Use of Medicines by Infants with Microcephaly Caused by Congenital Zika Virus Infection and Implications to Oral Health

Objective: To analyze the use of continued-use medications by Brazilian children with microcephaly caused by Congenital Zika Virus Infection. Material and Methods: Cross-sectional study with 76 children of both genders. Information on age, use of continued-use medications, number and type of drugs used was collected. Data were analyzed using descriptive statistics. Results: Continued-use medications were used by 89.4% of the children, anticonvulsants / antiepileptics (88.1%), and those indicated for behavioral disorders (27.1%) were the most frequent. Sodium saccharin, sucrose, and sorbitol are the most common sugars in the composition of these drugs. Conclusion: The use of medicines is high, predominantly anticonvulsants and antiepileptics, which contain sugars in their composition. These drugs can lead to irreversible dental problems, such as tooth decay if proper oral hygiene is not present. Therefore, parents/guardians should be advised about adopting healthy oral hygiene habits after the administration of these drugs.


Introduction
The first description of the Zika virus was made in Uganda in 1947 in the Zika Valley. It is a mild disease with fever, erythema, and arthralgia [1]. As there is no known medical treatment for this disease, a serious attempt has been needed to eradicate the mosquito and prevent the spread of the disease to other Brazilian states and across the border [2].
According to the National Institute of Neurological Disorders and Stroke (NINDS), "microcephaly is a medical condition in which the circumference of the head is smaller than normal because the brain has not developed properly or has stopped growing" [3]. Microcephaly can be present at birth or it may develop in the first few years of life [4].
In Brazil, "thousands of cases of infants with suspected microcephaly or other developmental anomalies of the central nervous system that may be associated with ZIKV infection have been reported" [5].
Paraíba is the state with the second-highest number of suspected cases of microcephaly. Most of those were born into low-income families that reported difficulties in accessing medicine and attention from the public health system [6].
There are several studies that warn of the deleterious effects of drugs on primary teeth, due to the presence of sugars in the composition of these drugs [7][8][9]. This study aimed to describe the usage of continued-use drugs by children with microcephaly caused by congenital zika syndrome (CZS) and the possible implications for oral health.

Design and Study Location
This cross-sectional study was conducted in the city of Campina Grande, State of Paraíba, northeastern Brazil. The research was developed in one rehabilitation center that offers assistance to children with congenital zika syndrome, providing physical, intellectual, auditory and visual rehabilitation treatment.

Sampling
The sample consisted of 76 children with confirmed diagnosis of microcephaly of both sexes, attended at the Specialized Center for Rehabilitation.

Data Collection
Through a questionnaire, information was collected by two researchers from September 2016 to April 2017 regarding the demographic situation and continued-use medicine treatments.

Data Analysis
Data were organized and analyzed with Statistical Package for Social Sciences, Version 21.0 (IBM Corporation, Chicago, IL, USA) using descriptive statistics.

Ethical Aspects
This study was approved by the Human Research Ethics Committee of the State University of Paraíba in compliance with Brazilian National Health Council Resolution 466/12. All parents received information regarding the objectives of the study and provided written informed consent regarding their child's participation.

Results
Most of the children were female (53.9%), aged between 13 and 24 months (81.6%). The average age was 21.1 months (SD ± 4.8), minimum of 8 months, and a maximum of 38 months.
Continued-use medications were confirmed in 85.9% of the children, with most using only one medication (41.0%). The average medication per child was 1.7 (± 1.2). The most commonly used medications were Anticonvulsant/Antiepileptic (85.9%) ( Table 1).

Discussion
In most cases of microcephaly, there is severe neurological damage that can result in impaired cognition and motor coordination. Therefore, episodes of epileptic seizures and mood swings are common, leading children with microcephaly, even at an early age, to use continued-use medications [10].
Children with special needs are mostly dependent on their caregivers for their daily living activities [9,11], including tooth brushing. Parents and/or caregivers of children with microcephaly have an intense routine of therapies, which often occur in different places and may compromise the persistence and routine necessary to perform oral hygiene [12]. Added to this is the low age of most of the children in this study (81.6% of them were 13 to 24 months old), which can potentiate these oral hygiene difficulties.
Literature has also mentioned a higher prevalence of enamel defects, which entails a higher risk of dental caries [13].
Analysis of the drug leaflets revealed that anticonvulsants and antiepileptics, the class of drugs most commonly administered by the children in the study, can cause vomiting. At these times, intrinsic acids in the organism, present in the gastric juice, are taken to the oral cavity through the atypical flow of content from the stomach [15], and this is responsible for making the dental surface soft and susceptible to abrasion and friction wear [16]. Because of the higher risk of dental erosion development in these cases, the constant monitoring of the children who use this type of medication by a dentist is recommended.
Special attention is advised to possible oral symptoms resulting from the use of Trileptal ® , an antiepileptic medicine that, in addition to inducing vomiting, may cause swelling of the lips, throat or mouth, difficulty to speak or swallow, blistering of mucous membranes of the lips and mouth, and mouth ulcers, which can negatively affect the quality of life of these children.
More than half of the children use more than one drug, possibly due to the number of sequelae resulting from neurological damage, such as visual alterations, speech and hearing disorders, hypertonia, intracranial calcifications, choroid plexus enlargement, ventriculomegaly, and hydrocephalus [13]. Therefore, it is cautioned that undesirable oral effects may be added to children exposed to more than one drug.
Most pediatric drugs contain high levels of sucrose [7,9]. The analysis of the leaflets reveals that this substance is present in the composition of the medications administered to the children in this study. The addition of sucrose improves palatability, favoring acceptance and continuity of the children; sucrose also has preservative, antioxidant, solvent and thickening properties [17]. Children who use this substance are exposed to a cumulative harmful effect, which can manifest as carious lesions [18].
Recommendation to immediately rinse in water and delay tooth-brushing after ingestion of syrup medications could be proposed at the time of prescription. Previous authors reported that "medicine labels should also alert in relation to the possibility of causing dental caries and erosion since many products could be consumed for prolonged periods, several times a day, at bedtime, and without adequate oral hygiene, which would certainly contribute to dental caries and erosion" [19].
Microcephaly is a condition that causes numerous problems in children's health; so knowing which medications are used is extremely relevant. Therefore, dentists should be aware of sugars in child medicine and the parents should be informed of the need for proper oral hygiene after medication administration.

Conclusion
The use of medicines that contain sugars in their composition is high, predominantly anticonvulsants and antiepileptics. These drugs can lead to irreversible dental problems, such as tooth decay if proper oral hygiene is not present. Therefore, parents/guardians should be advised about adopting healthy oral hygiene habits after the administration of these drugs.

Financial Support
Brazilian National Council for Scientific and Technological Development (CNPq) -Research Productivity Grant (Process 302850 / 2016-3).