PONE-D-23-42863Management of Childbearing with Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorders: A Scoping Review and Expert Co-creation of Evidence-based GuidelinesPLOS ONE

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PLOS ONE

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[SP reports receiving honorariums from the Ehlers-Danlos Society. AH reports receiving honorariums from the Ehlers-Danlos Society. NB reports receiving honorariums from the Ehlers-Danlos Society. Other authors report no conflict of interest.]. 

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Reviewers' comments:

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Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1: Excellent summary and recommendations, which are greatly needed. The hypermobility population, including patients and physicians, will appreciate your hard work on this publication. You may consider recommendations for methylated folate instead of folic acid supplementation, but this is not necessary for publication.

This publication is going to help many!

Reviewer #2: The authors underwent a process to create management guidelines for those with hEDS/HSD related to childbearing from conception, pregnancy, delivery, and post-partum concerns. They relied on literature review that was comprehensive involving several databases and languages; however, the literature was limited. The approach also involved experts in the various fields as well as patients themselves to create these guidelines. While the literature has pointed out some recommendations, these guidelines tried to be complete in looking at pregnancy in its entirety but with important perspectives from experienced professionals and patients themselves. The approach was vigorous trying to use acceptable standards in such guideline development as well as fills a much needed clinical gap.

Unfortunately, the limitations of the literature also include EDS often reported by the patients themselves (which may or may not be correct) as well as including EDS as a whole which would include all types of which classic and vascular would likely have increased complications. As HSD/hEDS does represent the vast majority of EDS types, it is likely representative of the complications reported but a few cases of complications from one of the rarer types of EDS would skew results and interpretation of risks. It is difficult to get around this without prospective studies. This is a major limitation of this guideline and should be discussed more thoroughly.

It is hoped that the mention of these many issues does not over medicalize pregnancy when as the authors mentions, most pregnancies go as expected. I would suggest that this is also addressed as many patients also have misconceptions about pregnancy and so do health providers. I have heard many tell me that their doctors have told them to never get pregnant, an abhorrent misconception of the risks for hEDS/HSD.

Recommendation is to accept with revisions:

Major:

The guidelines recommend consideration of midodrine use during pregnancy for those with dysautonomia. The US FDA lists this as pregnancy category C with animal studies documenting decrease fetal size and increased fetal demise. For the expected physiologic response to this drug as a vasoconstrictor, this is very plausible. Clinical experience is limited reporting no detrimental outcomes but this is not unusual [Morgan et al., “POTS and Pregnancy”, Int J Women’s Health, 2022]. Recommendation without expressing this concern is potentially harmful especially as this guideline is to inform clinical decision-making.

Many of the references do not list a journal title which is not appropriate.

Minor:

As the guidelines use a compilation of articles related to symptomatic joint hypermobility which includes hEDS and HSD as well as joint hypermobility syndrome. Statement addressing JHS as unable to be distinguished from hEDS/HSD is necessary as this guideline should also apply to those diagnostically labeled as JHS which is considered likely allelic to hEDS and definitely within the hypermobility spectrum disorders.

Table 1 reports data from a published source. The title reports “Signs and symptoms of EDS…” therefore it is not clear if this relates to all type of EDS or hEDS/HSD specifically. This citation could not be verified using the information provided. The data should also outline if this is for females only or a preponderance of females as expected for this population.

Table 3, Castori et al. 2012 reference: in the 4th column and 4th bullet point, it should read “births at >37 weeks gestation (66.7%)”

Table 3, Holick et al. 2021 reference: unfortunately, this was focused on the birth outcome when the fetus/infant had another genetic condition altogether. It should be deleted as irrelevant as not to give the impression that fetal fractures are a rare outcome of hEDS.

Table 3, Sizer et al. 2014 reference: 3rd column lists mobility as decreased. As the manuscript talks about joint hypermobility this is a confusing term suggesting to the less avid reader that the joints can acquire decrease mobility during pregnancy (when it is often increased) when this is talking about ambulation of the person. This is also used confusingly in the manuscript itself and alternate terminology would be useful.

Table 4, Overview: I was surprised to see geneticist not listed as part of the multidisciplinary team especially as the discipline was included in the co-creators. Of course, not every patient needs all specialists but many geneticists may help manage these patients. A geneticist may also be helpful in discussing the diagnosis and heritability risks as well as discussion on testing as appropriate since many may be referred for ruling out the rarer forms of EDS.

Table 4, Comorbidities: adrenal insufficiency is listed which in my experience of thousands of patients is not the case. Diagnostic studies are often negative but patients do show abnormal cortisol levels which may be due to many other concerns. If the authors contend that this is a co-morbidity and can worsen during pregnancy, should not an endocrinologist be listed as a team member?

Table 4, Sexual Intercourse: phrasing “cromolyn and/or compounded topical or internal muscle relaxers”. Cromolyn is not a muscle relaxer. I suspect that the sentence/phrasing is incomplete.

Table 4, Miscarriage: column 2 has “due to due to” is repetitive.

Table 4, wound healing: column 2, “suture dehiscence” is unclear. Is it meant suture failure or wound dehiscence. Both would be appropriate.

Table 4, Additional resources: website “Statement on the use of opioids…” used twice

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Reviewer #1: Yes: Jacques Courseault, MD

Reviewer #2: No

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Management of childbearing with hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorders: A scoping review and expert co-creation of evidence-based clinical guidelines

PONE-D-23-42863R1

Dear Dr. Pezaro,

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Kind regards,

Martin E. Matsumura, MD

Academic Editor

PLOS ONE

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