Role of maternal serum c-reactive protein levels in early second trimester as a marker of preterm labour: A study protocol

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The primary cause of infant death is preterm birth (PTD), which is linked to long-term neurodevelopmental and behavioural effects for preterm survivors. A maternal vascular disease pathway and an inflammation/infection pathway are two suggested pathways that have collected sufficient evidence. The identification of women who are more likely to develop PTD and the understanding of the underlying physiological mechanisms would be made possible by reliable biomarkers for these pathways. Systemic maternal infections cause elevated levels of inflammatory cytokines, which then drive the creation of prostaglandins, which can cause cervical ripening and uterine contractions that result in preterm birth. Women with signs of preterm labour have been found to have high serum levels of proinflammatory which have been prospectively linked to preterm birth. A non-specific biomarker of inflammation, C-reactive protein (CRP) is an acute phase reactant in the innate immune response. The production of C-reactive protein, a serological marker that is readily identifiable, occurs largely in the hepatocytes in response to cytokine releases from the inflammatory site. Cytokines released, by an intrauterine infection go through the maternal bloodstream to the liver, where they activate the production of CRP. Forty-eight hours after stimulation the acute-phase response has reached its maximum and a meaningful measurement can be made from a blood sample. Although the exact cause of inflammation is unknown, modest and long-lasting elevations of CRP have been linked to a range of illnesses, including normal pregnancy. Elevated CRP levels in the peripheral circulation have been connected to the presence of intrauterine infection. It has been investigated to diagnose subclinical infections using the maternal CRP concentration. The purpose of this study is to determine the link between maternal serum CRP and subsequent preterm birth in single pregnant women." } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/12-1278/v1", "name": "Role of maternal serum c-reactive protein levels in early second trimester..." } } ] } Home Browse Role of maternal serum c-reactive protein levels in early second trimester... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Gudapati S and Chaudhari K. Role of maternal serum c-reactive protein levels in early second trimester as a marker of preterm labour: A study protocol [version 1; peer review: 1 approved with reservations] . F1000Research 2023, 12 :1278 ( https://doi.org/10.12688/f1000research.140738.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Study Protocol Role of maternal serum c-reactive protein levels in early second trimester as a marker of preterm labour: A study protocol [version 1; peer review: 1 approved with reservations] Sravya Gudapati https://orcid.org/0009-0001-2993-518X 1 , Kamlesh Chaudhari https://orcid.org/0000-0002-1673-7467 2 Sravya Gudapati https://orcid.org/0009-0001-2993-518X 1 , Kamlesh Chaudhari https://orcid.org/0000-0002-1673-7467 2 PUBLISHED 06 Oct 2023 Author details Author details 1 junior resident, Department of Obstetrics and Gynaecology, datta meghe institution of higher education and research, wardha, maharastra, 442107, India 2 professor,Department of Obstetrics and Gynaecology, datta meghe institue of higher education and research, wardha, maharastra, 442107, India Sravya Gudapati Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Kamlesh Chaudhari Roles: Supervision, Visualization OPEN PEER REVIEW DETAILS REVIEWER STATUS This article is included in the Datta Meghe Institute of Higher Education and Research collection. Abstract Preterm labour is a birth that occurs between 22 and 37 weeks after conception. The primary cause of infant death is preterm birth (PTD), which is linked to long-term neurodevelopmental and behavioural effects for preterm survivors. A maternal vascular disease pathway and an inflammation/infection pathway are two suggested pathways that have collected sufficient evidence. The identification of women who are more likely to develop PTD and the understanding of the underlying physiological mechanisms would be made possible by reliable biomarkers for these pathways. Systemic maternal infections cause elevated levels of inflammatory cytokines, which then drive the creation of prostaglandins, which can cause cervical ripening and uterine contractions that result in preterm birth. Women with signs of preterm labour have been found to have high serum levels of proinflammatory which have been prospectively linked to preterm birth. A non-specific biomarker of inflammation, C-reactive protein (CRP) is an acute phase reactant in the innate immune response. The production of C-reactive protein, a serological marker that is readily identifiable, occurs largely in the hepatocytes in response to cytokine releases from the inflammatory site. Cytokines released, by an intrauterine infection go through the maternal bloodstream to the liver, where they activate the production of CRP. Forty-eight hours after stimulation the acute-phase response has reached its maximum and a meaningful measurement can be made from a blood sample. Although the exact cause of inflammation is unknown, modest and long-lasting elevations of CRP have been linked to a range of illnesses, including normal pregnancy. Elevated CRP levels in the peripheral circulation have been connected to the presence of intrauterine infection. It has been investigated to diagnose subclinical infections using the maternal CRP concentration. The purpose of this study is to determine the link between maternal serum CRP and subsequent preterm birth in single pregnant women. READ ALL READ LESS Keywords Preterm, term labour, maternal serum c-reactive protein levels Corresponding Author(s) Kamlesh Chaudhari ( [email protected] ) Close Corresponding author: Kamlesh Chaudhari Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2023 Gudapati S and Chaudhari K. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Gudapati S and Chaudhari K. Role of maternal serum c-reactive protein levels in early second trimester as a marker of preterm labour: A study protocol [version 1; peer review: 1 approved with reservations] . F1000Research 2023, 12 :1278 ( https://doi.org/10.12688/f1000research.140738.1 ) First published: 06 Oct 2023, 12 :1278 ( https://doi.org/10.12688/f1000research.140738.1 ) Latest published: 06 Oct 2023, 12 :1278 ( https://doi.org/10.12688/f1000research.140738.1 ) Introduction Labor is a physiological process during which fetus and viable products of conception are expelled through the vagina into the world. Labor typically starts for most women between 37 and 42 weeks of pregnancy. Preterm or premature labour is defined as beginning before 37 weeks of pregnancy. 1 In developing nations, preterm labour is the main contributor to prenatal morbidity and mortality. Preterm birth rates vary by country and range from 5% to 18% of all births. 2 However, despite decades of research, little progress has been achieved in determining its cause, physiology, and aetiology. There are high chances of cerebral impairment, respiratory distress, feeding, visual, and hearing difficulty for newborns who survive. The most frequent cause of preterm labour, which accounts for about 50% of premature birth is idiopathic. Up to 40% of women who give birth prematurely through spontaneous labour lack obvious, well-known risk markers for preterm labour. 18.7% to 28.8% of preterm births are caused by iatrogenic (medical) causes related to maternal or fetal factors like hypertensive disease, gestational diabetes and twin pregnancies or intrauterine growth restriction respectively. Of all preterm births, early rupture of the membranes occurs in 7.1% to 51.2% (or 25% on average) of cases. 3 Identification of those at risk is a crucial first step in combating the issue of preterm birth. Risk score systems, biochemical markers of inflammation, and infection screening are some of the methods that have been considered. In the asymptomatic population, it is crucial to assess these possible predictors both singly and together, as well as to consider the financial implications of these screening procedures. Numerous studies have identified a link between inflammation or infection and premature birth. Although there is evidence that bacterial vaginosis increases the risk of preterm birth, antibiotic treatment has not been proven to offer any protective advantages. In order to identify infection in pregnant women who experienced premature membrane rupture and preterm labour, maternal concentrations of CRP have been examined. Few studies have found an association between maternal blood CRP levels that are elevated in the second trimester and subsequent preterm birth. The current study's objective is to assess maternal serum CRP. Aim To study the role of maternal serum C- reactive protein levels in early second trimester as a marker of preterm labour. Objectives 1. To evaluate the preterm delivery in women with normal CRP levels. 2. To evaluate preterm delivery in women with altered CRP levels. 3. To compare between the women with preterm delivery with normal CRP levels and women with preterm delivery with altered CRP levels. Protocol Study design This will be an observational study where CRP levels will be measured in all pregnant women presenting to the outpatient department with 14-20 weeks of gestational age and will be followed up to delivery and then will be divided in to preterm and term groups. The study will take place at the Department of Obstetrics and Gynecology J.N.M.C., AVBRH, D.M.I.H.E.R. (Deemed University), Wardha over the course of two years. Inclusion criteria 1. Every single instance of singleton pregnancy (as determined by early second trimester ultrasonography). 2. Pregnancy age of 14 to 20 weeks, as determined by LMP and ultrasound. 3. Amniotic membranes that are intact. 4. Women willing to give consent to participate in the study. Exclusion criteria 1. Multiple gestation. 2. Less than 13 weeks of gestation or more than 20 full weeks. 3. Patients with premature rupture of membranes. 4. Pregnancies complicated by Pre-eclampsia, Gestational diabetes mellitus, heart disease. 5. Pre-term births in previous pregnancies. 6. Patients with fetal congenital abnormalities. 7. Patients with cardiovascular, abdominal, and respiratory pathology. 8. History of recent bacterial or viral infections. 9. Women not willing to give consent to participate in the study. Sample size We will recruit 113 patients for this study. The sample size was calculated using the following formula. Formula: Cochrane formula for sample size. 4 ή = Z ∝ / 2 2 . P . 1 − P E 2 Where; Z ∝ / 2 is the level of significance at 5% i.e., 95% confidence interval = 1.96 P = incidence of preterm labour = 12% = 0.12 E = error of margin = 6% = 0.06 N = 1.96 2 × 0.12 × 1 − 0.12 0.06 2 = 112.68 N=113 patients needed STUDY REFERNCE – Cochran WG. Sampling techniques. John Wiley & Sons; 1977. A blood sample is collected in a testube without anticoagulant and allowed to clot and then it is sent to laboratory for evaluation. Statistical analysis Using a specified structure, data was obtained and entered into a spreadsheet (MS Excel 2010, Microsoft Inc. Redmond, Washington, USA). The chi-square test (x-2) and student's unpaired t-test were used to statistically analyse the data using descriptive and inferential statistics. The analysis will be conducted using SPSS 21.0, OPEN EPI version 3.01, which computes data using JavaScript and HTML. 0.05 as the p-value and 95%. Methods The institutional ethical committee's ethical approval has been taken. Every woman will be told about the study's purpose and design as well as the significance of evaluating CRP levels in predicting preterm birth after informed, valid and written consent has been obtained. We have applied for funding from the ICMR, synopsis concession, and intramural grant. Each group will be observed for a total of 113 patients who meet the inclusion and exclusion criteria. Serum C-Reactive Protein levels will be assessed between weeks 14 and 20 of pregnancy, followed through birth, and then divided into preterm and non-preterm groups depending on gestational age. Detailed obstetric, menstrual, past, personal, and family history will be taken. To evaluate the serum C-reactive protein concentrations between 14 and 20 weeks of gestation, venous blood samples from the patient will be taken. To avoid haemolysis, the serum will be removed as quickly as possible and kept frozen until the lab analyses the samples. In a test tube without anticoagulant, samples will be collected and allowed to clot. A highly sensitive quantitative immunoassay (ELISA) will be used to measure the amounts of C-Reactive protein. A reference level of 1.5 mg/dl is taken. Therefore, pregnancies with high maternal serum CRP levels will be defined as those in which the maternal serum level CRP is above 1.5 mg/dl. Preterm labour is associated with increased maternal serum c-reactive protein. The normal CRP levels during preterm labour and raised CRP levels during preterm labour will be compared. Outcome In this study we are expecting the values of maternal serum C-reactive protein levels to be raised in the preterm labour group than in term labour group. Dissemination Articles arising from this study will be published in index journals. Study status Not yet started, is expected to begin from October 2023. Discussion CRP is an acute phase reactant protein that is largely made in liver cells in response to proinflammatory cytokines including IL-6 and alpha TNF. The presence of intrauterine infection is related with C-reactive protein in maternal peripheral circulation. Subclinical amnionitis and preterm birth are associated with its elevated levels in maternal serum. A significant connection was seen between CRP plasma concentrations greater than 1.5 mg/dl. 5 A study by Shahshahan and Rasouli showed that measuring maternal CRP concentrations can be a useful biomarker for predicting preterm labour. It also showed that, despite the study's patient population's limitations, measuring these women's CRP levels could predict how well these women would respond to tocolytic therapy. However, this finding calls for additional research to evaluate other biologic markers as predictors. 6 Research by Halder A et al. , indicated that a high chance of preterm labour can be predicted by an increased CRP level (>6mg/dl) in early pregnancy in the absence of any obstetric or medical complications. The levels of oligohydramnios, IUGR, and PROM are positively correlated with CRP. The study's weakness is because both pathological and physiological situations cause an increase in CRP. Therefore, further proof is needed to support the widespread use of CRP as a predictor of poor maternal and foetal outcomes. 7 A study by Grgic G et al. , asserts that in pregnant women who do not have any established risk factors for preterm delivery, C-reactive protein (CRP) is a valid marker of idiopathic preterm delivery. The threshold level of CRP that was linked to the emergence of idiopathic preterm birth was 4 mg/L. A link exists between CRP and low birth weight in babies. 8 Research by Pitiphat W et al. , states that in early pregnancy, CRP levels more than 8 mg/liter were linked to preterm birth, regardless of the presence of several other risk factors. The connection was mainly significant for unplanned premature birth. These results back up the theory that persistent low-grade inflammation may increase CRP levels and result in preterm birth. 9 A study by Hvilsom GB et al. , shows that higher CRP levels in the early stages of pregnancy are linked to an increased risk of premature delivery. They have not found a clinical test that can be utilized on all pregnant women in the early stages of pregnancy because the sensitivity and specificity vary depending on the chosen cut-off number. They did note, however, that a small subgroup of women who had CRP levels above 9.9 mg/l but had never given birth prematurely did have a greater chance. 10 Research of Ghezzia et al., (2002) demonstrated that compared to pregnant women who delivered at term, those who had premature deliveries (before 37 weeks gestation) had greater levels of CRP in their amniotic fluid. This research adds to the theory that early-stage intrauterine inflammation or subclinical conditions may play a significant role in the risk of premature birth. 11 Ethical considerations Institutional ethical committee approval has been taken. Reference number: DMIMD (DU)/IEC/2023/773 Date: 21.03.2023 Data availability No data associated with this article. References 1. Preterm Birth|Maternal and Infant Health |Reproductive Health|CDC.2022 [cited 2023 Jan 19]. Reference Source 2. Preterm birth|National Health Portal Of India.[cited 2023 Jan 20]. Reference Source 3. Goldenberg RL, Culhane JF, Iams JD, et al. : Epidemiology and causes of preterm birth. Lancet Lond Engl. 2008; 371 (9606): 75–84. PubMed Abstract | Publisher Full Text | Free Full Text 4. Cochran WG: Sampling techniques. John Wiley & Sons; 1977. 5. Sproston NR, Ashworth JJ: Role of C-Reactive Protein at Sites of Inflammation and Infection. Front. Immunol. 2018 Apr 13; 9 : 754. PubMed Abstract | Publisher Full Text | Free Full Text 6. Shahshahan Z, Rasouli O: The use of maternal C-reactive protein in the predicting of preterm labor and tocolytic therapy in preterm labor women. Adv. Biomed. Res. 2014 Jul 31; 3 : 154. PubMed Abstract | Publisher Full Text | Free Full Text 7. Halder A, Agarwal R, Sharma S, et al. : Predictive significance of C reactive protein in spontaneous preterm delivery: a prospective cohort study. Int. J. Reprod. Contracept. Obstet. Gynecol. 2013 Mar 1; 2 (1): 47–51. Publisher Full Text 8. Grgic G, Skokic F, Bogdanovic G: C-reactive protein as a biochemical marker of idiopathic preterm delivery. Med. Arh. 2010; 64 (3): 132–134. PubMed Abstract 9. Pitiphat W, Gillman MW, Joshipura KJ, et al. : Plasma C-Reactive Protein in Early Pregnancy and Preterm Delivery. Am. J. Epidemiol. 2005 Dec 1; 162 (11): 1108–1113. PubMed Abstract | Publisher Full Text | Free Full Text 10. Hvilsom GB, Thorsen P, Jeune B, et al. : C-reactive protein: a serological marker for preterm delivery? Acta Obstet. Gynecol. Scand. 2002 May; 81 (5): 424–429. PubMed Abstract | Publisher Full Text 11. Ghezzi F, Franchi M, Raio L, et al. : Elevated amniotic fluid C-reactive protein at the time of genetic amniocentesis is a marker for preterm delivery. Am. J. Obstet. Gynecol. 2002 Feb; 186 (2): 268–273. PubMed Abstract | Publisher Full Text Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 06 Oct 2023 ADD YOUR COMMENT Comment Author details Author details 1 junior resident, Department of Obstetrics and Gynaecology, datta meghe institution of higher education and research, wardha, maharastra, 442107, India 2 professor,Department of Obstetrics and Gynaecology, datta meghe institue of higher education and research, wardha, maharastra, 442107, India Sravya Gudapati Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Kamlesh Chaudhari Roles: Supervision, Visualization Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (1) version 1 Published: 06 Oct 2023, 12:1278 https://doi.org/10.12688/f1000research.140738.1 Copyright © 2023 Gudapati S and Chaudhari K. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Gudapati S and Chaudhari K. Role of maternal serum c-reactive protein levels in early second trimester as a marker of preterm labour: A study protocol [version 1; peer review: 1 approved with reservations] . F1000Research 2023, 12 :1278 ( https://doi.org/10.12688/f1000research.140738.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 1 VERSION 1 PUBLISHED 06 Oct 2023 Views 0 Cite How to cite this report: Sheller-Miller S. Reviewer Report For: Role of maternal serum c-reactive protein levels in early second trimester as a marker of preterm labour: A study protocol [version 1; peer review: 1 approved with reservations] . F1000Research 2023, 12 :1278 ( https://doi.org/10.5256/f1000research.154125.r242939 ) The direct URL for this report is: https://f1000research.com/articles/12-1278/v1#referee-response-242939 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 05 Mar 2024 Samantha Sheller-Miller , University of Texas, Galveston, Texas, USA Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.154125.r242939 Sravya Gudapati and Kamlesh Chaudhari seek to understand the predictive potential of maternal c-reactive protein levels in preterm birth. Scientists have been trying to identify biomarkers to determine those at risk for preterm birth, however, little progress has been made ... Continue reading READ ALL Sravya Gudapati and Kamlesh Chaudhari seek to understand the predictive potential of maternal c-reactive protein levels in preterm birth. Scientists have been trying to identify biomarkers to determine those at risk for preterm birth, however, little progress has been made in the last 30 years. CRP is a marker for inflammation, which is the underlying cause of preterm labor and subsequent preterm birth. Because it is part of the innate inflammatory pathway, it could be a potential biomarker for preterm labor, although its non-specificity to labor associated inflammation may cause challenges in achieving the proposed objectives. Comments The study design is inconsistent on how many groups will be recruited, lacking details on what will the controls be, and frequency of sample collection Additional details are necessary to define what is considered a high level of CRP and how that level was selected. Methods are disconnected, parts are repeated and some details are missing. Please expand to include more details so could be repeated by another. What handling will occur in the laboratory? How long will the sample be clotting? Will it be centrifuged prior to storage in the freezer? Will it be stored at -20 or -80 degrees C? Is the rationale for, and objectives of, the study clearly described? Yes Is the study design appropriate for the research question? Partly Are sufficient details of the methods provided to allow replication by others? Partly Are the datasets clearly presented in a useable and accessible format? Not applicable Competing Interests: No competing interests were disclosed. Reviewer Expertise: Inflammation, extracellular vesicles, parturition, preterm labor I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Sheller-Miller S. Reviewer Report For: Role of maternal serum c-reactive protein levels in early second trimester as a marker of preterm labour: A study protocol [version 1; peer review: 1 approved with reservations] . F1000Research 2023, 12 :1278 ( https://doi.org/10.5256/f1000research.154125.r242939 ) The direct URL for this report is: https://f1000research.com/articles/12-1278/v1#referee-response-242939 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 06 Oct 2023 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 Version 1 06 Oct 23 read Samantha Sheller-Miller , University of Texas, Galveston, Texas, USA Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Sheller-Miller S. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 05 Mar 2024 | for Version 1 Samantha Sheller-Miller , University of Texas, Galveston, Texas, USA 0 Views copyright © 2024 Sheller-Miller S. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Sravya Gudapati and Kamlesh Chaudhari seek to understand the predictive potential of maternal c-reactive protein levels in preterm birth. Scientists have been trying to identify biomarkers to determine those at risk for preterm birth, however, little progress has been made in the last 30 years. CRP is a marker for inflammation, which is the underlying cause of preterm labor and subsequent preterm birth. Because it is part of the innate inflammatory pathway, it could be a potential biomarker for preterm labor, although its non-specificity to labor associated inflammation may cause challenges in achieving the proposed objectives. Comments The study design is inconsistent on how many groups will be recruited, lacking details on what will the controls be, and frequency of sample collection Additional details are necessary to define what is considered a high level of CRP and how that level was selected. Methods are disconnected, parts are repeated and some details are missing. Please expand to include more details so could be repeated by another. What handling will occur in the laboratory? How long will the sample be clotting? Will it be centrifuged prior to storage in the freezer? Will it be stored at -20 or -80 degrees C? Is the rationale for, and objectives of, the study clearly described? Yes Is the study design appropriate for the research question? Partly Are sufficient details of the methods provided to allow replication by others? Partly Are the datasets clearly presented in a useable and accessible format? Not applicable Competing Interests No competing interests were disclosed. Reviewer Expertise Inflammation, extracellular vesicles, parturition, preterm labor I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (0) Sheller-Miller S. Peer Review Report For: Role of maternal serum c-reactive protein levels in early second trimester as a marker of preterm labour: A study protocol [version 1; peer review: 1 approved with reservations] . F1000Research 2023, 12 :1278 ( https://doi.org/10.5256/f1000research.154125.r242939) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/12-1278/v1#referee-response-242939 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. 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