Dear Dr Gowland,

Thank you for submitting your manuscript entitled "The haemodynamics of the human placenta in utero" for consideration as a Research Article by PLOS Biology.

The Academic Editor and I have now assessed your revised manuscript and I am writing to let you know that we would like to send your submission out for external peer review.

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Lauren A Richardson, Ph.D

Senior Editor

PLOS Biology

Dear Dr Gowland,

Thank you for submitting your revised Research Article entitled "The haemodynamics of the human placenta in utero" for publication in PLOS Biology. I have now obtained advice from the original reviewers and have discussed their comments with the Academic Editor.

Based on the reviews, we will probably accept this manuscript for publication, assuming that you will modify the manuscript to address the remaining points raised by the reviewers including the criticism from reviewer 1 regarding less sufficient histopathological correlations and improving your discussion on Figure 2C also from this reviewer.

Please also make sure to address the data and other policy-related requests noted at the end of this email.

We expect to receive your revised manuscript within two weeks. Your revisions should address the specific points made by each reviewer. In addition to the remaining revisions and before we will be able to formally accept your manuscript and consider it "in press", we also need to ensure that your article conforms to our guidelines. A member of our team will be in touch shortly with a set of requests. As we can't proceed until these requirements are met, your swift response will help prevent delays to publication.

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Sincerely,

Di Jiang

PLOS Biology

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Reviewer remarks:

Reviewer #1: The text has improved, but there are lingering issues, largely related to the lack of histopathological correlations (except for four participants, listed in Table S2a). This was mentioned by more than one reviewer. In addition, the authors did not really address my comment regarding Fig. 2C, and in the revised version (page 4) they have removed any text reference to Fig. 2C.

While the paper is indeed important, greater attention to readability and flow can improve the revised text.

Reviewer #2 (Ananth Karumanchi, signed review): Manuscript is significantly improved.

Reviewer #3 (John Kingdom, signed review):

Thank you for taking the time to prepare thoughtful responses and edits to your manuscript, in response to all reviewers.

I remain skeptical about your proposed concept of a utero-placental pump, but I'm open-minded enough to allow the reader to decide.

I spend a lot of time scanning pregnancies with complex placental problems, and focal (non-concentric) uterine contractions are common; they can very easily lead to mis-interpretation via placental distortion, so its important to re-assess the placenta when the uterus is soft and the myometrium is uniform.

Some investigators have previously reported that placentas of near-term pregnancies with preeclampsia are heavier than average, and increased central placental thickness has been reported in the 1st trimester (NT scan) examination, in women who subsequently develop preeclampsia, and this phenomenon persists in the 2nd trimester.

Most women who develop preeclampsia at term (37+ weeks) have no demonstrable placental disease ; rather, they have "maternal" disease, as opposed to "placental MVM" disease (eg see prospective cohort study, Wright E, & Kingdom J, Obstet Gynecol, Nov 2017). They have well-perfused placentas with normal uterine artery Doppler, and so do not have hypopxia-reoxygenation injury (which represses PlGF production) as is found in the preterm preeclamptic placenta, with histologic features of MVM including deciudual vasculopathy. That is why maternal PlGF testing is only valid up until 36 weeks' gestation.

I hope you include PlGF testing and placental pathology costs in your future grant applications, as they are cost-effective and important phenotypic tests.

Sincerely, Dr. John Kingdom MD, University of Toronto, Mount Sinai Hospital, Canada.

Dear Dr Gowland,

On behalf of my colleagues and the Academic Editor, Masahito Ikawa, I am pleased to inform you that we will be delighted to publish your Research Article in PLOS Biology.

The files will now enter our production system. You will receive a copyedited version of the manuscript, along with your figures for a final review. You will be given two business days to review and approve the copyedit. Then, within a week, you will receive a PDF proof of your typeset article. You will have two days to review the PDF and make any final corrections. If there is a chance that you'll be unavailable during the copy editing/proof review period, please provide us with contact details of one of the other authors whom you nominate to handle these stages on your behalf. This will ensure that any requested corrections reach the production department in time for publication.

Early Version

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PRESS

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Thank you again for submitting your manuscript to PLOS Biology and for your support of Open Access publishing. Please do not hesitate to contact me if I can provide any assistance during the production process.

Kind regards,

Alice Musson

Publishing Editor,

PLOS Biology

on behalf of

Di Jiang,

Senior Editor

PLOS Biology