Impact of magnesium levels in pregnancy on adverse birth outcomes: a protocol for a systematic review and meta-analysis

doi:10.21203/rs.3.rs-4297863/v1

Background:

Magnesium, an often-overlooked trace element, may play a pivotal role in maternal and fetal health outcomes during pregnancy. Magnesium deficiency has been observed to contribute to several maternal complications, such as intrauterine growth restriction, pregnancy-induced hypertension and pre-eclampsia. Pre-eclampsia, a hypertensive disorder of pregnancy, presents substantial risks to both maternal and fetal health. Magnesium sulphate is a cornerstone in the management of pre-eclampsia, underscoring the importance of magnesium in pregnancy. Notably, pre-eclampsia is more prevalent in low-to-middle-income countries, where other co-morbidities such as HIV, anaemia and obesity are also common. Understanding the dynamics of magnesium levels in pregnancy and their interactions with co-morbidities could be critical for improving maternal and fetal health outcomes worldwide.

Method:

This protocol is for a systematic review and meta-analysis that aims to comprehensively map the literature on magnesium levels in pregnancy. Following the Preferred Reporting Items for Systematic Review and Meta-analysis for Protocols guidelines, our study will provide a rigorous synthesis of available evidence. By conducting a thorough search across multiple databases, including PubMed, Scopus, Directory of Open Access Journals, and Google Scholar, we aim to identify studies reporting on magnesium levels during pregnancy. Through screening and data extraction, we will analyze the association between magnesium levels and pregnancy complications, with further exploration of the impact of co-morbidities on magnesium status in pregnancy.

Discussion:

The findings of this study may have the potential to affect maternal and fetal health outcomes globally. Improved understanding of magnesium's role in pregnancy physiology can guide targeted interventions aimed at reducing the burden of pre-eclampsia and its associated complications, particularly in low-to-middle-income countries where maternal and infant mortality rates remain unacceptably high.

Prospero Registration: CRD42024518427

Pregnancy

magnesium

maternal health

pregnancy outcomes

co-existing conditions

Pregnancy marks a crucial phase requiring optimal nutritional support to safeguard both maternal and fetal well-being. Among essential nutrients, magnesium stands out as pivotal, orchestrating over 600 enzymatic reactions critical for DNA synthesis, muscle and nerve function, and blood glucose regulation [1,2]. Despite its importance, magnesium deficiency during pregnancy remains widespread, and has been implicated in a variety of adverse outcomes, such as gestational hypertension, preterm labour, and fetal growth restriction [3]. The prevalence of magnesium deficiency and its impact on pregnancy outcomes vary significantly worldwide, and are influenced by dietary habits, socioeconomic factors, and access to prenatal care. Moreover, comorbid conditions such as HIV, anaemia, and obesity can exacerbate magnesium deficiency risks, further complicating pregnancy [4].

This protocol for a systematic review and meta-analysis aims to consolidate global evidence concerning the impact of magnesium levels during pregnancy on adverse birth outcomes. By elucidating these associations, the review endeavours to inform the development of targeted interventions to enhance maternal and fetal health outcomes worldwide.

The role of magnesium and in pregnancy

Magnesium’s pivotal role in pregnancy transcends its biochemical functions to its potential in mitigating complications such as gestational diabetes mellitus (GDM), pregnancy-induced hypertension (PIH), intrauterine growth restriction (IUGR), and pre-eclampsia (PE) [3]. These conditions not only impact immediate maternal and fetal outcomes but, also have long-term health implications. For instance, GDM is associated with an increased risk of obesity, impaired glucose metabolism, and cardiovascular diseases in both mother and child [5]. Intrauterine growth restriction, which is linked to maternal malnutrition, diabetes, and hypertension, among other factors, predisposes individuals to metabolic diseases later in life [6]. Pregnancy-induced hypertension and PE contribute significantly to maternal and infant morbidity and mortality, particularly in sub-Saharan Africa (SSA) where the prevalence exceeds global averages [7,8,9].

Magnesium sulphate is an essential pharmacotherapy in the management of PE [1]. Its efficacy in stabilizing blood pressure and preventing the progression of PE to eclampsia,with far more serious untoward effects, highlights the importance of maintaining adequate magnesium levels. However, maintaining the homeostatic balance of magnesium is delicate, with both hypomagnesaemia and hypermagnesaemia posing risks to maternal and fetal health. The former, often resulting from insufficient dietary intake, has been associated with metabolic disorders, IUGR, and an increased risk of PIH and PE [1,3]. Conversely, hypermagnesaemia, though rare, poses risks when magnesium is excessively supplemented [1,4].

Gaps in current research and the need for exploration

Despite the recognized importance of magnesium in pregnancy, there has been limited research into its role, particularly against the backdrop of co-existing conditions prevalent in low-to-middle-income countries (LMICs), such as obesity, anaemia, and HIV [4]. The interactions between these conditions and magnesium levels in pregnancy, especially considering the potential effects of antiretroviral therapy on weight dynamics in HIV-positive individuals, warrant further investigation [10,11]. Furthermore, the limited data available with regards to the implications of the interaction of magnesium levels in pregnancy in the context of obesity, anaemia, and HIV, underscores an urgent need for comprehensive research.

Given the critical role of magnesium in pregnancy and its association with various adverse outcomes, this protocol for a systematic review and meta-analysis, through a thorough examination of global studies, seeks to synthesize evidence on the impact of magnesium levels on pregnancy outcomes, and, identify potential avenues for targeted, nutritional interventions. Addressing existing knowledge gaps is imperative for developing strategies to improve maternal and fetal health, particularly in regions burdened by high rates of pregnancy-related complications and co-existing health conditions.

Objectives:

To systematically map the existing literature for magnesium levels during pregnancy and adverse pregnancy outcomes.

To assess the impact of maternal magnesium deficiency on pregnancy complications, including GDM, PIH, IUGR, and PE.

To investigate the role of magnesium supplementation in mitigating the risk of adverse pregnancy outcomes, particularly in populations at higher risk due to factors such as dietary habits, socioeconomic status, and comorbid conditions like HIV, anaemia, and obesity.

To explore potential interactions between magnesium levels and co-existing conditions prevalent in low-to-middle-income countries (LMICs), such as obesity, anaemia, and HIV, and their impact on maternal and fetal health outcomes.

To identify research gaps in the current literature and propose recommendations for future studies aimed at enhancing our understanding of the role of magnesium in pregnancy and improving maternal and fetal health globally.

This protocol is written in accordance with the conditions of the Preferred Reporting Items for Systematic Review and Meta-analysis for Protocols (PRISMA-P) 2015 checklist [12]. This systematic review will be reported in compliance with the PRISMA 2020 statement [13].

Eligibility of research question:

The Populations Exposure Outcomes (PEO) framework (Table 1) will be used to determine the eligibility of the research question. Studies reporting on the levels of magnesium during pregnancy will be included; there will be no restriction on the study design, setting or publication date. Articles of all languages will be accepted, with an English translation being conducted using Google Translate where applicable. Any articles that are unable to be translated will not be included in the study but will be listed as an appendix.

Table 1

PEO framework for eligibility of research question
Population	Pregnant women, including those with co-existing conditions such as HIV, anaemia, and obesity, across diverse geographical regions and socioeconomic backgrounds.
Exposure/Intervention	Maternal magnesium levels during pregnancy, influenced by factors such as dietary intake, supplementation, and physiological changes inherent to pregnancy.
Outcomes (not limited to)	Gestational diabetes mellitus (GDM) Pregnancy-induced hypertension (PIH) Intrauterine growth restriction (IUGR) Pre-eclampsia (PE) Preterm birth Neonatal outcomes (e.g., birth weight, Apgar scores)

Identifying relevant studies:

The following databases will be used to source articles: PubMed, Scopus, Directory of Open Access Journals (DOAJ) and Google Scholar. The uniterms and Boolean operators in English to be used in search strategies are: (pregnancy OR pregnant OR maternal OR mother OR gestation OR gestational) AND (preeclampsia OR hypertension OR hypertensive OR eclampsia OR disease OR disorder OR pregnancy disorder OR hypertensive pregnancy OR hypertensive disorder OR hypertensive pregnancy disorder OR pregnancy outcome OR pregnancy complication OR gestational diabetes OR gestational diabetes mellitus OR gdm OR intrauterine growth restriction OR iugr OR fetal growth restriction OR fgr OR gestational hypertension OR pregnancy induced hypertension OR pih OR preterm labour) AND (magnesium OR magnesium sulphate OR magnesium sulfate OR mgso4 OR hypermagnesemia OR hypermagnesemia OR high magnesium OR low magnesium) AND (HIV OR human immunodeficiency virus OR antiretrovirals OR antiretroviral therapy) AND (obesity OR overweight OR high bmi OR high body mass index OR obese). The search strategy will be adapted for other electronic databases to be searched. The search strategy was piloted on the 25th of March 2024 to determine the appropriateness of the selected keywords and electronic databases (Table 2).

Table 2

Potential search strategy on PubMed
Search	Query
#1	((((("pregnant"[All Fields]) OR ("pregnancy"[All Fields])) OR ("maternal"[All Fields])) OR ("mother"[All Fields])) OR ("gestation"[All Fields])) OR ("gestational"[All Fields])
#2	(((((((((((((((((((((((((((("preeclampsia"[All Fields]) OR ("eclampsia"[All Fields])) OR ("hypertension"[All Fields])) OR ("hypertension"[MeSH Terms])) OR ("hypertensive disorder"[All Fields]))) OR ("hypertensive pregnancy"[All Fields])) OR ("hypertensive pregnancy disorder"[All Fields])) OR ("disease"[MeSH Terms])) OR ("disease"[All Fields])) OR ("disorder"[All Fields])) OR ("pregnancy disorder"[All Fields])) OR ("hypertensive"[All Fields])))) OR ("pregnancy outcome"[All Fields])) OR ("pregnancy outcome"[MeSH Terms])) OR (pregnancy complication) ("hypertensive"[All Fields]))) OR ("gestational diabetes"[All Fields])) OR (gestational diabetes[MeSH Terms])) OR (gestational diabetes mellitus[MeSH Terms])) OR ("gestational diabetes mellitus"[All Fields])) OR ("gdm"[All Fields])) OR ("intrauterine growth restriction"[All Fields])) OR ("iugr"[All Fields])) OR ("fetal growth restriction"[All Fields])) OR ("fgr"[All Fields])) OR ("gestational hypertension"[All Fields]) OR ("pregnancy induced hypertension"[All Fields]) OR ("pih"[All Fields]) OR ("preterm labour"[All Fields])
#3	((((((((("magnesium"[All Fields]) OR ("magnesium"[MeSH Terms])) OR ("magnesium sulphate"[All Fields])) OR ("magnesium sulfate"[All Fields])) OR ("magnesium sulfate"[MeSH Terms])) OR ("mgso4"[All Fields])) OR ("hypermagnesemia"[All Fields])) OR ("hypomagnesemia"[All Fields])) OR ("low magnesium"[All Fields])) OR ("high magnesium"[All Fields])
#4	#1 AND #2 AND #3

Study selection:

The eligibility of the retrieved studies will be determined using the following criteria:

Inclusion criteria

Full text
Focuses on magnesium in pregnancy

Exclusion criteria

No full text available
Non-human subjects used
No reporting of magnesium
Case reports, short reports, letters, notes, conference abstracts, review articles

The titles and the abstracts of the sourced articles will be screened. The first and second authors (NA and VD) will independently screen the identified titles and abstracts. After selection, a hand search will be conducted to further refine the search strategy. If there is any discord, a third author will mediate (CB). All duplicates will be removed, and full article screening will be conducted to establish the eligibility of the articles. All eligible articles will be exported to Zotero v6.0.30 (Zotero.org). Screening results will be reported using the PRISMA-P flowchart [13].

Data Extraction:

Microsoft® Excel will be used to design a data extraction template for the collection of data from eligible studies. The data will be analysed using the MetaXL add-on for Microsoft Excel [15]. The template will be continually piloted, edited, and updated. The data will be extracted independently by two authors (NA and VD), and further verified by a third (CB). The data will be extracted according to Table 3.

Table 3

Data extraction tool
1. Author 2. Publication year 3. Title 4. Country where study conducted 5. Type of study 6. Sampling method 7. Laboratory test used 8. Mg levels 9. Maternal outcomes 10. Birth outcomes 11. Age 12. Gravidity 13. Gestational age 14. PE status 15. Socioeconomic status 16. HIV status 17. ART use 18. BMI 19. Relevant findings 20. Comments 21. Conclusions

Risk of bias and quality assessment:

The Hoy’s Risk of Bias tool will be used to evaluate the risk bias and quality of the selected studies [16]. This tool uses a 10-item rating system to assess both the internal and external validities of the studies. The 10 items will be categorized as low or high risk of bias, with the overall risk of bias being determined by the number of high-risk biases per study (low = ≤ 2, moderate = 3–4, high = ≥ 5) [17]. Insufficient information will be deemed as a high risk of bias [18]. The quality of evidence in the studies will be assessed using the Grade of Recommendations Assessment, Development and Evaluation (GRADE) tool to determine risk of bias, inconsistency, imprecision, indirectness, and publication bias. All evidence will be categorized into four categories: high (the true effect is similar to the estimated effect), moderate (the true effect is probably close to the estimated effect), low (where the effect might be markedly different from the estimated effect) and very low (the true effect is probably markedly different from the estimated effect). The quality of the selected studies will be determined independently by two authors (NA and VD), with a third (CB) assisting with verification.

Data synthesis and analysis:

All data will be tabulated or presented graphically in the form of forest plots. Heterogeneity in the studies will be evaluated using the \({I}^{2}\) statistic. A quality effects model will be used to determine the pooled levels of magnesium where heterogeneity is both high and significant across the selected studies. Subgroup analysis and meta-regression will be carried out to detect possible sources of heterogeneity according to study design characteristics such as: study design, sample size, country, diagnostic test, and magnesium levels. Publication bias will be assessed using the Doi plot [19].

The implications of the systematic review and meta-analysis that is delineated by this protocol extend beyond academic curiosity, holding significant relevance for both maternal and fetal health outcomes globally. By elucidating the complex interplay between magnesium levels, the manifestation of pregnancy complications and co-morbidities, such as HIV and obesity, our findings have the potential to improve prenatal care and management strategies. By providing a global overview of the impact of magnesium on pregnancy outcomes, this systematic review and meta-analysis will fill a significant gap in current knowledge. The findings could have substantial implications for prenatal care guidelines, emphasizing the importance of magnesium supplementation and dietary recommendations to mitigate the risk of adverse birth outcomes. Moreover, by identifying modifiable risk factors such as magnesium deficiency, our study may strengthen public health initiatives aimed at improving maternal nutrition and overall health outcomes. Ultimately, this research contributes to the broader goal of achieving equitable access to high-quality maternal and reproductive healthcare services worldwide, thereby advancing the agenda of sustainable development and health equity.

HIV	Human Immunodeficiency Virus
DNA	Deoxyribonucleic acid
GDM	Gestational diabetes mellitus
PIH	Pregnancy-induced hypertension
IUGR	Intrauterine growth restriction
PE	Pre-eclampsia
LMICs	Low-to-middle income countries
PRISMA-P	Preferred Reporting Items for Systematic Review and Meta-analysis for Protocols
PEO	Populations Exposure Outcomes
DOAJ	Directory of Open Access Journals

Registration

Registered with Prospero ( CRD42024518427)

Amendments

The protocol will be amended where necessary to ensure accuracy his is the first iteration of the protocol. Should it be necessary to amend any part of this protocol, every amendment including the date, the nature of the change and the rationale behind it will be registered independently of the protocol his is the first iteration of the protocol. Should it be necessary to amend any part of this protocol, every amendment including the date, the nature of the change and the rationale behind it will be registered independently of the protocol

Support

Not applicable

Author Contributions

This systematic review protocol was conceptualized by NA and VD. NA,VD and CB participated in the design of the study. NA prepared the original draft and VD and CB contributed to the review and editing of this protocol. All authors read and approved the ﬁnal manuscript

Declarations of Interest

The authors declare no conflicts of interest.

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Impact of magnesium levels in pregnancy on adverse birth outcomes: a protocol for a systematic review and meta-analysis

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