Intrauterine Transmission of Hepatitis C Virus Concomitant with Isolated Severe Fetal Ascites

Round 1

Reviewer 1 Report

In this manuscript the authors report a case of a 42 yo mother with late prenatal care found to have isolated fetal ascites and fetal HCV infection.  They note that this is the second reported case of isolated fetal ascites in a child with confirmed HCV perinatal transmission.  They also provide a review of the literature around HCV perinatal transmission and separate literature around fetal ascites etiology and evaluation.

The case is of clinical interest but the report needs significant revision.  The writing would be improved if it were more concise and if it more clearly acknowledged alternative hypotheses.  For instance,  the child may not have had intrauterine HCV transmission at 31 weeks as the low level HCV RNA detection in the fetus might have reflected maternal blood contamination given the setting of concomitant 10,000 fold higher RNA level in the mother.  They also need to more simply state that their case may suggest but does not establish that HCV caused fetal ascites in this case.

Line by line comments:

Title:  The title wording is broad and should likely be changed to indicate that this is a case report.  Also, “association” probably should not be in the title as it may imply some sort of statistical relationship.  The authors describe only their case and one other case of fetal ascites in context of HCV infection.  In the case by Ling et al it is not clear that there was intrauterine HCV infection prior to onset of fetal ascites because HCV RNA was not even detected in the fetal blood on cordocentesis in that case. 

Abstract – line 23-24 in the abstract background is ambiguous and misleading.   Does the author mean maternal HCV may be asymptomatic or that fetal infection may be asymptomatic?   Given that there had been only one prior unconvincing case report I do not think the authors can state in the background that there is an “association” with fetal ascites.

Line 29 – do the authors mean that the ascites resolved, improved, or, as written, “resumed”, after paracentesis?

Line 31 – abstract conclusions – the abstract does not really state the authors’ opinion about the role of HCV in this case.   Perhaps they should state that this case may indicate that intrauterine HCV transmission might be a potential cause of isolated fetal ascites in the absence of other explanation, and further study necessary. 

Review of literature:  this section should be condensed.

Line 53 – the risk for cirrhosis doesn’t abruptly start at 20 years.  It may be more accurate to state that risk for cirrhosis increases after several decades of infection.

Lines 55-61 list redundant and confusing facts about transmission risk and should be better consolidated.

Lines 62 and 68 have redundant and differing findings about perinatal transmission rates and could be consolidated. Usually in the HCV literature, “vertical” and “perinatal” transmission rates are used interchangeably because breast feeding is not a significant risk. 

Again, lines 71-73 are redundant with lines 73-75 regarding increased risk of HCV vertical transmission risk in setting of maternal HIV coinfection.  In addition, the authors should cite several newer publications showing the extra risk of HCV transmission in setting of maternal HIV co-infection is reduced/eliminated if maternal HIV is well controlled with ART.

Line 93 – I don’t think it would be accurate to state there are only two long-term follow-up studies of national history of HCV in children and adolescents.  Eg, see study by Modin et al (J Hepatol. 2019 Mar;70(3):371-378) that includes longterm followup of over 1000 children, including over 100 vertically infected children.  Perhaps the authors meant to say that there are few prospective long-term studies?

Line 112.  Pan-genotypic DAA treatments (sof/vel and gle/pib) are now both FDA approved down to age 3 years.

Line 151 Syphilis and toxoplasma are not viral infections.

Line 213 – would change “a jeune” to fasting for standard English.

Line 268 – why would transfusion of blood products be the primary risk factor for maternal HCV in this case given no prior h/o receipt of transfusion?  Other common risk factors such as injection drug use or sexual contact may be more probable, particularly if lack of prenatal care reflects underlying high risk social situation. 

Figure 5 – is it necessary to include the photo of the newborn?  Did mother specifically consent to including infant’s full photo in the manuscript?  Unfortunately, I am unable to see the excess abdominal skin in the photo, so I don’t think the photo adds much value.  If I am overlooking the skin folds perhaps the authors could zoom in and include an arrow pointing to the most prominent location. 

Line 307-315  The very low fetal HCV RNA level (251 IU/ml) was 10,000 fold lower than the concomitant maternal level (2365000 IU/ml).  It would also be plausible that the HCV-RNA detected in the cordocentesis reflected maternal blood contamination, not fetal infection.  The authors should at least acknowledge this possibility in their discussion.   They should also point out that the possibility that cordocentesis, as required for anesthesia, could conceivably increase the risk for HCV vertical transmission, though this is not well studied.

Line 352 – what does “genitors” mean?

Line 357 – HCV RNA was not detected in the fetus with ascites described by Ling et al.  Thus, the timing of that child’s transmission event is unknown.  Thus, I would state that that case had perinatal or vertical HCV transmission (intrauterine or peripartum). 

Conclusion – Perhaps the author should more clearly state that is the first reported case of documented HCV RNA detection by cordocentesis in setting of isolated fetal ascites, possibly indicating that intrauterine HCV infection was the cause of the ascites.  The conclusion should perhaps recommend additional study to investigate whether HCV vertical transmission is truly associated with a higher risk of fetal ascites. 

Author Response

Please see the attatchment.

Author Response File: Author Response.pdf

Reviewer 2 Report

The case report describes an interesting case of foetal ascites presumably attributable to in utero HCV infection. The case report desrves publication as the evidence for in utero HCV infection is convincing and foetal ascites is rarely reported with HCV infection.

I have following minor changes

The authors seem to use "," instead of decimal points - this is confusing and needs to be corrected throughout

The introduction is too long and needs to be shortened without any subsections. If needed some of this information can be moved to discussion 

The quality of English writing needs improvement. It is recommended that this article is proofread by a native English speaker. For example in the abstract authors state that "The ascites resumed after paracentesis, and 29 the gastrointestinal and respiratory functions markedly improved" I am not clear what is meant by "ascites resumed".

Suggest masking eyes of the baby in the photograph

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

In the revised manuscript the authors have mostly addressed my concerns.  I have several remaining minor points to be addressed:

1) abstract conclusion line 33 - I realize the authors used my suggested phrase almost verbatim, but on reading it here I see that the conclusion is soften with 3 cautious hedging words ("may", "might", "potential"), which is excessive.  1 or 2 is probably adequate.

2) Introduction line 47.  The "Therefore" is not correct.  The reason that the CDC recently revised its recommendation from risk-based to universal screening for HCV in pregnancy is not because of the global prevalence of HCV.   The reason that the CDC revised its recommendation was the increasing prevalence of HCV in women of childbearing age in the US, recognition that risk-based testing failed to detect a large proportion of infected women, and evidence that universal testing in pregnancy would be cost-effective.  Deleting "Therefore" in line 47 would improve the accuracy of the text.

3) Lines 58-61 - this sentence is not grammatically correct.

4) Line 64 - I am not aware of data showing that HCV is transmitted in the first 28 days after birth.  

5) Lines 263 - 4.   I apologize for not mentioning this earlier, but the authors state that blood/blood product transfusion is the primary risk factor for HCV, but that is generally only true for transfusions before 1992, before HCV screening became available.  Even if this pt did not have h/o blood transfusion, other forms of iatrogenic transmission are also possible as well (eg Tavoschi et al, J Hosp Inf. 2019, vol 102 pg 359-368.; PMID: 30885816).

 

 

Author Response

Please see the attachment.

Author Response File: Author Response.pdf