Review for 10.1186/s12876-023-02871-8 (2023)

Title: Retrospective Analysis of Vertical Hepatitis C Exposure and Infection in Children in
Western New York
Version: 2 Date: 02 Apr 2023
Reviewer's report:
Dieye et al present valuable data they have gathered through a single center pediatric infectious
diseases clinic with a substantial subset of linked mother-infant pairs to investigate factors
affecting  perinatal HCV testing and vertical HCV infection. This remains an area with a paucity
of data, and this study adds to the literature. There are a number of areas that need to be addressed
to best clearly and accurately present this data, however, as detailed below.
Major:
1. The description of the new screening program needs additional historical context and detail.
Who was previously screening children/infants for vertical HCV exposure prior to 2019 if your
infectious disease clinic screened <1 infant per year prior to that? I suspect some were screened
at other sites such as gastroenterology clinics, primary care or other, no? Is there any way to
ascertain that information? It’s a significant limitation of the study if not because you don’t
know if those children were captured elsewhere before.
2. What was the protocol of the clinic – when were infants recommended to be tested, what
follow-up was done if not tested at first, how often and when were infants followed.
3. Please detail how data was abstracted – were all charts reviewed for the infant/child diagnoses,
then all remaining charts for mention of maternal exposure in note, then maternal charts if
information still unknown? Were maternal charts reviewed and present for all babies? It appears
not from the limitations section, but this needs to be mentioned elsewhere, and if it’s a significant
proportion of charts, then I would strongly consider not including those infants/pairs in the
statistical analyses. I’m unclear what order was used, and importantly whether all charts from
the clinic were reviewed or a selection based on primary diagnosis and age or something, and
in what way were data reviewed – ie was data extracted from a central database or were charts
individually reviewed by someone?
4. Do maternal characteristics refer to biologic mother or foster mother when foster mother
brings in the baby? Please make this clear in methods.
5. Very little space of background, abstract, or methods addresses the HCV testing analysis. The
last sentence of the statistical analysis section is the first time sensitivity of HCV PCR testing is
mentioned, which then is a prominent part of the results – would set up why you’re doing this
& describe the different testing methods used in the background section and describe in more
than one sentence in the methods what was done to analyze testing.
6. Please define how HCV positive is defined in children for your analysis – is this 2 PCR tests
positive? Is Ab after 18months without pcr testing included? What about a single positive PCR
test? The definition is alluded to in the discussion, but needs to be clear in the methods. Also, you
give additional data in the discussion about how many infants were tested according to different
definitions – this should also be in methods and results, and would argue that we have little if any
information from an infant with one positive antibody test at age <18mo and no further follow-
up. Therefore would consider whether you might change your primary outcome of ‘tested at all’
to one of the more stringent adequate testing definitions you mention.
7. Why are univariate comparisons done by both logistic regression and also chi square or fisher
exact tests? They are comparing the same thing, wouldn’t report results in text separately for
each unless just reporting crude and adjusted regression results, which presumably would be the
most useful, if the model is appropriately adjusted.
8. Table 2 – there are several characteristics where the unknown category is >40% of the entire
sample, and some where it comprises >90%. I don’t think data particularly in the 90% missing
variables are very helpful because it only represents a small proportion of the population and
does not seem appropriate for statistical analysis.
9. Discussion lines 177-183 – this whole section is very confusing as written, and I’m not sure
I agree with the conclusions. Most clinicians would not consider a PCR test of <15 IU/mL as a
clear positive – it suggests the potential for low level viremia if it is indeed detected by <15, but
I believe some labs also just report this as their negative tests.
10. Discussion line 195-197 – this is an odd finding, that in this small sample 2 mothers who
were reportedly HCV RNA negative transmitted to their infants, and needs additional data and/
or discussion. How recently before birth were the mothers tested? Ie were they RNA negative
during pregnancy? Third trimester? Or years prior? If it was years prior and they weren’t tested or
known to be tested during pregnancy, or if the mother was known to have ongoing injection drug
use or other risk, then this should be mentioned because the likelihood of undetected reinfection
and truly present viremia during pregnancy or delivery becomes much more likely than a truly
HCV RNA negative woman transmitting. If maternal RNA data is not known during pregnancy
in the majority of cases, it’s not clear that regression on this variable should be included in the
analysis rather than just including the data as exploratory. On the other hand, if there were two
women who were RNA-negative during pregnancy who transmitted, it is an important finding
to report as relates to third trimester screening in high risk patients.
11. Would consider mentioning/citing the new draft CDC guidelines that recommend
for the first time obtaining early RNA testing (2-6mo) instead of waiting until 18mo
to obtain Ab testing (https://www.federalregister.gov/documents/2022/11/22/2022-25421/cdc-
recommendations-for-hepatitis-c-testing-among-perinatally-exposed-infants-and-children-
united ) as this is very relevant to the topic.
12. Please be clear how unknown categories are treated in regression analyses - are they included
as a category or excluded to do complete case analyses?
Minor:
1. Language/grammar throughout – please review or have someone review to correct the many
small grammatical mistakes.
Introduction:
2. Line 34-36 “The identification of risk factors for horizontal transmission led to the
implementation of universal testing of all blood products for transfusion and syringe exchange
programs among people who inject drugs. However, less focus has been placed on preventing
vertical transmission.” – Testing of blood products started over two decades ago, but is only
one aspect of testing/prevention. If you bring this up would discuss testing recommendations at
the population level as well, including the recommendations for universal testing in pregnancy
as that clearly affects vertical transmission. I’m not sure you need to spend time discussing
horizontal risk factors at all in this paper on vertical transmission.
3. Lines 41-43 Ideal to reference primary sources rather than reviews (in reference to testing rates
among exposed infants). Also there is a fairly universally accepted testing protocol of waiting
until 18months to test infants per AAP, IDSA/AASLD, and CDC guidance. I agree there are
other recommended methods not (yet) endorsed by these guidelines, but will be endorsed if the
draft CDC guideline is accepted/published.
Methods:
4. Line 69 – technically that’s an 11-year period
5. Exclusion criteria are really just the opposite of inclusion criteria, would consider cutting or
at least reword iii) for grammar and specify in iv) whether negative antibody or RNA testing
was considered an exclusion.
6. Why was the ICD code for unspecified HCV used and not other HCV diagnosis ICD codes?
Results:
7. As indicated in the table footnote, would make very clear that the ‘positive’ PCR test for
the baby who had 2 subsequent negatives was detected but <15 (and would confirm it was
truly detected and not just done at a lab that indicates <15 for all negative tests as I believe
occurs at some labs). This has a very different clinical meaning than a positive result that is high
enough to be quantified. Please also indicate what the child’s antibody status was (did they clear
eventually?) and the age the child was at testing (at least whether younger than or older than 1-2
months), as it has been reported that children <2 months can be more likely to have a transient
positive PCR as you mention and thus why the draft CDC recommendations are to test between
2-6 months and not earlier.
8. Line 147-148, this is a methods sentence.
9. Do you know whether the mothers with HIV infection were on ART or well-controlled? This
has been a slightly contentious point in the literature that older studies showed a more clear
association between HIV co-infected mothers and vertical transmission that is thought to be
less strong when evaluating more contemporary cohorts with well-controlled moms on ART. It
would add to this study and understanding if you had this data.
Table 2:
10. ‘Ever undergone opioid agonist therapy’ – OAT is something someone chooses to take to
treat a medical condition – would rephrase ‘undergone’ - for example to ’treated with.’ Also is
this category just of those who have known opioid use disorder? Because if not, the ‘no’ is a
combination of those with high risk use not on therapy and those without OUD. Would consider
adding an ‘na’ category or something. Same thing for HCV treatment status – do you include in
this category women who weren’t viremic? Would exclude non-viremic women if you haven’t
already from this category.
Discussion:
11. First line – I would argue you ‘estimated’ the vertical transmission rate since you do not
know the true denominator or the results of tests for those untested.
12. As above, unless you can demonstrate that infants/children in 2011-2018 were not tested at
all rather than possibly tested elsewhere, I don’t think you can say the intervention dramatically
increased testing rates. If you’re able to say this based on knowledge of no other providers in
the area testing, or other charts reviewed of exposed children never tested, then this might be a
reasonable conclusion, but you need to include that information if so.
13. I’m not sure what to make of the findings that foster parents and those who don’t smoke
are associated with increased testing. How do we know this isn’t just an artifact of data or
confounding in some way? Is there anything useful we can take from these findings?
14. Lines 188-189 – This conclusion doesn’t make sense to me. What is meant by ‘healthy’
mothers and why would they be more likely to request testing? Shouldn’t testing be
recommended by the doctor also and not requested to begin with? Is there not testing ordered
on all children seen by the pediatric infectious diseases clinic for exposure to HCV?
15. Lines 199-201 – Would cite the primary data (the large study or meta-analysis that is cited by
the guidelines and compared SVD vs. csection on transmission rate) and guidelines here rather
than a commentary (or in addition) and would rephrase to say it’s consistent with prior data, as
that’s what the guidelines are based on.
16. Limitations – A key limitation is the small study size (particularly of complete data) and
small number of outcomes for the infected infants/factors associated with infection. This needs
to be more clear particularly in all negative outcomes reported (ie unless you’ve done a power
calculation to state otherwise, you cannot draw any conclusions from lack of associations found
here).
17. Last paragraph – 21-year-olds aren’t children, and this article is just focused on those <5.
Would focus on that population. The last sentence is also unrelated to the rest of the paper.