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\begin{document}

\title{Maternal supplementation with multiple micronutrients containing folic
acid increased the risk for Gestational Diabetes Mellitus: Results from
a prospective cohort study in China}



\author[1,2]{Shuangbo Xia}%
\author[1,2]{Yushan Du}%
\author[1,2]{Ziyang Ren}%
\author[1,2]{Jinjuan Zhang}%
\author[3]{Suhong Gao}%
\author[4]{Jiamei Wang}%
\author[2]{Zhiwen Li}%
\author[4]{Xiaohong Liu}%
\author[2]{Jufen Liu}%
\affil[1]{Peking University School of Public Health Department of Epidemiology and Biostatistics}%
\affil[2]{Institute of Reproductive and Child Health / National Health Commission Key Laboratory of Reproductive Health, Peking University}%
\affil[3]{Department of Child Health, Beijing Haidian Maternal and Child Health Hospital, Beijing, China}%
\affil[4]{Department of Gynaecology and Obstetrics, Beijing Haidian Maternal and Child Health Hospital, Beijing, China}%


\vspace{-1em}



  
  \date{May 19, 2024}


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\begin{abstract}
Objective To investigate the relationship between maternal
supplementation with folic acid/ multiple micronutrients containing
folic acid (MM-FA) and gestational diabetes mellitus (GDM) risk. Design
Prospective cohort study. Setting Haidian Maternal and Child Health
Hospital, Beijing, China. Population 3,458 pregnant women and 653 cases
of GDM were approached between October 2017 and December 2020. Methods
Sociodemographic characteristics, lifestyle data, and information on
folic acid supplementation were obtained from a structured
questionnaire. GDM was diagnosed according to IADPSG criteria (2010).
After adjusting for confounding variables, associations between folic
acid/MM-FA supplementation and GDM risk were estimated using binary
logistic regression analysis. Main outcome measures Incident GDM.
Results Taking MM-FA periconceptionally was associated with a higher GDM
risk (aOR 1.33; 95\% CI 1.05--1.69) compared to exclusive folic acid
supplementation. And this association was observed exclusively in women
with a pre-pregnancy BMI \textless{} 24kg/m2 (aOR 1.39; 95\% CI
1.06--1.82). In separate analysis of pre-conception supplementation,
women without folic acid supplementation before conception were more
likely to develop GDM than those taking folic acid alone (aOR 1.40; 95\%
CI 1.01--1.96). Conclusions Maternal MM-FA supplementation may enhance
the risk for GDM. These findings indicated that pregnant women should to
be mindful of the risk of iron and other micronutrients
over-supplementation when using folic acid supplements. It's recommended
that women take pure folic acid in preference and begin taking them from
pre-conception in accordance with the recommended guidelines. Key words
Folic acid; Multiple micronutrients; Gestational diabetes mellitus;
Cohort%
\end{abstract}%



\sloppy


Title Page

\textbf{Maternal supplementation with multiple micronutrients containing
folic acid increased the risk for Gestational Diabetes Mellitus: Results
from a prospective cohort study in China}

Shuangbo Xia\textsuperscript{1,2}, Yushan Du\textsuperscript{1,2},
Ziyang Ren\textsuperscript{1,2}, Jinjuan Zhang\textsuperscript{1,2},
Suhong Gao\textsuperscript{3}, Jiamei Wang\textsuperscript{4}, Zhiwen Li
Ph.D \textsuperscript{1,2}, Xiaohong Liu\textsuperscript{4*}, Jufen Liu
Ph.D \textsuperscript{1,2*}

\textbf{Affiliations:}

1 Department of Epidemiology and Biostatistics, School of Public Health,
Peking University, Beijing 100191, China

2 Institute of Reproductive and Child Health / National Health
Commission Key Laboratory of Reproductive Health, Peking University,
Beijing 100191, China

3 Department of Child Health, Beijing Haidian Maternal and Child Health
Hospital, Beijing 100080, China

4 Department of Gynaecology and Obstetrics, Beijing Haidian Maternal and
Child Health Hospital, Beijing 100080, China

\textbf{Corresponding Authors:}

\textbf{Jufen Liu,\emph{liujufen@bjmu.edu.cn}.}

Institute of Reproductive and Child Health/ National Health Commission
Key Laboratory of Reproductive Health; Department of Epidemiology and
Biostatistics, School of Public Health, Peking University, Beijing
100191, China.

Phone number: +86-010-82801760-221.

\textbf{Xiaohong Liu,\emph{13522099566@163.com}.}

Department of Gynaecology and Obstetrics, Beijing Haidian Maternal and
Child Health Hospital, Beijing 100080, China.

Phone number: +86-13522099566.

\textbf{Running Title} : Types of folic acid usage \& gestational
diabetes

It contains 243 words of abstract, 3225 words of main text, 3 tables, 1
figure and 39 references.

\textbf{Objective} To investigate the relationship between maternal
supplementation with folic acid/ multiple micronutrients containing
folic acid (MM-FA) and gestational diabetes mellitus (GDM) risk.

\textbf{Design} Prospective cohort study.

\textbf{Setting} Haidian Maternal and Child Health Hospital, Beijing,
China.

\textbf{Population} 3,458 pregnant women and 653 cases of GDM were
approached between October 2017 and December 2020.

\textbf{Methods} Sociodemographic characteristics, lifestyle data, and
information on folic acid supplementation were obtained from a
structured questionnaire. GDM was diagnosed according to IADPSG criteria
(2010). After adjusting for confounding variables, associations between
folic acid/MM-FA supplementation and GDM risk were estimated using
binary logistic regression analysis.

\textbf{Main outcome measures} Incident GDM.

\textbf{Results} Taking MM-FA periconceptionally was associated with a
higher GDM risk (aOR 1.33; 95\% CI 1.05--1.69) compared to exclusive
folic acid supplementation. And this association was observed
exclusively in women with a pre-pregnancy BMI \textless{}
24kg/m\textsuperscript{2} (aOR 1.39; 95\% CI 1.06--1.82). In separate
analysis of pre-conception supplementation, women without folic acid
supplementation before conception were more likely to develop GDM than
those taking folic acid alone (aOR 1.40; 95\% CI 1.01--1.96).

\textbf{Conclusions} Maternal MM-FA supplementation may enhance the risk
for GDM. These findings indicated that pregnant women should to be
mindful of the risk of iron and other micronutrients
over-supplementation when using folic acid supplements. It's recommended
that women take pure folic acid in preference and begin taking them from
pre-conception in accordance with the recommended guidelines.

\textbf{Key words} Folic acid; Multiple micronutrients; Gestational
diabetes mellitus; Cohort

\textbf{Tweetable abstract} Pregnant women with multiple micronutrients
containing folic acid (MM-FA) have higher risk for gestational diabetes
mellitus (GDM) compared to exclusive folic acid supplementation.

~

~~~~~~~~Gestational diabetes mellitus (GDM) refers to diabetes diagnosed
in the second or third trimester of pregnancy that was not clearly overt
diabetes prior to gestation (1).

~~~~~~

\par\null

\textbf{Discussion}

~~~~~~~

\par\null

\textbf{~}

{\textbf{\emph{Conflicts of interest:}}} No conflict of interest exits
in the submission of this manuscript.

\textbf{\emph{Acknowledgements:}} The authors would like to thank all
the participants in this study. The authors also thank the health care
workers at Haidian Maternal and Child Health Hospital for their
assistance with data collection.

\textbf{\emph{Funding:}} This study was supported in part by grants from
the Fundamental Research Funds for the Central Universities
(BMU2021YJ034), CNS-ZD Tizhi and Health Fund (CNS-ZD2020-115), and
National Natural Science Foundation of China (81673177).

~

\par\null



\textbf{Acknowledgements}

The authors would like to thank all the participants in this study. The
authors also thank the health care workers at Haidian Maternal and Child
Health Hospital for their assistance with data collection.

\textbf{Disclosure of Interests}

None declared. Completed disclosure of interests form available to view
online as supporting information.

\textbf{Funding}

This study was supported in part by grants from the CNS-ZD Tizhi and
Health Fund (CNS-ZD2020-115), Fundamental Research Funds for the Central
Universities (BMU2021YJ034), and National Natural Science Foundation of
China (81673177).

\textbf{Details of ethical approval}

This study was approved by the Biomedical Institutional Review Board of
Peking University (IRB00001052-17028). Written consent was received from
all participants.

\textbf{Contribution to authorship}

SX drafted the first manuscript. SX, YD and ZR analyzed data. JL and ZL
contributed to the conception, design of the study, and study
supervision. SG, JW and XL were responsible for enrolling participants.
SX, YD and JZ were involved in data collection. YD contributed to the
graphical abstract. JL and ZL obtained funding. JL and XL contributed to
the interpretation of the results and made critical revision to the
manuscript. All authors read, reviewed and approved the final
manuscript. JL and XL are the guarantors of this work and, as such, had
full access to all the data in the study and take responsibility for the
integrity of the data and the accuracy of the data analysis.

\textbf{}



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