Post lockdown COVID-19 seroprevalence and circulation at the time of delivery, France.

BACKGROUND: To fight the COVID-19 pandemic, lockdown has been decreed in many countries worldwide. The impact of pregnancy as a severity risk factor is still debated, but strict lockdown measures have been recommended for pregnant women.
OBJECTIVES: To evaluate the impact of the COVID-19 pandemic and lockdown on the seroprevalence and circulation of SARS-CoV-2 in a maternity ward in an area that has been significantly affected by the virus. STUDY
DESIGN: Prospective study at the Antoine Béclère Hospital maternity ward (Paris area, France) from May 4 (one week before the end of lockdown) to May 31, 2020 (three weeks after the end of lockdown). All patients admitted to the delivery room during this period were offered a SARS-CoV-2 serology test as well concomitant SARS-CoV-2 RT-PCR on one nasopharyngeal sample.
RESULTS: A total of 249 women were included. Seroprevalence of SARS-CoV-2 was 8%. The RT-PCR positive rate was 0.5%. 47.4% of the SARS-CoV-2-IgG-positive pregnant women never experienced any symptoms. A history of symptoms during the epidemic, such as fever (15.8%), myalgia (36.8%) and anosmia (31.6%), was suggestive of previous infection.
CONCLUSIONS: Three weeks after the end of French lockdown, SARS-CoV-2 infections were scarce in our region. A very high proportion of SARS-CoV-2-IgG-negative pregnant women, which is comparable to that of the general population, must be taken into consideration in the event of a resurgence of the pandemic. The traces of a past active circulation of the virus in this fragile population during the spring wave should encourage public health authorities to take specific measures for this independent at-risk group, in order to reduce viral circulation in pregnant patients.

Introduction

The coronavirus disease 2019 (n class="Disease">COVID-19) pandemic hit France at the end of February 2020. To date (August 29, 2020), more than 24,000,000 cases and 830,000 deaths have occurred worldwide [1]. France, and more particularly the Paris area, was one of the regions of the world most affected by the pandemic in spring 2020 [2, 3]. In order to slow down progression of the pandemic, lockdown has been decreed in many countries worldwide. French lockdown started on March 17, 2020, and ended on May 11, 2020.

Pregnancy as a severity risk factor of severe acute respiratory syndrome coronavirus 2 (n class="Species">SARS-CoV-2) infection has been debated, even though the third trimester seems to be a consensual risk factor [4-9]. Recent evidence in the literature suggests that infection among pregnant women with COVID-19 increases the risk of iatrogenic preterm birth, cesarean delivery and maternal complications in the postpartum period, making obstetric management of potentially infected patients a complex issue [10, 11]. In addition, it has recently been shown that the virus can be transmitted transplacentally and be responsible for neurological symptoms in newborns [12]. All of these maternal and neonatal data make it important to carefully consider the possibility of infection during pregnancy.

Lockdown has been shown to result in a very significant decrease in the incidence of COVID-19 n class="Disease">infections in pregnant women in France [13]. The main goal of this study was to evaluate the impact of the first wave of the COVID-19 pandemic in our region, the quantity of pregnant patients exposed to the virus and the effect of lockdown on seroprevalence in our maternity ward, which has been significantly affected by the virus (more than 40 confirmed infections among pregnant women between March 12 and April 20) [8].

Materials and methods

We conducted a prospective study at the Antoine Béclère Hospital maternity ward (Paris area, France) from May 4 (one week before the end of lockdown) to May 31, 2020 (three weeks after the end of lockdown). All patients admitted to the delivery room duriene">ng this period were offered a n class="Species">SARS-CoV-2 serology test as well as SARS-CoV-2 RT-PCR on a nasopharyngeal sample. A questionnaire was distributed to all included women, who were asked about symptoms (fever, cough, dyspnea, myalgia, anosmia, diarrhea and rash) affecting them and/or close relatives (household residents) from January 1 to their delivery, and if there were symptoms they were asked for the date of onset. Patients were also asked whether they strictly adhered to the rules of lockdown and social distancing.

Serology testing

Serum samples were run on the Abbott Architect instrument using the Abbott SARS-CoV-2 IgG assay (Abbott, Sligo, Irelaene">nd) followiene">ng the maene">nufacturer’s iene">nstructioene">ns. The assay is a chemilumiene">nesceene">nt microparticle immuene">noassay for detectioene">n iene">n n class="Species">human serum or plasma of IgG against the SARS-CoV-2 nucleocapsid protein. IgM detection was not performed. Based on our local evaluation of 500 serum samples (data not published), the result was considered negative if the IgG index value was < 0.8, equivocal if the IgG index was between 0.8 and 1.39, and positive if the IgG index value was ≥ 1.40 (0.40 is the Abbott determined positivity cut-off).

Molecular testing

Nasopharyene">ngeal swabs were collected from all the n class="Species">patients. Samples were tested by using the GeneFinderTM COVID-19 Plus RealAmp Kit (Elitech, Puteaux, France) on the ELITe InGenius® Platform, or the Xpert Xpress SARS-CoV-2 assay (CepheidTM, Sunnyvale, CA, USA), or the GenMark ePlex SARS-CoV-2 assay (Elitech, Puteaux, France), depending on the time of day. We adapted our algorithm of the assay choice to our workflow, to our reagent supply possibilities and to the urgency of the results for clinical management of some parturients.

The GeneFinder assay is a molecular in vitro test utilizing one-step reverse transcription real-time PCR to detect the RNA-dependent RNA polymerase, the envelope gene (E) and the nucleocapsid gene (N), as described in international guidelines (Corman et al. [14]). It was used as our routine test during the day.

The Xpert Xpress SARS-CoV-2 assay (Cepheid) aene">nd the Geene">nMark ePlex n class="Species">SARS-CoV-2 assay are sample-to-answer molecular diagnostic platforms. The former is based on the detection of 2 gene targets, N2 and E, according to an algorithm in parallel with the sample process control, and the latter is based on the detection of the N gene of SARS-CoV-2. They were used during the night, on weekends and for urgent results.

All data (clinical, laboratory, from both mothers and newborns) were prospectively collected from medical records.

All statistical analyses were performed using R software (Version 3.5.1, R Core Team [2018] https://www.R-project.org/). Continuous variables are expressed as medians with the interquartile range (IQR). Categorical variables are expressed as numbers with percentages. A two-tailed Mann-Whitney U test was used for statistical analysis of continuous variables. Fisher’s exact test was used for statistical analysis of categorical variables. Statistical significance was considered with a p<0.05.

This study was approved by the institutional review board of the French College of Obstetricians and Gynecologists (2020-OBST-0408) and was performed in accordance with the Declaration of Helsinki. All patients gave writteene">n coene">nseene">nt. All data were de-ideene">ntified to eene">nsure n class="Species">patient privacy and confidentiality.

Results

During the study period, SARS-CoV-2 serology testiene">ng was offered to all 272 n class="Species">patients admitted to the delivery room (Fig 1). A total of 249 (91.5%) serology results were available (22 women did not give consent and one missing result). Seroprevalence was 8% (n = 20/249). The main characteristics of the women and of their pregnancies and newborns are shown in Table 1. All patients were asymptomatic on admission to the delivery room. There were no significant differences between the groups of SARS-CoV-2-IgG-positive and SARS-CoV-2-IgG-negative women. Among women admitted for delivery, 190 had a SARS-CoV-2 RT-PCR test during the study period (59 women declined testing and one missing result). Exhaustivity was therefore 69.9% (190/272). Only one (0.5%) test was positive and this patient remained asymptomatic during delivery and early post-partum. This positive test was performed on May 25, 2020, using the Xpert Xpress assay, with detection of the nucleocapsid (N2) gene only at a CT value of 41.4 within the valid range and endpoint above the minimum setting of this FDA-approved assay. This indicates that the viral load of this sample is at the detection limit of the Xpert Xpress assay and may be related to an old infection. The serology was positive. The patient and her spouse reported symptoms such as headache, asthenia and anosmia as of March 10, 2020. Her newborn tested negative (negative SARS-CoV-2 RT-PCR performed on nasopharyngeal swabs at birth and at three days of life).

Fig 1

Flow chart of the study–universal serology screening for SARS-CoV-2 among a cohort of women admitted for delivery.

Table 1

Maternal, obstetric and neonatal characteristics according to SARS-CoV-2 serological status for women admitted for delivery.

	IgG-negative	IgG-positive	p
	n = 229	n = 20
Age, years, median [IQR]	33 [29–36]	31 [30.5–37]	0.88
Nullipara, n (%)	106 (46.3)	12 (60)	0.25
BMI, kg/m2, median [IQR]	23 [21–27]	25,5 [23–28.2]	0.07
History of preexisting:
- Diabetes mellitus, n (%)	2 (0.9)	0 (0)	1
- Chronic hypertension, n (%)	6 (2.6)	0 (0)	1
- Tobacco use, n (%)	44 (19.2)	2 (10.6)	0.54
- Asthma, n (%)	13 (5.7)	0 (0)	0.6
Gestational age at delivery, week median [IQR]	39.6 [38.2–40.7]	39.7 [38.2–40.3]	0.50
Delivery before 37 WG, n (%)	26 (11.4)	4 (21.1)	0.26
Birthweight, g median [IQR]	3241 [2829–3585]	3213 [2853–3471]	0.62
Infected neonates, n (%)	0 (0)	0 (0)

Analysis of the available questionnaires (n = 220/249; 88.3%) showed that 31.6% (6/19) of the SARS-CoV-2-IgG-positive n class="Species">women reported being asymptomatic throughout the first wave of the pandemic. SARS-CoV-2-IgG-positive women reported more symptoms compared to SARS-CoV-2-IgG-negative women (Table 2), such as fever (n = 3 (15.8%) versus n = 3 (1.5%); OR = 12.9 (95% CI 1.49–97.52); p = 0.009), myalgia (n = 7 (36.8%) versus n = 14 (7%); OR = 8.39 (95% CI 2.38–25.46); p<0.001) and anosmia (n = 6 (31.6%) versus n = 3 (1.5%); OR = 29.2 (95% CI 5.52–201); p<0.001). There was no difference regarding the symptoms of cough, dyspnea, diarrhea and rash. All women except one (in the negative group) reported they had strictly respected lockdown rules.

Table 2

Reported signs and symptoms according to SARS-CoV-2 serological status for women admitted for delivery.

	IgG-negative	IgG-positive	OR (95% CI)	p
	n = 201	n = 19
Fever, n (%)	3 (1.5)	3 (15.8)	OR = 12.9 (1.49–97.52)	0.009
Cough, n (%)	13 (6.5)	2 (10.5)	OR = 1.69 (0.17–8.52)	0.62
Dyspnea, n (%)	12 (6)	1 (5.3)	OR = 0.87 (0.02–6.6)	1
Myalgia, n (%)	14 (7)	7 (36.8)	OR = 8.39 (2.19–25.46)	<0.001
Anosmia, n (%)	3 (1.5)	6 (31.6)	OR = 29,2 (5.52–201)	<0.001
Diarrhea, n (%)	21 (10.4)	1 (5.3)	OR = 0.47 (0.01–3.34)	0,7
Rash, n (%)	5 (2.5)	1 (5.3)	OR = 2.16 (0.04–20.9)	0.42

Discussion

SARS-CoV-2 screeene">ning (serology and RT-PCR on nasopharyene">ngeal secretions) of all n class="Species">women at delivery showed that: 1- the seroprevalence of SARS-CoV-2 infection was 8% and most of the pregnant women remained uninfected; 2- half of the SARS-CoV-2-IgG-positive pregnant women were completely asymptomatic during the study period; 3- the virus was no longer in active circulation up to three weeks after the end of lockdown.

In our maternity ward, implementation and generalized respect of lockdown rules and social distancing allowed for a drastic reduction in the number of confirmed cases. Pregnant women reported full lockdowene">n compliaene">nce from March 17, 2020 uene">ntil delivery. Despite the eene">nd of lockdowene">n aene">nd the resumptioene">n of activity for members of the family circle, the rate of positive results by RT-PCR remaiene">ned very low. In additioene">n, the triad n class="Disease">fever, myalgia and anosmia was linked with previous infection with the SARS-CoV-2 virus.

The seroprevalence of our cohort was similar to that observed in the general population [15, 16]. Crovetto and colleagues have recently reported a seroprevalence of 14% among 874 pregnant women [17]. However, this cohort included more than 40% tested in the 1st trimester of pregnancy. In addition, seroprevaleene">nce included positivity for IgG but also for IgM and IgA. It is interesting to note that 60% of the seropositive n class="Species">patients in their cohort were asymptomatic, which is higher than that observed in our study.

To date, it has not been assessed whether SARS-CoV-IgG, detected with currently available ELISA assays, are neutralizing antibodies and consequently confer protection. However, it is of major importance to have an estimation of the rate of pregnant women who have not already been n class="Disease">infected, indeed the challenge of reducing severe forms in pregnant patients and decreasing obstetric iatrogenesis in mild forms will be directly determined by the potential number of patients infected in a second wave [10, 11]. Our study shows that there is a significant reservoir of future infections and that barrier measure recommendations, even when well respected by pregnant patients, were not enough to significantly reduce encounters with the virus in a population sensitive to infection prevention. This encourages us to suggest a reflection on specific measures to be implemented to protect this population, built on precise knowledge of the seroprevalence of COVID-19 in pregnant women [18, 19].

One could argue that the study period would need to be longer in order to fully estimate the effect of the end of the lockdown and the risk of a resumption of the pandemic (so-called second wave). The design of our study did not allow us to assess the existence of sequelae in our patient population, however, it has recently been shown that pregnancy in the 2nd and 3rd trimesters represents an independent risk factor for n class="Chemical">oxygen therapy, hospitalization in an intensive care unit and use of mechanical ventilation [20, 21]. It is important to note that pregnant women are subject to specific recommendations to limit the risk of infection and it appears that seroprevalence, although not high, is similar to that observed in the general population at the same time [19]. For these reasons, it is imperative that special attention be paid to this at-risk population in the event of a second wave of infections. Specific directed awareness should be given to these patients, particularly about their participation in family gatherings in closed environments, which seems to be an important source of viral transmission. We believe that our study provides an important snapshot at a given point in time of the exposure to COVID-19 in an at-risk population in a region highly exposed to the virus during spring.

Conclusion

Three weeks after the end of French lockdown, SARS-CoV-2 infections were scarce iene">n our regioene">n. A very high proportioene">n of n class="Species">SARS-CoV-2-IgG-negative pregnant women, which is comparable to that of the general population, must be taken into consideration in the event of a resurgence of the pandemic. The traces of a past active circulation of the virus in this fragile population during the spring wave should encourage public health authorities to take specific measures for this independent at-risk group, in order to reduce viral circulation in pregnant patients.

(XLSX)

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7 Aug 2020

PONE-D-20-20995

Post lockdown COVID-19 seroprevaleene">nce aene">nd circulatioene">n at the time of delivery, Fraene">nce

PLOS ONE

Dear Dr. Vivanti,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Four experts in the field handled your manuscript. We are thankful for their time and efforts. Although some interest was found in your study, several major comments arose that overshadowed this enthusiasm. These comments include that: several statements need citations; there are concerns about specifics of diagnosis and testing for COVID-19; numerous questions about the study design, including how the n class="Species">women were experimentally grouped and sensitivity of assays; the data presentation needs work, including the inclusion of data for the local evaluations; the discussion needs to be more developed; and the conclusions should better reflect the findings. ALL of the reviewers' comments must be addressed in your revised manuscript.

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Reviewer #1: The background and methods of this study are very good. It is impressive that you have managed to collect this amount of data for such a specific patient demographic. The data aene">nalysis has also beeene">n performed well.

I feel however that the discussion needs to have more detail. Furthermore, you have only written your conclusion in the abstract; you also need a conclusion section in the main body of the manuscript.

The conclusion you have reached is that SARS-Cov-2 negative n class="Species">women need to be taken into consideration in case of a second wave. However, I feel that you need more justification of this stance. Your results state that 47.4% of the positive women did not have any symptoms and those who did have symptoms appear relatively mild. Furthermore, your results also state that the majority of women were uninfected.

Did you find any serious sequelae of SARS-CoV-2 infection in your study as a whole? If yes, you need to include this. If not, then how have you come to the conclusion that these n class="Species">patients require more consideration than the general population?

In summary, you need to do further work in your discussion, because your actual results do not really justify your conclusion. You need to elaborate further on the potential consequences of SARS-CoV-2 infection iene">n pregene">naene">nt n class="Species">women if this is the conclusion you have made, and this requires more research into maternal and neonatal morbidity and mortality due to SARS-CoV-2. You need to compare and contrast your results to other research on this topic, and write a discussion that properly debates whether pregnancy puts mothers and neonates at higher risk of death or not.

Reviewer #2: Review: “Post lockdown COVID-19 seroprevaleene">nce aene">nd circulatioene">n at the time of delivery,Fraene">nce”

General comments:

This is a research involving the first wave of the COVID-19 paene">ndemic iene">n Paris aene">nd the effect of lockdowene">n oene">n seroprevaleene">nce iene">n your materene">nity ward, which has beeene">n sigene">nificaene">ntly affected by the virus (more thaene">n 40 coene">nfirmed n class="Disease">infections among pregnant women between March 12 and April 20). Pregnancy as a severity risk factor of severe acute respiratory syndrome coronavirus 2 77 (SARS-CoV-2) infection is still debated.This study prospectively to evaluate the impact of the first wave of the COVID-19 pandemic at the Antoine Béclère Hospital maternity ward (Paris area, France) from May 4 (one week before the end of lockdown) to May 31, 2020 86 (three weeks after the end of lockdown). I recommend a publication of this paper with major revisions.

Abstract:

1.Study design:“All patients admitted to the delivery room duriene">ng this period were offered a n class="Species">SARS-CoV-2 serology test as well concomitant SARS-CoV-2 RT-PCR on a nasopharyngeal sample”.As we all known, Throat swab nucleic acid positive rate is low,how many times do your study deign If the first nucleic acid test is negative?

2.Result: “A history of symptoms during the epidemic, such as fever, 54 n class="Disease">myalgia and anosmia, was suggestive of previous infection.” What is the distribution of various clinical symptoms.

Key words: Please add on.

Introduction:

1.The introduction is too simple to state the current studies of COVID-19.

2.“more than 40 confirmed infections amoene">ng pregene">naene">nt n class="Species">women between March 12 and April 20”，Do you have some references?

Materials and Methods:

1.“All patients admitted to the delivery room duriene">ng this period were offered a n class="Species">SARS-CoV-2 serology test as well as SARS-CoV-2 RT-PCR on a nasopharyngeal sample”. Did the serological testing include IgM and why it is’t mentioned in the full text?

2.“All data (clinical, laboratory, from both mothers and newborns) were prospectively collected from medical records.” This is a prospective study. Have you list which laboratory indicators need to be tested?

Results:

1. “Only one (0.5%) test was positive and this 143 patient remaiene">ned asymptomatic duriene">ng delivery aene">nd early post-partum”, Does this n class="Species">patient have a CT scan and how about the Image performance?

Reviewer #3: “Post lockdown COVID-19 seroprevaleene">nce aene">nd circulatioene">n at the time of 1

delivery, France” reported that the positive rates of SARS-COV2 IgG aene">nd virus RNA of throat samples iene">n group of n class="Species">patients in maternity ward around the end of LOCKdown timepoints. Although the data is convincing, it does not look conclusive since no data was shown the positive rates before the end of lockdown(ie. 14 days before lockdown; lockdown periods, postlockdown). Secondly, except that the only diagnosed patients were both RNAand IgG positive and had symptoms and epidemiological evidence, no current infections of SARS-COV-2 were completely tested for all other patients since no IgM test were performed(sensitivity of RNA detection is usually low). So , the conclusion that the virus was no longer circulating up to three weeks after the end of the lockdown may not be acurate. Thirdly. “ half of the SARS-CoV-2-IgG-positive pregnant women were completely asymptomatic “may not be acurate since a longer time (more than 5 months )of history of symptoms may be required. Therefore I do not think the manuscript merit to publish in Plos one Journal unless these issues are resolved. However, the conclusion that “a high proportion of SARS-CoV-2-IgG-negative pregnant women must be taken into into consideration in the event of a resurgence of the pandemic...” is helpful.

Reviewer #4: The authors have investigated an important issue for the field of obstetrics during the current pandemic. The reasoning behind and the research set up is sound. The results have additional value and provide insights into the clinical presentation and pathogenesis of COVID19 duriene">ng pregene">naene">ncy.

Comments:

Line 71-72: reference is missing

Line 73: reference is missing

Line 77-78 Please do explain the third trimester is a consensual factor for SARS-CoV-2 infection, iene">ncludiene">ng refereene">nce.

Line 79: the effect of the lockdown: how is the effect exactly investigated or evaluated?

Line 99: why not show the data of the local evaluation. This will added to the impact of the results. Is there a control group, on what is the threshold of < 0.8 based?

Lin 106: what is Cepheid, where is it based?

Line 107: why use different assay? What is the difference in sensitivity between assay or it there none?

Line 145: perhaps elaborate on the CT value, based on the used assay.

Line 161: how come 3 women report n class="Disease">anosmia (in general)? Does this occur often in Paris?

Line 164: which group did the woman who did not respect the lockdown belong to?

Line 173: were they also asymptomatic during possible infection? With positive seroprevaleene">nce, oene">ne caene">n assume she was post-n class="Disease">infection. Meaning: did they report symptoms at any time? Do pregnant women have asymptomatic infection?

Discussion. There should be more details about the IgG-positive women aene">nd possible preseene">ntatioene">n, effect, risks aene">nd implicatioene">ns for pregene">naene">ncy aene">nd hypotheses behiene">nd. What are the recommeene">ndatioene">n at a secoene">nd wave based oene">n the results.

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Reviewer #1: Yes: Shuliang Oliver Cheng

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Reviewer #3: No

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Submitted filename: Review of Post lockdown COVID.docx

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10 Sep 2020

Clamart, September 7, 2020

Dear Editor,

Thank you for the opportunity to revise our paper. On behalf of all authors, I’m sending you a revised version of our manuscript entitled “Post lockdown COVID-19 seroprevaleene">nce aene">nd circulatioene">n at the time of delivery, Fraene">nce”.

We have carefully considered the suggestions and comments of the reviewers to improve the quality of our work. We are willing to provide other changes or clarification if you so wish.

We hope that this revised version of the manuscript will still be considered for publication in Plos One.

Thank you again for your work,

Yours sincerely,

Alexandre VIVANTI (MD, PhD)

Reviewer #1

The background and methods of this study are very good. It is impressive that you have managed to collect this amount of data for such a specific patient demographic. The data aene">nalysis has also beeene">n performed well.

I feel however that the discussion needs to have more detail. Furthermore, you have only written your conclusion in the abstract; you also need a conclusion section in the main body of the manuscript.

Thank you for your comments. We have added a conclusion to the main text of the manuscript.

The conclusion you have reached is that SARS-Cov-2 negative n class="Species">women need to be taken into consideration in case of a second wave. However, I feel that you need more justification of this stance. Your results state that 47.4% of the positive women did not have any symptoms and those who did have symptoms appear relatively mild. Furthermore, your results also state that the majority of women were uninfected.

Did you find any serious sequelae of SARS-CoV-2 infection in your study as a whole? If yes, you need to include this. If not, then how have you come to the conclusion that these n class="Species">patients require more consideration than the general population?

The design of our study did not allow us to assess the existence of sequelae in our patient populatioene">n. However, it has receene">ntly beeene">n showene">n that pregene">naene">ncy iene">n the 2ene">nd aene">nd 3rd trimesters represeene">nts aene">n iene">ndepeene">ndeene">nt risk factor for n class="Chemical">oxygen therapy, hospitalization in an intensive care unit and use of mechanical ventilation (1,2). It is important to note that pregnant women are subject to specific recommendations to limit the risk of infection and it appears that seroprevalence, although not high, is similar to that observed in the general population at the same time. For these reasons, it is imperative that special attention be paid to this at-risk population in the event of a second wave of infections. We have provided further details in the manuscript.

1) Ellington S, Strid P, Tong VT, Woodworth K, Galaene">ng RR, Zambraene">no LD, et al. Characteristics of n class="Species">Women of Reproductive Age with Laboratory-Confirmed SARS-CoV-2 Infection by Pregnancy Status — United States, January 22–June 7, 2020. MMWR Morb Mortal Wkly Rep. 2020;69: 769–775. doi:10.15585/mmwr.mm6925a1

2) Badr DA, Mattern J, Carlin A, Cordier A-G, Maillart E, Hachem LE, et al. Are clinical outcomes worse for pregnant women ≥ 20 weeks’ gestatioene">n n class="Disease">infected with COVID-19? A multicenter case-control study with propensity score matching. American Journal of Obstetrics & Gynecology. 2020;0. doi:10.1016/j.ajog.2020.07.045

In summary, you need to do further work in your discussion, because your actual results do not really justify your conclusion. You need to elaborate further on the potential consequences of SARS-CoV-2 infection iene">n pregene">naene">nt n class="Species">women if this is the conclusion you have made, and this requires more research into maternal and neonatal morbidity and mortality due to SARS-CoV-2. You need to compare and contrast your results to other research on this topic, and write a discussion that properly debates whether pregnancy puts mothers and neonates at higher risk of death or not.

Consistent with your suggestions, we have enhanced the discussion in relation to recent data in the literature.

Reviewer #2

Review: “Post lockdown COVID-19 seroprevaleene">nce aene">nd circulatioene">n at the time of delivery,Fraene">nce”

General comments:

This is a research involving the first wave of the COVID-19 paene">ndemic iene">n Paris aene">nd the effect of lockdowene">n oene">n seroprevaleene">nce iene">n your materene">nity ward, which has beeene">n sigene">nificaene">ntly affected by the virus (more thaene">n 40 coene">nfirmed n class="Disease">infections among pregnant women between March 12 and April 20). Pregnancy as a severity risk factor of severe acute respiratory syndrome coronavirus 2 77 (SARS-CoV-2) infection is still debated. This study prospectively to evaluate the impact of the first wave of the COVID-19 pandemic at the Antoine Béclère Hospital maternity ward (Paris area, France) from May 4 (one week before the end of lockdown) to May 31, 2020 86 (three weeks after the end of lockdown). I recommend a publication of this paper with major revisions.

Abstract:

1.Study design:“All patients admitted to the delivery room duriene">ng this period were offered a n class="Species">SARS-CoV-2 serology test as well concomitant SARS-CoV-2 RT-PCR on a nasopharyngeal sample”. As we all known, Throat swab nucleic acid positive rate is low,how many times do your study deign If the first nucleic acid test is negative?

Indeed, the sensitivity of the PCR is considered average (60-80%). As this is a routine screening in a population of asymptomatic women, we performed only one nasopharyene">ngeal swab. In our opinion, multiple tests can be considered when there is a strong clinical presumption.

We have added details to the abstract.

2.Result: “A history of symptoms during the epidemic, such as fever, 54 n class="Disease">myalgia and anosmia, was suggestive of previous infection.” What is the distribution of various clinical symptoms.

A history of symptoms during the epidemic, such as fever (15.8%), n class="Disease">myalgia (36.8%) and anosmia (31.6%), was suggestive of previous infection.

Details added to the abstract

Key words: Please add on.

Keywords added: Pregnancy, SARS-CoV-2, n class="Disease">Covid-19, Seroprevalence, RT-PCR

Introduction:

1.The introduction is too simple to state the current studies of COVID-19.

We have provided more information about the issues that justify a seroprevalence study in pregnant women.

2.“more than 40 confirmed infections amoene">ng pregene">naene">nt n class="Species">women between March 12 and April 20”，Do you have some references?

Pregnant patients iene">n our materene">nity ward who were n class="Disease">infected with SARS-CoV-2 were the subject of a publication.

We have provided the reference in the manuscript.

Vivanti AJ, Mattern J, Vauloup-Fellous C, Jani J, Rigonnot L, El Hachem L, et al. Retrospective description of 100 pregnant women with n class="Disease">SARS-CoV-2 infection, France. Emerg Infect Dis. 2020.

Materials and Methods:

1.“All patients admitted to the delivery room duriene">ng this period were offered a n class="Species">SARS-CoV-2 serology test as well as SARS-CoV-2 RT-PCR on a nasopharyngeal sample”. Did the serological testing include IgM and why it is’t mentioned in the full text?

The serological test did not not include IgM. Mention added.

2.“All data (clinical, laboratory, from both mothers and newborns) were prospectively collected from medical records.” This is a prospective study. Have you list which laboratory indicators need to be tested?

Only serological data and RT-PCR results were collected.

Results:

1. “Only one (0.5%) test was positive and this 143 patient remaiene">ned asymptomatic duriene">ng delivery aene">nd early post-partum”, Does this n class="Species">patient have a CT scan and how about the Image performance?

The patient did not have a CT scan. In our center, patients with a positive RT-PCR test with no sign of severity do not undergo a CT scan.

The design of our study does not allow us to evaluate the performance of the scanner in pregnant women n class="Disease">infected with COVID-19.

Reviewer #3

“Post lockdown COVID-19 seroprevaleene">nce aene">nd circulatioene">n at the time of 1

delivery, France” reported that the positive rates of SARS-COV2 IgG aene">nd virus RNA of throat samples iene">n group of n class="Species">patients in maternity ward around the end of LOCKdown timepoints.

Although the data is convincing, it does not look conclusive since no data was shown the positive rates before the end of lockdownc(ie. 14 days before lockdown; lockdown periods, postlockdown).

We didn’t test all the patients duriene">ng the lockdowene">n (oene">nly symptomatic n class="Species">women), so we didn’t have the previous positive rate, but we assumed that this one was much higher.

Secondly, except that the only diagnosed patients were both RNA and IgG positive and had symptoms and epidemiological evideene">nce, no curreene">nt n class="Disease">infections of SARS-COV-2 were completely tested for all other patients since no IgM test were performed (sensitivity of RNA detection is usually low). So, the conclusion that the virus was no longer circulating up to three weeks after the end of the lockdown may not be acurate.

You are right, RT-PCR sensitivity must be taken into account. However, we used the same RT-PCR test that resulted in the diagnosis of over 40 patients with symptoms related to the 15/03 -18/04 period. Eveene">n takiene">ng iene">nto accouene">nt a seene">nsitivity of 60% of the RT-PCR test (low raene">nge), oene">ne could imagiene">ne that the detectioene">n of IgM could have allowed diagene">nosis for oene">ne more n class="Species">patient.

We have, however, tempered the conclusions regarding the non-circulation of the virus.

Thirdly. “ half of the SARS-CoV-2-IgG-positive pregene">naene">nt n class="Species">women were completely asymptomatic “may not be acurate since a longer time (more than 5 months) of history of symptoms may be required.

We do not fully agree with this assertion, since to date no robust published data have defined the monitoring period that enables us to assert the absence of symptoms/sequelae.

Consistent with your suggestion, we mention that the absence of symptoms was related to the duration of the study.

Therefore I do not think the manuscript merit to publish in Plos one Journal unless these issues are resolved. However, the conclusion that “a high proportion of SARS-CoV-2-IgG-negative pregnant n class="Species">women must be taken into into consideration in the event of a resurgence of the pandemic...” is helpful.

Reviewer #4

The authors have investigated an important issue for the field of obstetrics during the current pandemic. The reasoning behind and the research set up is sound. The results have additional value and provide insights into the clinical presentation and pathogenesis of COVID19 duriene">ng pregene">naene">ncy.

Comments:

Line 71-72: reference is missing

Added

Line 73: reference is missing

Added

Line 77-78 Please do explain the third trimester is a consensual factor for SARS-CoV-2 infection, iene">ncludiene">ng refereene">nce.

It has recently been shown that pregnancy in the 2nd and 3rd trimesters represents an independent risk factor for oxygen therapy, hospitalizatioene">n iene">n aene">n iene">nteene">nsive care uene">nit aene">nd use of mechaene">nical veene">ntilatioene">n.

These data are from case-control studies using a propensity score, which allows a robust response regarding the involvement of pregnancy as an independent risk factor.

1) Ellington S, Strid P, Tong VT, Woodworth K, Galaene">ng RR, Zambraene">no LD, et al. Characteristics of n class="Species">Women of Reproductive Age with Laboratory-Confirmed SARS-CoV-2 Infection by Pregnancy Status — United States, January 22–June 7, 2020. MMWR Morb Mortal Wkly Rep. 2020;69: 769–775. doi:10.15585/mmwr.mm6925a1

2) Badr DA, Mattern J, Carlin A, Cordier A-G, Maillart E, Hachem LE, et al. Are clinical outcomes worse for pregnant women ≥ 20 weeks’ gestatioene">n n class="Disease">infected with COVID-19? A multicenter case-control study with propensity score matching. American Journal of Obstetrics & Gynecology. 2020;0. doi:10.1016/j.ajog.2020.07.045

Line 79: the effect of the lockdown: how is the effect exactly investigated or evaluated?

Lockdown has been shown to result in a very significant decrease in the incidence of COVID-19 n class="Disease">infections in pregnant women in France.

Kayem G, Alessandrini V, Azria E, Blanc J, Bohec C, Bornes M, et al. A snapshot of the Covid-19 paene">ndemic amoene">ng pregene">naene">nt n class="Species">women in France. Journal of Gynecology Obstetrics and Human Reproduction. 2020; 101826. doi:10.1016/j.jogoh.2020.101826

We aimed to evaluate the effects of the lifting of lockdown on a possible increase of the incidence of COVID-19 n class="Disease">infection rates.

We provide extra information throughout the manuscript.

Line 99: why not show the data of the local evaluation. This will added to the impact of the results. Is there a control group, on what is the threshold of < 0.8 based?

The data are from a large cohort of patients. A coene">ntrol group is required to set a threshold.

These data will be submitted for publication. A manuscript is in preparation

Lin 106: what is Cepheid, where is it based?

Cepheid is an American molecular diagnostics company based in California, USA.

We have detailed this in the manuscript.

Line 107: why use different assay? What is the difference in sensitivity between assay or it there none?

We adapted our algorithm of the assay choice to our workflow, to our reagent supply possibilities and to the urgency of the results for clinical management of some parturients.

We now mention this in the manuscript

The GeneFinder assay was used as our routine test during the day and this technique requires personnel qualified in molecular biology and a relatively high turnaround time (4 hours).

We specify this in the manuscript: It was used as our routine test during the day.

The Xpert Xpress SARS-CoV-2 assay (Cepheid) aene">nd the Geene">nMark ePlex n class="Species">SARS-CoV-2 assay (ELItech) are two platforms that integrate specimen processing, nucleic acid extraction and reverse transcription PCR. Samples can be tested as soon as they are received, and results are generated in about 45 min. They were used during the night, on weekends and for urgent results.

We now mention this in the manuscript

All assays used have the same analytical performances.

Line 145: perhaps elaborate on the CT value, based on the used assay.

Only one PCR was positive and only nucleocapsid (N2) gene was detected at a CT value of 41.4 within the valid range and an endpoint above the minimum setting of this FDA-approved assay. This indicates that the viral load of the sample is at the limit of detection of the Xpert Xpress assay.

We now mention this in the manuscript

Loeffelholz MJ, Allaene">nd D, Butler-Wu SM, Paene">ndey U, Perene">no CF, Nava A, Carroll KC, Mostafa H, Davies E, McEwaene">n A, Rakemaene">n JL, Fowler RC, Pawlotsky JM, Fourati S, Baene">nik S, n class="Species">Banada PP, Swaminathan S, Chakravorty S, Kwiatkowski RW, Chu VC, Kop J, Gaur R, Sin MLY, Nguyen D, Singh S, Zhang N, Persing DH. Multicenter Evaluation of the Cepheid Xpert Xpress SARS-CoV-2 Test. J Clin Microbiol 2020 23;58(8):e00926-20. doi: 10.1128/JCM.00926-20.

Line 161: how come 3 women report n class="Disease">anosmia (in general)? Does this occur often in Paris?

We have not particularly explored these specific patient responses. We do not have any data that could lead us to believe that n class="Disease">anosmia often happens in Paris, but we can report that this symptom has been highly publicized in France. These reported symptoms may come from impressions reinforced by the strong media coverage of anosmia during the peak of the epidemic, making this benign symptom a potential marker of an infection encountered just before lockdown.

It could also be the result of false-negative IgG test

Line 164: which group did the woman who did not respect the lockdown belong to?

She belonged to the negative group (now specified).

Line 173: were they also asymptomatic during possible infection? With positive seroprevaleene">nce, oene">ne caene">n assume she was post-n class="Disease">infection. Meaning: did they report symptoms at any time? Do pregnant women have asymptomatic infection?

Patients from this cohort have reported aene">ny symptoms occurriene">ng from Jaene">nuary 1st.

We have no reason to think that pregnant patients have more asymptomatic n class="Disease">infections than the general population. Rather, the tendency is to believe that pregnancy increases the severity of symptoms.

The test used to assess the presence of SARS-CoV-2 IgG is a commercial chemilumiene">nesceene">nt immuene">noassay validated for cliene">nical use by the FDA with high aene">nalytical aene">nd cliene">nical performaene">nces.

Ref:

Bryan A, Pepper G, Wener MH, Fink SL, Morishima C, Chaudhary A, Jerome KR, Mathias PC, Greene">niene">nger AL. Performaene">nce Characteristics of the Abbott Architect n class="Species">SARS-CoV-2 IgG Assay and Seroprevalence in Boise, Idaho. J Clin Microbiol. 2020 Jul 23;58(8):e00941-20.

EUA Authorized Serology Test Performance. https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergeene">ncy-use-authorizatioene">ns-medical-devices/eua-authorized-serology-test-performaene">nce)

In just the past few months, multiple studies have characterized the kinetics of IgM and IgG, in the immune response to SARS-CoV-2 infection. IgM aene">ntibodies are readily produced as early as 1 day after n class="Disease">infection, and the time of IgG seroconversion is expected to be in the range of 7 to 14 days after the onset of symptoms. However, Okba et al. reported that IgG and IgA kinetics depended on disease severity, and especially that patients with more severe disease developed an antibody response sooner and in higher concentrations. As our patients had mild symptoms, a late seroconversion is possible. Unfortunately, sera collected later were not available.

Ref:

Wang Y, Zhang L, Sang L. Kinetics of viral load and Antibody Responses in relation to COVID-19 severity. J Cliene">n Invest. 2020; 138759. DOI: 10.1172/JCI138759.

Wölfel R, Corman VM, Guggemos W, et al. Virological assessment of hospitalized patients with n class="Disease">COVID-2019. Nature 2020; 581(7809): 465-9. DOI: 10.1038/s41586-020-2196-x

Long QX, Liu BZ, Deng HJ, et al. Antibody responses to SARS-CoV-2 iene">n n class="Species">patients with COVID19. Nature Med 2020; 26(6): 845-8. DOI: 10.1038/s41591-020-0897-1.

Okba NMA, Müller MA, Li W, et al. n class="Species">Severe Acute Respiratory Syndrome Coronavirus 2-Specific Antibody Responses in Coronavirus Disease Patients. Emerg Infect Dis. 2020; 26(7): 1478-88. DOI: 10.3201/eid2607.200841

Discussion. There should be more details about the IgG-positive women aene">nd possible preseene">ntatioene">n, effect, risks aene">nd implicatioene">ns for pregene">naene">ncy aene">nd hypotheses behiene">nd. What are the recommeene">ndatioene">n at a secoene">nd wave based oene">n the results.

We have added extra explanations to the discussion section

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

5 Oct 2020

Post lockdown COVID-19 seroprevaleene">nce aene">nd circulatioene">n at the time of delivery, Fraene">nce

PONE-D-20-20995R1

Dear Dr. Vivanti,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Academic Editor

PLOS ONE

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Reviewer #1: All comments have been addressed

Reviewer #3: All comments have been addressed

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Reviewer #1: Thank you for adding to the discussion and highlighting recommendations that ought to be made to pregnant women to reduce traene">nsmissioene">n of n class="Species">SARS-CoV-2. Furthermore, thank you for highlighting the added risk due to pregnancy of severe sequelae of SARS-CoV-2 infection.

Reviewer #3: The author has answered all the questions and I recommend publication of this manuscript in Plos One

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Reviewer #1: Yes: Shuliang Oliver Cheng

Reviewer #3: No

Submitted filename: Dear Editor.docx

Click here for additional data file.

7 Oct 2020

PONE-D-20-20995R1

Post lockdown COVID-19 seroprevaleene">nce aene">nd circulatioene">n at the time of delivery, Fraene">nce

Dear Dr. Vivanti:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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