The impact of DNA methylation as a factor of Adverse Pregnancy and Birth Outcomes (APBOs): A Systematic review protocol.

doi:10.21203/rs.3.rs-2582375/v1

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The impact of DNA methylation as a factor of Adverse Pregnancy and Birth Outcomes (APBOs): A Systematic review protocol.

https://doi.org/10.21203/rs.3.rs-2582375/v1

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Journal Publication

published 02 Jan, 2024

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Background

Deoxyribonucleic acid (DNA) methylation is one the epigenetic modifications which has gain a lot of interest as a factor influencing fetal programming and as a biomarker for adverse pregnancy and birth outcomes (APBOs). Epidemiological studies have demonstrated that DNA methylation can result in adverse pregnancy and birth outcomes (APBOs) including miscarriage, intrauterine growth restriction (IUGR), low birth weight (LBW), sepsis as well as preterm birth (PB), which may later result in diseases in adulthood. However, the mechanism at which DNA methylation influences these APBOs remain unclear. The systematic review will assess the association between global and gene specific DNA methylation with adverse pregnancy outcomes.

Method

The Preferred Reporting Items for Systematic review and Meta-Analysis Protocol (PRISMA-P) 2015 checklist will be followed when conducting this systematic review. To develop the search strategy the PECOS (population, exposure, comparator/control, outcome, and study designs) framework will be followed. A systematic search will be conducted on electronic databases such as Cochrane library, PubMed, as well as MEDLINE. For identification of unpublished studies in journals indexed in electronic databases, Google Scholar will be used. Two reviewers will separately extract data from the articles and screen them, if there are any disagreements between reviewer one and two, then the third reviewer will resolve them. The methodological quality and bias risk of the included studies will be evaluated using Critical Appraisal Skill Programme CASP) checklist. \({I}^{2}\) and \({X}^{2}\) alpha = 0.10 statistic will be used for assessing statistical heterogeneity between studies. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach will be used to assess and grade the overall quality of extracted data.

Discussion

The systematic review will assess available literature on possible associations between DNA methylation with adverse pregnancy and birth outcomes (APBOs) including LBW, IUGR, miscarriage, sepsis and PB. The findings could help guide future research assessing DNA methylation and other APBOs.

PROSPERO registration number: CRD42022370647

Epigenetics

DNA methylation

Preterm birth (PB)

Low birth weight (LBW)

Sepsis

Adverse pregnancy outcomes

intrauterine growth restriction (IUGR)

Adverse pregnancy and birth outcomes (APBOs) including miscarriage, Low birth weight (LBW), preterm birth (PB), sepsis, and intrauterine growth restriction (IUGR) are major public health problems and have been linked with high risk of mortality and morbidities during both the neonatal period and later in life. ¹ Majority of these APBOs are associated with maternal exposure to genetic and environmental factors during pregnancy. Pregnancy is a vital period of plasticity wherein the maternal exposure to multiple environmental, behavioural, and hereditary factors may significantly affect fetal development as well as mother’s health.^{2 3}

Epidemiological studies have shown that intrauterine exposure to adverse environmental factors are associated with adverse pregnancy and birth outcomes which may increase the risk of developing chronic diseases later in life. ⁴These studies were inconsistent with the Developmental Origins of Health and Disease (DOHaD) hypothesis. Intrauterine exposure to these factors may also influence offspring’s health later in adulthood, thus influencing susceptibility to long-term risk of chronic diseases from neonatal period to adulthood. ^5–8 ). Hence, the idea of fetal programming. ^9–11 Researchers has shown that perinatal nutrition has significant impact on fetal programming and pregnancy and birth outcomes. ^{12 13}

The accurate diagnosis and prognosis of the adverse pregnancy and birth outcomes (APBOs) including PB, LBW, sepsis, IUGR, and miscarriage remain a big challenge or difficult, as the majority of these APBOs may share similar clinical sign and symptoms.^14–17 Therefore, there is a need for understanding the etiology and the underlying molecular mechanism behind these APBOs as well to identify the biomarkers that could be useful for diagnosis of APBOs during early pregnancy.^{18 19} Molecular mechanisms such as epigenetic modifications have gain a lot of interest for the identification of potential diagnostic biomarker for an increased risk having these APBOs, this because of their specificity, prognostic efficacy, and sensitivity as compared to protein expression-based technique.^{20 21}

Epigenetics is the study of inheritable genetic changes that can affect gene expression, without altering DNA sequence. These alterations include DNA methylation, non-coding Ribonucleic acid (RNA) regulation, histone modification as well as chromatin remodelling. ^{1 6 10} Among epigenetic modification, DNA methylation (DNAm) which involves the addition of a methyl group to cytosine nucleotide of the cytosine-guanine (CpG) dinucleotides, is the well-researched epigenetic mechanism. ^{7 22} Enzymes known as DNA methyltransferase act as catalysts and S-adenosyl-methionine as the methyl donor during this process of DNA methylation. ^{23 20}

Studies recently have made a huge breakthrough on how DNA methylation influence fetal programming and APBOs. ^{1 24} For instance, studies have reported on the association of both global and specific-gene DNA methylation with APBOs including IUGR, PB, LWB, miscarriage and sepsis separately. ^{19 25 17}In these studies, APBOs were associated with either hypermethylation or hypomethylation of certain gene. ^{18 25} Furthermore, studies demonstrated the association between DNA methylation of nuclear receptor subfamily 3 group C member 1(NR3C1), Long interspersed nuclear element (LINE-1), Calcitonin-related polypeptide alpha (CALCA) and Insulin-like factor 2 (IGF2) genes with APBOs. ^{26 7 16}

The association between maternal exposure to environmental factors at birth with pregnancy outcome have been investigated by several systematic reviews. For instances, various systematic reviews have been conducted to examine the association between global and gene specific epigenetics on namely IGF-related genes, NR3C1 and Hydroxysteroid 11-beta dehydrogenase type 1/2 (HSD11 B1/2) with pregnancy and birth outcomes. ^{27 28} However, to our knowledge, there are no exiting systematic review and meta-analysis that aimed on evaluating the association between both global and gene specific DNA methylation with APBOs as well as sepsis all at once. Therefore, the reason for this review is to search for the studies addressing the association between DNA methylation with APBOs such as LBW, PB, miscarriage, sepsis and IUGR.

Objectives

This systematic review’s main objective is to assess the relationship of both global and gene specific methylation status with the adverse pregnancy and birth outcomes including intrauterine growth restriction, miscarriage, sepsis, preterm birth as well as low birth weight.

Specific objectives

To investigate the association between both neonatal and maternal DNA Methylation status at birth with adverse pregnancy and birth outcomes.

Protocol and registration

The Preferred Reporting Items Systematic Review and Meta-Analysis Protocol (PRISMA-P 2015) guideline will be followed when conducting this systematic review and Meta-analysis, which is very crucial in improving the integrity of this review. ²⁹ For this systematic review protocol, a filled-out PRISMA checklist has been provided in a form of word document. The protocol used in this systematic review was adopted from the already published systematic review protocol by Vanterpool et al., (2016) and it was submitted for registration in the international prospective register of systematic review PROSPERO (CRD42022370647). ³⁰

Eligibility criteria

A PECOS framework will be used to guide the search method, wherein P stand for population, E for exposure, C for comparator/control, O for outcome and S for study designs.

Types of studies

Observational studies such as cross-sectional studies, prospective cohort, case control, and retrospective cohort focusing on the association between DNA methylation with APBOs will both be considered for the systematic review and meta-analysis. The systematic review will include studies which used either placental samples, mother’s peripheral blood, neonatal cord blood or urine samples. Studies published with any languages that Google can translate to English will be considered as well as systematic reviews and meta-analysis meeting the inclusion criteria.

Population of interest

For inclusion in this review, only studies which examined the association between DNA methylation with either LBW, PB, sepsis, miscarriage, and IUGR in women who are pregnant and their new-born regardless of gender and ethnicity will be considered.

Exposure (s), intervention (s)

The exposure of interest will be DNA methylation status of the participants. There are no interventions that will be reviewed.

Comparator

The comparison group will include neonates without any complications after birth and women not known for possible confounders (smoking, age, and alcohol).

Outcomes

The main purpose of this systematic review is to determine whether DNA methylation is associated with adverse pregnancy outcomes. Adverse pregnancy outcomes are any complications that occur during pregnancy, labour, delivery, or 6 weeks after delivery (postpartum period). ³¹ For the interest of the systematic review, the following primary and secondary pregnancy and birth outcomes will be taken into consideration based on their occurrence:

Primary outcomes

DNA methylation level of the specific gene in pregnant women and neonates

Preterm birth, which is a birth before 37 complete weeks of gestation (this includes very preterm, moderates preterm as well as extremely preterm). ³²

Miscarriage, which is spontaneous loss of pregnancy before 20 weeks. ²⁹

Secondary outcomes

Low birth weight less than 2500 g (LBW). ³²

When the fetus in the womb is not developing or growing as excepted or when the anticipated fetal weight is less than 10th percentile at birth. This condition is known as intrauterine growth restriction (IUGR). ²⁹

Neonatal sepsis, systemic condition usually caused by bloodstream bacterial pathogens which is characterised by pro-inflammatory and anti-inflammatory responses, occurring in neonates (particularly PB and LBW). It is divided into two categories based on the timing of the infection. Thus, Early onset sepsis (EOS) which occurs within 72 hours of life and Late onset sepsis (LOS) which occurs after 72 hours of life ^14–16

Settings

There will not be any time and geographical restraints.

Exclusion criteria

Studies focusing on animals as well as narrative review will be excluded from the systematic review. Studies that did not adhere to any PI(E)COS framework will not be consider in the systematic review. Studies examining the relationship between DNA methylation and APBOs in animals.

Information source and search strategy

For inclusion in this review, the literature search for systematic review will be carried-out on the following electronic databases in MEDLINE, Cochrane library, as well as PubMed. For ensuring a complete coverage, reference lists as well as screening citations of the included studies will be manually searched using search engines such as Google Scholar and Web of sciences. Searching for grey literature, Google Scholar will also be used to identify published articles. The first search approach in PubMed will involve the mixture of Medical Subject Headings (MeSH) and free text search words relating to birth and pregnancy, DNA methylation, epigenetics, intrauterine growth restriction/retardation, low birth weight, miscarriage, and preterm birth. For search in other electronic databases including Cochrane library and MEDLINE, we will adapt the search strategy used in PubMed with some adjustments. Thus, to remove any contradictions that can affect data extraction. The search terms will be then combined using Boolean operators. The second search technique will focus on the grey literature thus, to identify more studied that are not published in journals indexed in Cochrane library, MEDLINE as well as PubMed.

Table 1

Demonstrating search strategy for PubMed to be adopted by reviewer for search in other databases.
Search	Query
#1. Terms for population	((("infant, newborn" OR NEONATES) OR ("infant" OR INFANT)) OR ("pregnancy" OR pregnancy)) OR ("fetus" OR FETAL
#2. Terms for exposure	("epigenomics" OR EPIGENETICS) OR (("DNA Methylation")
#3. Terms for outcomes	("Premature Birth") OR ("Infant, Low Birth Weight") OR ("Fetal Growth Retardation") OR ("Abortion, Spontaneous") OR ("Neonatal sepsis")
#4 search	#1 AND #2 AND #3

"" represent the MeSH terms while words without quotation mark are free text words

Study selection

All studies identified from electronic database (PubMed, MEDLINE, and Cochrane library) will be combined and imported onto a Mendeley Desktop file. Grey literature studies will be manually entered into Mendeley Desktop file. The duplicate publications will be first detected and removed automatically using Mendeley reference manager. For the screening, two reviewers will screen tittles and abstracts and the full text of potentially relevant articles. If there are any disagreements between the first reviewer and the second reviewer weather the study is to be included, discussion will be made with the third reviewer to resolve the differences. Figure 1 showing the PRISMA flowchart that will be used in summering the whole process of study selection.

Data collection process

To ensure that the appropriate data for the systematic review is gathered, a structured form with the following descriptive details: Author’s information (name and publication year), country of author, type of study, types of the samples, characteristics of participant, investigated genes, DNA methylation techniques, pregnancy outcomes as well as statistical method used to analyse data will be created. Then if there any disagreements and conflict between first reviewer and second reviewer, they will be resolve by discussing with the third reviewer. In case some of information will be missing from the individual study, there will be efforts to contact the primary author (with a maximum of three email attempt) to obtain the missing data.

Risk of bias in individual studies

The first and second reviewers will evaluate the study’s methodological quality and bias risk of the studies using the Critical Appraisal Skill Programme (CASP) tool. ³³ CASP learning and development opportunities tool that is a part of the Oxford Centre for Triple Value Health Ltd (3v) portfolio that aims to support the development of critical appraisal skills in United Kingdom. ³³ It is recommended for new qualitative researchers to use CAPS which provide appraisal checklist for analysing systematic reviews, Cohort studies, Clinical prediction rule, Economic evaluation, Case control studies, observational studies, Randomized control trials as well as Diagnostic studies and it is recommended for new qualitative researchers. ³⁴ The World Health Organisation (WHO) and Cochrane also support CAPS for qualitative evidence synthesis. In case reviewers one and two disagree, the third reviewer will resolve the discrepancies.

Data synthesis and analysis

For this review data synthesis and analysis will be conducted separately: (1) Narrative synthesis wherein the studies meeting the inclusion criteria will be summarized and discussed and (2) statistical analysis wherein the relationship between DNA methylation and APBOs will be investigated.

Narrative synthesis

Regardless of whether the meta-analysis is appropriate or not, studies meeting the inclusion criteria will be narratively synthesized. A table summarizing the PECO characteristics and results of the included studies, thus author name, year of study, study design, participants characteristics, definition of exposure and outcomes will be developed. ³⁵ Lastly, the bias risk will be accessed for each of the included studies.

Statistical analysis

For the purpose of the systematic review, it is predicted that there will be variation amongst the included studies based on methodological variability (diversity in risk of bias and study design) and clinical variability (diversity in PECO). ²⁹ Therefore, inverse variance weighting will be used in a meta-analysis to calculate pooled effect estimate. ²³ For the assessment of the degree of inconsistency, forest plot for pooled estimate of the outcomes will be used first. In prospective cohorts, retrospective cohorts, and cross-sectional studies, the risk ratio (RR with 95% CI) will be used to measure the relationship between gene specific DNA methylation with APOs while odd ratio (OR with 95% CI) will be used in case-control (Ahn and Kang., 2018). Chi-square (\({X}^{2}\)) alpha = 0.10 and \({I}^{2}\) statistic will be used for assessing statistical heterogeneity between studies. Adding to X ² and I ² statistics, T ² statistics will be reported thus, to determine how widely distributed the true effects are, especially in the case of meta-analyses with small number of studies.

\({I}^{2}\) of 50% as a moderate or substantial heterogeneity as a guide will be considered in the systematic review. ²³ For a meta-analysis with absent or low heterogeneity (I ²< 50%), a fixed-effected model will be used whereas for moderate or severe heterogeneity, random-effects will be performed. ²⁰ The cause of heterogeneity will be investigated using the meta-regression and subgroup analysis. Variables such as study design, study population, sample size as well as outcomes will be used to identify the source of heterogeneity. ³² Meta-analyses will be performed using Comprehensive Meta-analysis (CMA) software Version 3.

Meta-biases assessment

A funnel plot will be used to assess the probability of publication bias in case there are more than 10 publications looking at the association between DNA methylation status with pregnancy and birth outcomes. For the purpose of evaluating potential publication bias in meta-analysis, Egger’s test for funnel plot will be used. ³⁶ In case of less than 10 studies, cumulative meta-analysis will be performed, with the studies arranged from the largest to the smallest.

Confidence in cumulative evidence

The overall quality of extracted data will be assessed and graded using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method considering the following factors: limitation in study design, unexplained heterogeneity, inaccuracy of effect estimates and risk of publication of bias. ^{23 29 32}

Expected outcomes

Several studies have published on the association between DNAm with pregnancy and birth outcomes. To our knowledge, there are evidence-based and comprehensive reviews published on the association between gene-specific DNAm during pregnancy with pregnancy and birth complications such as PB, LBW, IUGR, sepsis, and miscarriage all at once. These calls out for the need of comprehensive and systematic information about this association, and to identify the knowledge gaps and to guide future research that will explain how epigenetics affect pregnancy outcomes. Therefore, the main reason for the systematic review and meta-analysis will be to compile data or information from the published studies on the association between DNA methylation with APBOs.

The Preferred Reporting Items Systematic Review and Meta-Analysis Protocol (PRISMA) guideline will be followed in reporting the systematic review protocol. Both systematic review and the protocol will be the part of Moagi’s MSc research dissertation which A Samie is a main supervisor, L Mabasa and M.S Maputle are the co-supervisors. Prior being submitted for publication in peer-reviewed journal, the finding from the systematic review will be presented at conferences.

Funding

The research reported herein was made possible through funding/partial funding by the South African Medical Research Council through its Division of Research Capacity Development under the Research Capacity Development Initiative. The content hereof is the sole responsibility of the authors and does not necessarily represent the official views and sentiments of the funders.

Authors’ contributions

I.M., A.S., and L.M help designed the study and conceived the idea. I.M, drafted the systematic review protocol revised by A.S and S.M.M with the input from M.T., N.M.L., and R.N.S. The search strategies were developed by I.M, A.S, D.N and L.M and they will conduct the study selection as well. I.M, A.S and D.N will oversee data extraction and will also perform statistical analysis. All co-authors read and approved the final manuscript.

Ethics approval and consent to participate

The are no individual person’s data used in this manuscript, therefore ethical approval and consent are not applicable.

Competing interests

The author declares no potential conflicts of interest with respect to the publication of the systematic review and other authors.

ORCID Id

Moagi Innocent https://orcid.org/0000-0002-4869-3841

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You are reading this latest preprint version

The impact of DNA methylation as a factor of Adverse Pregnancy and Birth Outcomes (APBOs): A Systematic review protocol.

Status:

Journal Publication

Version 1

Abstract

Figures

Background

Objectives

Specific objectives

Methods

Protocol and registration

Eligibility criteria

Types of studies

Population of interest

Exposure (s), intervention (s)

Comparator

Outcomes

Primary outcomes

Secondary outcomes

Settings

Exclusion criteria

Information source and search strategy

Study selection

Data collection process

Risk of bias in individual studies

Data synthesis and analysis

Narrative synthesis

Statistical analysis

Meta-biases assessment

Confidence in cumulative evidence

Expected outcomes

Dissemination

Declarations

References

Supplementary Files

Status:

Journal Publication

Version 1