weight-for-age, of being very short and short in length/height-for-age (p < 0.000), with the exception of the period from 13 to 24 months. In the assessment of weight-for-length/height and BMI-for-age, there was no difference between the groups. In turn, Soares et al. monitoring children born to women both exposed and not exposed to ZIKV infection during pregnancy until 3 months of age, described that weight and length, arm circumference, arm muscle circumference and fat-free mass were different between children in the two groups in the third month of life and suggested changes in the nutritional status of children born to women exposed to the Zika virus25. Another study, in children with microcephaly aged between 12 and 23 months, observed changes in the z-score from length to age26. Despite some differences in the variables and groups compared in these studies, the results seem to converge to a nutritional deficit in children exposed to congenital ZIKV infection.
We observed differences in the monthly growth for weight-for-age, weight-for-length/height and length/height-for-age, observing that the group of children with microcephaly demonstrated a decrease in the z-score during the follow-up period. For the parameters weight-for-age and length-for-age, the z-score remained constant until 20–40 months, starting to decrease in the group of children with microcephaly from then on. For the weight-for-height parameter, the drop in the z-score started to occur after 30 months of age. The inadequacy of the abovementioned parameters may be related to insufficient caloric intake. Appropriate nutrition involves exclusive breastfeeding until the sixth month, with the introduction of solid food from that point onwards and a family menu for children from 24 months onwards26. Taking into account the presence of dysphagia in children with microcephaly, it may be stated that the difficulty in eating some foods may justify the nutritional deficit of these children when compared to those without microcephaly, especially after the breastfeeding period. Another possible explanation for some cases is endocrinological disorders associated with brain damage that affects the hypothalamic-pituitary axis, which may also cause then to be short27.
The growth curves recommended by the WHO10 are widely used tools for monitoring child growth, since they enable an accurate assessment of growth trajectories and nutritional monitoring. They serve as a basis for formulating health policies for specific groups of children. Finding an index that most closely approximates children with specific characteristics to a pattern of normality is crucial for clinical practice. In this study, we observed that there was no difference in the BMI-age index between the groups of children with and without microcephaly, and therefore this index may become a tool to assess children with microcephaly. However, we would admit that one limitation of the research is the fact that we did not assess the body composition, and therefore, this indicator may be valorizing a greater fat mass.
In a study carried out in the Northeast region of Brazil with children presenting congenital infection with and without microcephaly, Cavalcante et al observed that the mean weight-for-age, weight-for-length/height and length/length-for-age z-scores of children with microcephaly tended to decrease slightly after birth up to 36 months. Moreover, they reported that the mean length-for-age z-cores differed significantly between the two groups at six, 12, and 24 months of age, and consistent decreases in z scores were observed in children with and without microcephaly. In the present study, it was also observed that children with microcephaly presented with malnutrition until 12 months of age, after which they remained stable28. In our study29, we observed weight stability up to approximately 30 months, after which there was a drop. This result indicates that there are losses in the nutritional status of children with microcephaly in both studies.
In another study, only involving children with microcephaly, the weight-for-age z-score was − 1.12 at birth and decreased by -0.08 per month, while the length-for-age z-score was − 1.57. at birth, and decreased by − 0.16 per month29. This finding brings a similar result to our study that detected a loss in the parameters of the z-score of weight and height of children with microcephaly of -0.001, although it was not statistically significant.
Although there are specific charts for children with neurological impairment, taking into account that the ZIKV infection and the children affected by it are still being characterized, we prefer to adopt the assessment suggested by the WHO and the Brazilian Ministry of Health to monitor the growth pattern of children from 0 to 5 years. Furthermore, WHO accepts the use of a common international framework, particularly in countries that do not have their own chronologically and methodologically updated framework, with the aim of reducing costs and enabling comparisons between different population groups30,31.
This investigation has presented strengths and limitations. The study compared two groups with intrauterine exposure to ZIKV, but with different clinical conditions, expanding the view of the growth trajectory of these children. The broad inclusion criteria allowed us to assess growth with the criteria adopted by WHO and the Brazilian Ministry of Health, across the entire spectrum of congenital Zika syndrome. One of the main limitations of this study is the lack of other measures that could provide data on body composition, as well as the lack of an assessment on food consumption, which could inform the caloric quota of the usual diet compared to the nutritional needs of children. Thus, we suggest studies that may assess children regarding these aspects, in both groups. The description of the z-score behavior over time in addition to the β calculation enabled a greater understanding of how these parameters developed over time.
We have concluded that children with Zika-related microcephaly remained with nutritional parameters, i.e., weight-for-age, weight-for-length/height and length/height-for-age below those presented by children without microcephaly. Following both groups over time will allow us to understand the evolution of dietary characteristics and growth parameters and provide support for defining therapeutic and care strategies.