Long term miscarriage-related hypertension and diabetes mellitus. Evidence from a United Kingdom population-based cohort study.

BACKGROUND: Miscarriages affect up to a fifth of all pregnancies and are associated with substantial psychological morbidity. However, their relationship with cardiometabolic risk factors is not well known. Therefore, in this study we aimed to estimate the burden of cardiovascular risk factors including diabetes mellitus (type 1 or 2) and hypertension in women with miscarriage compared to women without a record of miscarriage.
METHODS: A population-based retrospective cohort study was conducted using IVQIA Medical Research Data UK (IMRD-UK) between January 1995 and May 2016, an anonymised electronic health records database that is representative of the UK population. A total of 86,509, 16-50-year-old women with a record of miscarriage (exposed group) were matched by age, smoking status, and body mass index to 329,865 women without a record of miscarriage (unexposed group). Patients with pre-existing hypertension and diabetes were excluded. Adjusted incidence rate ratios (aIRR) and 95% confidence intervals (95% CI) for diabetes and hypertension were estimated using multivariable Poisson regression models offsetting for person-years follow-up.
RESULTS: The mean age at cohort entry was 31 years and median follow up was 4.6 (IQR 1.7-9.4) years. During the study period, a total of 792 (IR 1.44 per 1000 years) and 2525 (IR 1.26 per 1000 years) patients developed diabetes in the exposed and unexposed groups, respectively. For hypertension, 1995 (IR 3.73 per 1000 years) and 1605 (IR 3.39 per 1000 years) new diagnoses were recorded in the exposed and unexposed groups, respectively. Compared to unexposed individuals, women with a record miscarriage were more likely to develop diabetes (aIRR = 1.25, 95% CI: 1.15-1.36; p<0.001) and hypertension (aIRR = 1.07, 95% CI: 1.02-1.12; p = 0.005).
CONCLUSIONS: Women diagnosed with miscarriage were at increased risk of developing diabetes mellitus and hypertension. Women with history of miscarriage may benefit from periodic monitoring of their cardiometabolic health.

Introduction

Non-communicable diseases are the leading cause of mortality worldwide accounting for almost 70% of global deaths [1]. Diabetes mellitus and hypertension are some of the most important non-communicable diseases, with diabetes responsible for 4% of non-communicable deaths while 19% of the global deaths are attributable to hypertension [1,2]. Recent statistics show that 3.5 million people live with diabetes in the United Kingdom (UK), while up to 30% of the adult population have hypertension [3]. As these numbers continue to increase, identifying further risk factors for diabetes and hypertension is of great importance for early prevention and treatment.

Conventional and well-studied risk factors common to the development of cardiovascular disease and risk factors such as hypertension and diabetes include obesity, physical inactivity, family history, ethnicity, poor dietary habits, and smoking [4-7]. In addition, emerging research has shown that exposure to some obstetric complications, among them miscarriage, may be risk factors for the development of future maternal cardio-metabolic outcomes [8]. Miscarriage is defined as the spontaneous loss of pregnancy prior to foetal viability, from conception up to 24 weeks gestation, and is the most common pregnancy complication [9]. Estimates show that up to a third of all biochemical pregnancies and up to a fifth of all clinical pregnancies end up as miscarriage [9,10].

Pre-eclampsia and other obstetric complications have been included in the American Heart Association guidelines as cardiovascular risk factors for women, but miscarriage was omitted despite the fact that some of these complications share common pathological origins with miscarriage [11]. Furthermore, research through large population studies and meta-analyses has confirmed the strong association of miscarriage with cardiovascular outcomes, providing another reason for scientists to consider miscarriage in the assessment of future cardiovascular risk [12-14]. However, the link between miscarriage and the subsequent development of cardiovascular disease are not well argued or documented. There is limited evidence describing common risk factors such as family history of cardiovascular diseases, obesity, smoking and endothelial dysfunction [15-17] while other cardiovascular risk factors, such as diabetes and especially hypertension remain under explored.

Hence, the aim of this study was to conduct a population-based retrospective matched cohort to investigate the rates of diabetes and hypertension among women in the UK with incident miscarriage compared to women with an otherwise normal pregnancy who have not experienced miscarriage.

Methods

Study design

We conducted a population-based, retrospective open cohort study, to estimate the risk of developing diabetes (type 1 or type 2) and hypertension in women who experienced a miscarriage (exposed) compared to those who had not (unexposed), between 1st January 1995 and 15th May 2016.

Data source

The study used data from general practices in the UK contributing to the IMRD-UK database. The database contains more than 3 million active patients from over 700 participating general practices spread across the UK. The individuals contributing to the database are representative of the UK population [18]. The dataset consists of recorded medical diagnoses, medical prescriptions, socio-demographic details, and information from hospital admissions. Participating practices collect patient data using an electronic health record system called Vision software. Medical diagnoses and other related patient data are recorded using a hierarchical coding system called Read codes [19]. A wide range of medical conditions using IMRD-UK database have been validated, including cardiovascular diseases and diabetic conditions [20,21]. The process for selecting Read codes for the exposure and outcomes are documented in the text in S1 Table. Data extraction and cohort selection were facilitated using the Data Extraction for Epidemiological Research (DExtER) tool [22].

Practice eligibility criteria

Practices were eligible for inclusion from the later of the date when the practice met the acceptable mortality reporting standard and one year after the practice implemented use of the Vision software system to allow for sufficient time for the recording of important patient data [23].

Study population

Adult women aged 16–50 years at study entry date were eligible for inclusion in the study estimating incidence rate of diabetes and hypertension. Participant entry into the study was at the latest of their 16th birthday, one year after registration with an eligible practice, or study start date.

Exposure

Women with a Read code record of miscarriage diagnosis (exposure) were matched with up to four women without a record of miscarriage (unexposed) randomly selected from the pool of patients with a record of a previous pregnancy carried to delivery. The exposed and unexposed participants were matched by age (within 1 year), body mass index (BMI: +/-2 kg/m2) and smoking status.

Follow up period

The date of diagnosis of miscarriage served as the index date for newly diagnosed patients (incidence cases). To mitigate immortal time bias, matched unexposed patients were assigned the same index date as their corresponding exposed patients. The follow up period was defined as the time between the patient’s index date and exit date. The exit date was defined as the earliest of (i) a diagnosis of type 1 or 2 diabetes or hypertension, (ii) death of patient, (iii) study end date, (iv) patient left the practice, (v) last data collection from the practice.

Outcomes

The outcome was the incident diagnosis of either diabetes mellitus (type 1 or 2) or hypertension. The outcomes were identified using the relevant Read codes. Both outcomes are part of the quality outcomes framework (QOF) and are well recorded in primary care settings [18].

Ethical approval

IQVIA Medical Research Data (IMRD) incorporates data from The Health Improvement Network (THIN) a Cegedim database [24]. Reference made to THIN is intended to be descriptive of the data asset licensed by IQVIA.

Anonymised data were used throughout the study provided by the data provider to the University of Birmingham. Studies using IMRD-UK database have had initial ethical approval from the NHS South-East Multicentre Research Ethics Committee, subject to prior independent scientific review. The Scientific Review Committee (IQVIA) approved the study protocol (SRC Reference Number: 17THIN075).

Study covariates

The following potential confounders were included in the study: age, Townsend quintiles of deprivation, smoking status, BMI, lipid medication (current users), connective tissue disorders, and reproductive comorbidities (pre-eclampsia, gestational diabetes mellitus) [25].

For each of the study covariates the most recently documented record prior to study entry was used. Self-reported smoking status was categorised as never smoker, ex-smoker, current smoker or missing. BMI measured in kg/m2 was categorised as underweight or normal (<25kg/m2), overweight (25–30 kg/m2), obese (>30 kg/m2), and missing for those with missing or implausible values. A record for prescription of lipid-lowering medication was used as a proxy for high cholesterol levels. Patients prescribed lipid medication within the last sixty days prior to cohort entry were defined as current users. Connective tissue disorders (CTD) are a group of autoimmune diseases which include systemic lupus erythematosus, polymyalgia rheumatica, polymyositis, and rheumatoid arthritis.

Statistical analysis

Continuous variables were presented as mean ± standard deviation (SD) or median and interquartile range (IQR) depending on their distribution, and proportions were used for categorical variables.

Incidence rates (IR) were calculated for each outcome separately. These were estimated as the number of incident cases of the outcome divided by the total number of person-years follow up. The person-years follow up was from the entry date to the exit date. Incidence rates were expressed as per 1000 person-years at risk.

Poisson regression models offsetting for person-years follow-up, were used to estimate incidence rate ratios (IRR) and 95% confidence intervals by making comparisons between those with a record of miscarriage (exposed) to those without a record of miscarriage (unexposed). Crude and adjusted IRRs were calculated. Patients with a record of the outcome at baseline were excluded from the corresponding analysis. For example, for the analysis examining the association between miscarriage and diabetes, patients with diabetes at baseline were excluded from the analysis. Statistical significance was set at p<0.05. Regression models were adjusted for age, Townsend quintile of deprivation, smoking status, BMI, polycystic ovary syndrome (PCOS), connective tissue disorders, pre-eclampsia, and gestational diabetes mellitus. Statistical analysis was performed using Stata version 14.2 (Stata Corps, College Station, Texas, USA).

Results

Population characteristics

Following application of inclusion/exclusion criteria, the final study population comprised 416,374 women aged between 16–50 years. Fig 1 presents the study participants flow chart. 86,509 women with a record of miscarriage were included in the exposed population, and 329,865 women without a record of miscarriage were included in the unexposed population. The median duration of follow-up in the miscarriage cohort was 4.8 (IQR 1.9–9.4) years, while in the unexposed cohort it was 4.4 (IQR 1.6–9.1) years.

Fig 1

Study participant flow chart.

summarises the baseline characteristics by exposure status. Overall, the participant characteristics between the two groups were broadly similar. However, compared to women without a record of miscarriage, women with a record of miscarriage were more likely to be ex- smokers (14.2% versus 13.6%) and be diagnosed with PCOS (3.4% versus 2.9%), while they were less likely to be diagnosed with gestational diabetes (0.8% versus 1.6%).

Diabetes mellitus

During follow up, there were a total of 792 incident diagnoses of type 1 or 2 diabetes in the miscarriage group, while 2,525 incident diagnoses of diabetes were reported in the unexposed group. The incidence rate per 1000 person-years at risk in the miscarriage cohort and the unexposed cohort was 1.44 and 1.26, respectively. Women exposed to miscarriage had a 15% higher incidence of diabetes compared to women unexposed to miscarriage (crude IRR = 1.15, 95% CI: 1.06–1.24, p = 0.001). After adjustment for age, BMI, Townsend deprivation index, smoking, lipid profile, connective tissue disorders, gestational diabetes mellitus, PCOS and pre-eclampsia, a record of miscarriage was associated with a 25% (IRR = 1.25, 95% CI: 1.15–1.36, p<0.001) higher incidence of diabetes compared to women in the unexposed group. The results are summarised in .

Hypertension

During the follow up period, there were 1,995 incident diagnoses of hypertension among women with a record of miscarriage and 6,637 incident diagnoses among women without a record of miscarriage. The incidence rate per 1000 person-years at risk was 3.73 and 3.39 among women with and without a record of miscarriage, respectively. Compared to unexposed women, women with a record of miscarriage were more likely to develop hypertension (crude IRR = 1.10, 95% CI: 1.05–1.16, p<0.001). This result remained statistically significant (IRR = 1.07, 95% CI: 1.02–1.12, p = 0.005) in the fully adjusted model. The results are summarised in .

Discussion

The aim of this cohort study was to estimate the burden of the cardiovascular risk factors, diabetes (type 1 or 2) and hypertension, subsequent to miscarriage among women in the UK aged 16–50 years. Our analysis revealed that women with a record of miscarriage developed diabetes and hypertension at significantly higher rates compared to women without a record of miscarriage. These associations remained significant after adjustment for confounders, with exposure to miscarriage being associated with 25% and 7% higher rates of diabetes and hypertension, respectively.

There is limited published evidence describing the long-term outcomes of miscarriage relating to diabetes and hypertension. A range of pregnancy characteristics have been recorded as determinants for higher blood pressure later in a woman’s life [26]. In contrast to our findings, a Finnish cross-sectional study found no association between miscarriage and the risk of developing hypertension (OR 0.8; 95% CI, 0.7–1.1) [27]. A Danish cohort study that investigated the association between pregnancy loss and subsequent risk of atherosclerotic disease among women aged 12 years and above, reported that women exposed to miscarriage had a higher risk of developing secondary, reno-vascular hypertension (adjusted IRR 1.20; 95% CI, 1.05–1.38) [28]. However, information on key confounders such as BMI and socioeconomic status were missing from the Danish study, and biased effect estimates can therefore not be ruled out. We found a significant the association between miscarriage and hypertension after adjustments for BMI, socioeconomic status, PCOS, gestational diabetes, and connective tissue disorders, conditions which may predispose to both miscarriage and hypertension. This may explain the lower effect estimates for hypertension that were reported in our study. The findings from our study are consistent the results of a US prospective cohort study which reported that women with early miscarriage (<12 weeks) had a slightly higher risk of hypertension (adjusted HR 1.06; 95% CI: 1.02–1.10) and type 2 diabetes (adjusted HR 1.20; 95% CI: 1.07–1.34) [29].

A Scottish retrospective cohort study published in 2003, investigated the association between reproductive factors, BMI and risk of diabetes. The study reported 70% (adjusted OR 1.70: 95% CI 0.82–3.52) higher odds of developing diabetes among women with a record miscarriage compared to women without a record of miscarriage after adjustment for age and BMI only [30]. More comparable to the findings of our study, a German cohort study found that women with miscarriage had a 30% (HR 1.30; 95% CI 1.01–1.68) higher risk of developing diabetes after adjustment for a number of confounders [31]. In addition to age, BMI, socioeconomic status, and hyperlipidaemia, our model was further adjusted for gestational diabetes, polycystic ovary syndrome, and connective tissue disorders, as these conditions predispose to spontaneous pregnancy loss and have been identified as risk factors for the development of diabetes [32-36]. A study in a Chinese population also found a statistically significant increase in risk of diabetes in women with miscarriage compared to women without, the effect estimate was smaller (HR 1.03; 95% CI, 1.00–1.05) compared to women without a record of miscarriage [37].

The mechanisms linking miscarriage to future maternal risk of cardiometabolic outcomes are unclear but may involve endothelial dysfunction, genetics, and metabolic syndrome. Adverse pregnancy outcomes (APOs) including pre-eclampsia, gestational diabetes, miscarriage, and pre-term birth are linked to future maternal risk of cardiometabolic complications [25,35,38]. The common underlying etiology of these APOs are placental anomalies triggered by endothelial dysfunction. It is postulated that endothelial dysfunction persists for several years beyond APOs leading to future risk of vascular complications [16]. There is an association between miscarriage and family history of cardiovascular complications suggesting that there are shared genetic anomalies. A study by Smith et al noted that women with history of two or more pregnancy losses prior to their first delivery had higher risk of family history of coronary heart disease [17]. Women with history of miscarriage may have an underlying susceptibility to metabolic syndrome, a condition that manifests with a combination of high blood glucose, hypertension, obesity and dyslipidemia [39].

This study provides evidence describing the incidence of diabetes and hypertension after miscarriage compared to women with normal pregnancies in a large, well-powered cohort study that adjusted for a wide range of well-defined risk factors. However, despite the strengths of the study, the results should be interpreted taking into account its limitations. The study explored diabetes as a broad endpoint, therefore specific association between miscarriage and either type 1 or type 2 diabetes was not evaluated. Misclassification of the exposure (miscarriage) or the outcome (diabetes or hypertension) may occur as some patients may be undiagnosed or asymptomatic. We do not expect there to be a systematic difference in the recording of the outcomes among women with and without miscarriage. However, the effect of including the exposure or the outcome in the wrong cohort is not clear and may not necessarily bias the effect estimate towards the null [40]. Furthermore, miscarriage maybe under recorded in primary care and therefore the number of incident cases may be underestimated. Although our study shows an association between history of miscarriage and future maternal risk of diabetes or hypertension, there is potential for unmeasured confounding for example from factors such as pregnancy weight gain or micronutrient deficiencies which are poorly recorded in UK primary care.

In terms of clinical practice, results from this study suggest that women with a history of miscarriage might be considered for referral for hypertension and diabetes screening and follow up. Current diabetes and hypertension guidelines do not mention this population as a high-risk population for monitoring, but our evidence in combination with the previous literature suggesting that this population is also at higher risk for cardiovascular outcomes indicate that these risk factors should be considered by clinicians [41,42]. Future research should be focused on the mechanism behind miscarriage and cardiometabolic risk.

Conclusion

To conclude, higher rates of diabetes and hypertension were observed among women exposed to miscarriage compared to those unexposed to miscarriage. Given that diabetes and hypertension are leading causes of morbidity and mortality, women with history of miscarriage may benefit from periodic monitoring of their cardiometabolic health. Future studies are required to confirm findings from the present study, clarify the biological mechanism behind the observed associations, and investigate whether interventions that prevent miscarriage will be effective in reducing the excess burden of diabetes and hypertension among women with miscarriage.

Search strategy based to read codes.

(DOCX)

Click here for additional data file.

Transfer Alert

This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present.

31 Aug 2021

PONE-D-21-18971

Long term miscarriage-related hypertension and diabetes mellitus. Evidence from a United Kingdom population-based cohort study.

PLOS ONE

Dear Dr. Okoth,

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.

The manuscript and the reviewers’ comments were carefully evaluated. The manuscript was appreciated by the Reviewers. Nevertheless, as suggested, the manuscript requires extensive improvement before to be considered for publication. Further suggested revisions are in detail reported in the Reviewers’ comments.

Please submit your revised manuscript by Oct 15 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see:  http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at  https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Simone Garzon

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Please update your submission to use the PLOS LaTeX template. The template and more information on our requirements for LaTeX submissions can be found at http://journals.plos.org/plosone/s/latex.

3. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability.

Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized.

Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access.

We will update your Data Availability statement to reflect the information you provide in your cover letter.

4. Please note that in order to use the direct billing option the corresponding author must be affiliated with the chosen institute. Please either amend your manuscript to change the affiliation or corresponding author, or email us at plosone@plos.org with a request to remove this option.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Dear editor,

Thank you for your invitation of reviewing the manuscript entitled ”Long term miscarriage-related hypertension and diabetes mellitus. Evidence from a United Kingdom population-based cohort study”. This study investigated the burden of the cardiovascular risk factors hypertension and diabetes mellitus (type 1 or 2) in women with and without a record of miscarriage. It found that women diagnosed with miscarriage were at increased risk of developing diabetes mellitus and hypertension.

The analysis method of this paper is correct and the text is fluent. But there are several very important issues that need to be further considered, such as how to consider the condition of having hypertension and diabetes before pregnancy. This has a great influence on the results and conclusions of this study. I hope the authors can respond to the following questions first, and then consider further. My comments to the article are listed below:

1.Page 2, line 37-39, the sentence “Therefore, in this study we aimed to the burden of the cardiovascular risk factors hypertension and diabetes mellitus (type 1 or 2) in women with and without a record of miscarriage” needs revision.

2.Table 1, “Smoking status, n (%)” should be bold.

3.Please pay attention to the formatting of references, such as letter case and the full name and abbreviation of the journal (eg Reference 38)

4.Are there people with diabetes who had hypertension before pregnancy in this study? Or in other words, how to define the relationship between the occurrence of hypertension and diabetes in this study and the miscarriage of this pregnancy?

5.Was weight gain during pregnancy considered in this study, because weight gain during pregnancy is also closely related to the occurrence of diabetes and hypertension.

6.What do you think is the possible mechanism for miscarriage to increase the risk of high blood pressure and diabetes? Please describe in the discussion.

7.Should the conclusion of this study include the importance of preventing preterm birth? What are the main conclusions and significance of this research? And modify it in the text.

8.When referring to hypertension and diabetes in this study, sometimes it is “hypertension and diabetes”, sometimes it is “diabetes and hypertension”, please be consistent.

Reviewer #2: The research inference comes from the medical record, but it does not deal with the possible bias from the record. What percentage of subjects are pregnant or have miscarriages that are not recorded in the medical records? Is there anyone who has developed signs of diabetes or hypertension, but has not yet started medical treatment and therefore has not entered a diagnosis? If there are any of the above, the impact on the results should be taken into consideration.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

30 Oct 2021

14th October 2021

Dear Dr Garzon,

Thank you for considering our manuscript, ‘Long term miscarriage-related diabetes mellitus and hypertension. Evidence from a United Kingdom population-based cohort study.’, for publication in PLOS ONE.

We thank the reviewers for their comments and suggestions, and we respond as follows.

Reviewer 1

1.Page 2, line 37-39, the sentence “Therefore, in this study we aimed to the burden of the cardiovascular risk factors hypertension and diabetes mellitus (type 1 or 2) in women with and without a record of miscarriage” needs revision.

Thank you. We have revised line 37-39 to read as follows “Therefore, in this study we aimed to estimate the burden of cardiovascular risk factors including diabetes mellitus (type 1 or 2) and hypertension among women with miscarriage compared to those without miscarriage.”

2.Table 1, “Smoking status, n (%)” should be bold.

The text “Smoking status, n (%)” in table 2 is in bold in the revised manuscript.

3.Please pay attention to the formatting of references, such as letter case and the full name and abbreviation of the journal (eg Reference 38)

We have revised reference 38 (Reference 41 in revised manuscript) as below

Williams B, Mancia G, Spiering W, Rosei EA, Azizi M, Burnier M, et al. 2018 ESC Scientific Document Group, ESC/ESH Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH) Vol. 39, European Heart Journal. Oxford University Press; 2018. p. 3021–104.

We have also checked that all the other references are cited appropriately.

4.Are there people with diabetes who had hypertension before pregnancy in this study? Or in other words, how to define the relationship between the occurrence of hypertension and diabetes in this study and the miscarriage of this pregnancy?

Yes, there were participants who had various comorbidities including diabetes and hypertension before pregnancy. We have presented this information in the baseline table (Table 1). We excluded patients with a record of the outcome (diabetes or hypertension) at baseline, from the corresponding univariable and multivariable analysis. For instance, for the analysis examining the association between miscarriage and diabetes, patients with diabetes at baseline were excluded from the analysis. On the other hand, in the analysis examining the association between miscarriage and hypertension patients with hypertension at baseline were excluded from the analysis. We have now clarified this in the manuscript; please see line 192 to 194 of the revised manuscript.

In the revised manuscript, we have clarified the covariates that were included in the multivariable model as follows

The model (*) examining the relationship between miscarriage and diabetes adjusted for age, BMI, Townsend deprivation index, smoking, lipid profile, connective tissue disorders, gestational diabetes mellitus, polycystic ovary syndrome, pre-eclampsia, and hypertension. The model (#) examining the relationship between miscarriage and hypertension adjusted for age, BMI, Townsend deprivation index, smoking, lipid profile, connective tissue disorders, gestational diabetes mellitus, polycystic ovary syndrome, pre-eclampsia, and diabetes (type 1 and 2).

5.Was weight gain during pregnancy considered in this study, because weight gain during pregnancy is also closely related to the occurrence of diabetes and hypertension.

We agree with the reviewer that weight gain during pregnancy is associated with an increased risk of diabetes and hypertension. Information on pregnancy weight gain is poorly recorded in UK primary care since there is poor linkage of health records among the various services (local maternity units, GP surgery, children centers, and hospitals) that provide ante-natal care.

We have included the following statement in the limitation section to address this issue

“Although our study shows an association between history of miscarriage and future maternal risk of diabetes or hypertension, there is potential for unmeasured confounding for example from factors such as pregnancy weight gain or micronutrient deficiencies which are poorly recorded in UK primary care.”

6.What do you think is the possible mechanism for miscarriage to increase the risk of high blood pressure and diabetes? Please describe in the discussion.

The mechanistic links behind the association between miscarriage and future risk of diabetes and hypertension are not clear but may involve endothelial dysfunction, genetics or metabolic syndrome.

We have included the following paragraph in the revised manuscript as suggested.

“Biological plausibility”

“The mechanisms linking miscarriage to future maternal risk of cardiometabolic outcomes are unclear but may involve endothelial dysfunction, genetics and metabolic syndrome. Adverse pregnancy outcomes (APOs) including pre-eclampsia, gestational diabetes, miscarriage, and pre-term birth are linked to future maternal risk of cardiometabolic complications.(1–3) The common underlying aetiology of these APOs are placental anomalies triggered by endothelial dysfunction. It is postulated that endothelial dysfunction persists for several years beyond APOs leading to future risk of vascular complications.(4) Endothelial dysfunction is also associated later risk of type 2 diabetes mellitus after adjustment for known risk factors.(5) Therefore, endothelial dysfunction may potentially precede future development of both diabetes and hypertension among women with history of miscarriage. There is an association between miscarriage and family history of cardiovascular complications suggesting that there are shared genetic anomalies. A study by Smith et al noted that women with history of two or more pregnancy losses prior to their first delivery had higher risk of family history of coronary heart disease.(6) Women with history of miscarriage may have an underlying susceptibility to metabolic syndrome, a condition that manifests with a combination of high blood glucose, hypertension, obesity and dyslipidemia.(7)”

7.Should the conclusion of this study include the importance of preventing preterm birth? What are the main conclusions and significance of this research? And modify it in the text.

We agree that the conclusion of our study should highlight the importance of preventing miscarriage. The mechanistic links between miscarriage and poor cardiometabolic health are unclear. Miscarriage may be the initial event that triggers poor cardiometabolic health or it may serve as a stress test that unmasks women already predisposed to cardiometabolic complications. Whether preventing miscarriage will translate to a reduced risk of diabetes and hypertension is not clear and should be the subject of future research.

We have now expanded the conclusion to read as follows

“To conclude, higher rates of diabetes and hypertension were observed among women exposed to miscarriage compared to those unexposed to miscarriage. Given that diabetes and hypertension are leading causes of morbidity and mortality, women with history of miscarriage may benefit from periodic monitoring of their cardiometabolic health. Future studies are required to confirm findings from the present study, clarify the biological mechanism behind the observed associations, and investigate whether interventions that prevent miscarriage will be effective in reducing the excess burden of diabetes and hypertension among women with miscarriage.”

8.When referring to hypertension and diabetes in this study, sometimes it is “hypertension and diabetes”, sometimes it is “diabetes and hypertension”, please be consistent.

We thank the reviewer for bringing this to our attention. Diabetes and hypertension are now referred to consistently in the revised manuscript.

Reviewer 2

The research inference comes from the medical record, but it does not deal with the possible bias from the record. What percentage of subjects are pregnant or have miscarriages that are not recorded in the medical records? Is there anyone who has developed signs of diabetes or hypertension, but has not yet started medical treatment and therefore has not entered a diagnosis? If there are any of the above, the impact on the results should be taken into consideration.

We thank the reviewer for their comment. The proportion of subjects that were pregnant or had miscarriage that was recorded in UK primary care is not entirely clear. A survey of maternity services in the UK revealed that 96% of pregnant women had contacted a healthcare professional (midwife or general practitioner) by the time they were 12 weeks pregnant. The majority of women (66%) contacted their general practitioner. For women who are pregnant for the first time the median number of antenatal care visits was 9 while for women with a previous pregnancy it was 8.(8) We believe a substantial proportion of miscarriage cases will be documented in primary care. With regard to undiagnosed outcomes (diabetes and hypertension), 5.5 million people in England live with undiagnosed hypertension while 1 million people in the UK live with undiagnosed diabetes.(9,10)

We agree with the reviewer that there is potential for misclassification bias as some women with the exposure (miscarriage) and the outcome (diabetes and hypertension) may be missed. We have added the following paragraph under the limitations section.

“Misclassification of the exposure (miscarriage) or the outcome (diabetes or hypertension) may occur as some patients may be undiagnosed or asymptomatic. We do not expect there to be a systematic difference in the recording of the outcomes among women with and without miscarriage. However, the effect of including the exposure or the outcome in the wrong cohort is not clear and may not necessarily bias the effect estimate towards the null.(11)”

If you have any further queries, please do not hesitate to contact us.

Yours sincerely,

Kelvin Okoth on behalf all authors

References

1. Okoth K, Chandan JS, Marshall T, Thangaratinam S, Thomas GN, Nirantharakumar K, et al. Association between the reproductive health of young women and cardiovascular disease in later life: Umbrella review. Vol. 371, The BMJ. BMJ Publishing Group; 2020.

2. Li S, Zhang M, Tian H, Liu Z, Yin X, Xi B. Preterm birth and risk of type 1 and type 2 diabetes: systematic review and meta-analysis. Obes Rev. 2014 Oct 1;15(10):804–11.

3. Wu P, Kwok CS, Haththotuwa R, Kotronias RA, Babu A, Fryer AA, et al. Pre-eclampsia is associated with a twofold increase in diabetes: a systematic review and meta-analysis. Diabetologia. 2016 Dec 1;59(12):2518–26.

4. Germain AM, Romanik MC, Guerra I, Solari S, Reyes MS, Johnson RJ, et al. Endothelial Dysfunction. Hypertension. 2007 Jan;49(1):90–5.

5. JB M, FB H, N R, JE M. Biomarkers of endothelial dysfunction and risk of type 2 diabetes mellitus. JAMA. 2004 Apr 28;291(16):1978–86.

6. Smith G, Wood A, Pell J, Hattie J. Recurrent miscarriage is associated with a family history of ischaemic heart disease: a retrospective cohort study. BJOG An Int J Obstet Gynaecol. 2011 Apr;118(5):557–63.

7. Sharma S, Yadav S, Chandiok K, Sharma RS, Mishra V, Saraswathy KN. Protein signatures linking history of miscarriages and metabolic syndrome: a proteomic study among North Indian women. PeerJ. 2019;7(2).

8. The National Perinatal Epidemiology Unit. Safely delivered : a national survey of women’s experience of maternity care 2014. 2015.

9. CA W, S O, RIG H. Diabetes in the UK: 2019. Diabet Med. 2020 Feb 1;37(2):242–7.

10. CVD prevention: detecting and treating hypertension [Internet]. [cited 2021 Oct 13]. Available from: https://stpsupport.nice.org.uk/cvd-prevention-hypertension/index.html

11. Brakenhoff TB, Van Smeden M, Visseren FLJ, Groenwold RHH. Random measurement error: Why worry? An example of cardiovascular risk factors. PLoS One. 2018;13(2):1–8.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

10 Dec 2021

Long term miscarriage-related hypertension and diabetes mellitus. Evidence from a United Kingdom population-based cohort study.

PONE-D-21-18971R1

Dear Dr. Okoth,

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.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. 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.

Kind regards,

Simone Garzon

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

**********

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

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: All comments have been addressed.

According to the reply, the bias should be limited.

No further recommendation to be given.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

15 Dec 2021

PONE-D-21-18971R1

Long term miscarriage-related hypertension and diabetes mellitus. Evidence from a United Kingdom population-based cohort study.

Dear Dr. Okoth:

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.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Simone Garzon

Academic Editor

PLOS ONE

Table 1

Baseline characteristics of the study population.

	Exposed to miscarriage n = 86,509	Unexposed to miscarriage n = 329,865
Maternal Age, mean (SD)	30.9 (6.8)	30.4 (6.5)
Body Mass Index, n (%)
<25kg/m2	41,494 (48)	161,716 (49)
25–30 kg/m2	16,826 (19.5)	68,045 (20.7)
>30 kg/m2	11,398 (13.2)	44,316 (13.4)
Missing	16,791 (19.4)	55,788 (16.9)
Smoking status, n (%)
Non-smokers	47,146 (54.5)	179,301 (54.4)
Ex-smokers	12,305 (14.2)	44,757 (13.6)
Smokers (current)	20,948 (24.2)	81,461 (24.7)
Missing	6,110 (7.1)	24,346 (7.4)
Use of lipid lowering medication, n (%)
On medication	370 (0.4)	1174 (0.4)
Townsend deprivation Index, n (%)
1 (Least deprived)	17,862 (20.7)	68,708 (20.8)
2	15,997 (18.5)	61,036 (18.5)
3	17,805 (20.6)	67,313 (20.4)
4	16,464 (19.0)	63,305 (19.2)
5 (Most deprived)	12,638 (14.6)	46,625 (14.1)
Missing	5,743 (6.6)	22,878 (6.9)
Co-morbidities at baseline, n (%)
Hypertension	1,150 (1.3)	4,103 (1.2)
Diabetes	734 (0.9)	2,181 (0.7)
Ischaemic heart disease	31 (0.0)	180 (0.1)
Atrial fibrillation	21 (0.0)	100 (0.0)
Heart failure	13 (0.0)	64 (0.0)
Stroke/ TIA	108 (0.1)	425 (0.1)
Gestational diabetes	651 (0.8)	5170 (1.6)
Pre-eclampsia	400 (0.5)	2,539 (0.8)
Connective tissue disorders	403 (0.5)	1,365 (0.4)
Polycystic ovary syndrome	2,918 (3.4)	9,581 (2.9)

SD = standard deviation; TIA = transient ischaemic attack.

Table 2

Crude and adjusted incidence rate ratio for diabetes mellitus and hypertension.

	Diabetes mellitus		Hypertension
	Exposed	Unexposed	Exposed	Unexposed
Population	85,775	327,684	85,359	325,762
Events, n (%)	792	2,525	1995	6637
Person-years at risk	546,599	2,001,260	535,541	1,959,223
Incidence rate/1000 person years	1.45	1.26	3.73	3.39
Crude IRR (95% CI)	1.15 (1.06–1.24)		1.10 (1.05–1.16)
P-value	0.001		<0.001
Adjusted IRR 95% CI	1.25* (1.15–1.36)		1.07# (1.02–1.12)
P-value	<0.001		0.005

IR = Incidence Rate, IRR = Incidence Rate Ratio.

* = Adjusted for: Age, BMI, Townsend deprivation index, smoking, lipid profile, connective tissue disorders, gestational diabetes mellitus, polycystic ovary syndrome, pre-eclampsia and hypertension.

# = Adjusted for: Age, BMI, Townsend deprivation index, smoking, lipid profile, connective tissue disorders, gestational diabetes mellitus, polycystic ovary syndrome, pre-eclampsia and diabetes (type 1 and 2).