Acquired Hip Dysplasia in Children with Congenital Zika Virus Infection in the First Four Years of Life

Round 1

Reviewer 1 Report

This is an interesting paper from a group with important experience in caring for children with Congenital Zika Syndrome, covering a topic that has had very limited attention.

The introduction is succinct and reads well – I have no comments.

Methods

Line 61 – clarify that this is suspected or confirmed maternal ZIKV infection

Line 63 – the authors should be more specific about the calendar time around the “aftermath” here

Lines 65-74 – I am not convinced that this long list of findings related to CZS is useful here. For this study, if this was used as a formal case definition for inclusion, then that needs to be made clearer. Otherwise, this could go into the introduction as background to CZS as an emerging disease.

Line 86 – consider rewording this slightly, given that most mother-infant pairs did not have testing done at all.

Line 95-96  – it is a little unclear whether the GMFM was used as part of clinical care, or for research purposes, or both. Regarding the minimum of two time points – should this come under the inclusion/exclusion criteria section, alongside the radiology assessment? It is understood that the radiological assessment timing depends on the GMFCS, but it is not clear what the procedures were regarding the timing of GMFM assessments after the initial one.

Line 116 – not clear about the three and five years – is this at ages?

Results

It is preferable to give the median rather than the mean for ages and durations, as this helps the reader understand the distribution of the assessments. It would be good if the number and percentage of included children with a total of 2, 3 and 4 assessments was given.

Line 134 – “Hip dysplasia was diagnosed in 26 (41%) children during follow-up”. This is either not the correct calculation or needs rewording (regarding the “follow-up”) because 18 children (as stated in line 137 and in the table) were prevalent cases and already had hip dysplasia at the first assessment.

This study involves longitudinal data – and children can move between GMFCS classifications (for example, 4 went from a classification of >I to I over follow-up – so their motor function improved and similarly, there was improvement at the top end of the scale, with the proportion of children in the V category decreasing from 28% to 12.5%). More information on regression/progression of motor function over the assessment period would be very interesting – for example, confirmation that the 4 who moved to category I at the last assessment were the 4 children in II at their first assessment, and more information on the number and proportion who improved  vs got worse. This may also be related to severity of microcephaly, so that would be interesting to describe.

Table 1

Some formatting needs attention – to differentiate between the sub-groups (eg within the microcephaly variable and the hip dysplasia variable).

I would suggest that the authors split out the ZIKV PCR results of mother and child – at least in the text.

Table 2 – it isn’t clear what proportions were compared to obtain the p value. Similarly to table 2, care is needed in how the sub-sets within categories are presented.

Lines 152-3 – please add in the methods how these parent/carer-reported variables were collected.

Line 159 – was this hip surgery? Please specify.

 

Discussion

Lines 160-167 I would suggest that the authors move the text on the osteoarticular manifestations that were not covered by this study to a later part of the discussion.

Line 178 – the results and analysis in this study have not adequately addressed incidence (see my earlier point regarding the results). This text should be altered to reflect the approach that the study took (or, if the authors want to be able to say something about incidence, then they need to do some additional analyses).

Lines 189-200 – suggest that some of this is cut or shortened.

Line 231 – whilst study limitations are briefly mentioned, there should be a longer paragraph to describe the strengths and limitation of this study.

Generally, the discussion is quite long and could benefit from being a bit more focussed. Given the age of the Brazilian cohort of children with CZS now, I would suggest some more comment on their needs for care and support going forward and the impact on their lives as they attend school etc.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

After the initial description of a new teratogenic syndrome, the Congenital Zika Syndrome (CZS), many questions were raised on how these children would develop.  This manuscript addresses an important issue which is acquired hip dysplasia and brings essential facts to health professionals. Hip dysplasia worsens motor limitations and is also a source of chronic and intense pain. The manuscript reads well, is clear and scientifically sound. However, I think that Table 1 would be more meaningful if the frequencies of hip dysplasia were expressed in lines, comparing YES and NO in the different categories of microcephaly, rather than in columns. I would also suggest presenting the YES column first.  Therefore, it would be clear that hip dysplasia was present in 43% of children with microcephaly; 59% in severe microcephaly, but only 17% in moderate microcephaly and 0% in children without microcephaly, reinforcing that this is a consequence of the brain disruption, and more frequent to those described in CP (15-30%).

I have no other comments and I wish to congratulate the authors for this important work .

 

Author Response

Please see the attachment. 

Author Response File: Author Response.pdf