Effects of Gestational Diabetes Mellitus on Children
Effects of Gestational Diabetes Mellitus on Children
Abstract Gestational diabetes mellitus (GDM) refers to different degrees of glucose
 intolerance or impaired glucose tolerance,which are commonly found on non-diabetic persons
 during pregnancy.GDM is an important public health issue that has a huge impact on children's
 health.According to statistics,the global occurrence of GDM in 2017 was as high as 16.2%.As
 well as lifestyle changes that are leading to an increased number of women with
 overweightness and obesity,the increasing number of"older mothers"responding to the
 second-child policy are raising up the percentile of GDM by the year.infancy and pre-school
 age are the important stages of physical growth and psychomotor development.At present,there
 are few domestic and International studies on the impact of GDM on the health of children,and
 the conclusions are not the same.There is a lack of long-term follow-up and Chinese samples.
 This study focuses on the current new hotspot in the research of the children's health
 problems, based on the 1000-day life concept and theory of DOHaD. Prospective cohort study
 methods and real-world studies were used. To study and clarify the effect of GDM on the
 neuropsychological development and physical growth indicators of children in China, and
 further explore the possible mechanism of action and the related indicators of predictive
 value, looking for possible early intervention targets. The results are expected to expand
 the data sources of this type of research in China, improve the data quality and clarify the
 characteristics of this type of population in China, and provide data support for the
 revision of maternal and child health related policies.
1. Introduction:

 According to statistics, the occurrence of GDM in 2017 of China was roughly 14.8%. A
 preliminary test performed by the obstetrics outpatient department of the First People's
 Hospital of Chongqing Liangjiang New Area, China (Project partner) revels that the GDM
 percentile was 17.5%.

 It is currently believed that GDM can affect the perinatal health of next generation
 including "giant children". Recently, the impact of GDM on the health of children in
 childhood has become a research hot spot. GDM is an important public health issue that
 has a huge impact on children's health.

 "1000 days in the early life" refers to the period from the combination of sperm and egg
 to the second year of life, which has a profound impact on children's growth and
 development and adulthood health and even the health of their children. Children at this
 age are in the window period of interaction between genetics and environmental factors,
 and yet, are also in the "opportunity window" of epigenetic regulation. The disease and
 nutrition of pregnant mothers will greatly affect the growth and development of children
 in the first 1000 days of their lives, as well as the long-term health of the children
 and that of the children's children.

 International studies have shown that the children of GDM mothers may have abnormalities
 in nervous system development, including cognitive memory impairment and bradykinesia.
 Recent studies have found that GDM diagnosed before 26 weeks of gestation can increase
 the risk of autism spectrum disorders in the 18-24-month-old children, and GDM treatment
 cannot reduce the risk. A study in Spain found that GDM significantly reduced test
 scores for language and gross motor development in 18 months old children(P<0.05).

 The mechanism of GDM on the development of children psychomotor development is more
 complicated. Studies have shown that the middle and late pregnancy is an important stage
 of nervous system development. chronic hypoxia in GDM fetuses prompts the body to
 mobilize iron from other tissues, including the brain, to produce sufficient hemoglobin
 for oxygen. Iron is involved in the differentiation of neurons in the brain, the
 synthesis and decomposition of neurotransmitters and the myelin sheath of the brain,
 etc. Iron deficiency in the brain can lead to changes in the structure and function of
 the hippocampus and striatum, thus affecting the development of sensation, movement,
 emotion, learning, memory and behavior. Currently considered, Some indicators of blood
 routine can comprehensively reflect the iron storage in the body. Iron deficiency in
 developing children causes irreparable damage to cognitive and memory functions.

 Researchers believe that GDM during pregnancy affects children's iron metabolism,
 thereby increasing the risk of impaired neuropsychological development such as cognitive
 memory and exercise after birth, and that the iron nutrition status after returning to
 normal cannot reverse this damage.

 The new concept of the origin of human disease ,"The developmental origins of health and
 disease (DOHaD)."theory, that is, environmental factors (such as maternal nutrition,
 diseases, etc.) in early life (such as fetal period) will affect some adult
 non-communicable diseases (such as obesity and metabolic diseases),and even affects the
 health of multiple generations.

 Foreign related studies had found that the birth weight of the children in the GDM group
 was higher than that of the non-GDM mothers (P<0.01), and the height of the children in
 the GDM group was lower than that of non-GDM group when the children were 1.5 years old
 (P<0.01). At the age of 7.7 years, the children weight of GDM group was significantly
 higher than that of the non-GDM group (P<0.01).

 Researchers believe that GDM during pregnancy affects fetal fat synthesis and weight,
 further affects the weight and body symmetry of the children after delivery, and
 increase the risk of physique growth deviation of the children.

 2. Purpose and Significance of Research 2.1 Purpose 2.1.1 To clarify whether GDM during
 pregnancy affects children's iron metabolism, thereby increasing the risk of postnatal
 cognitive memory, motion and other neuropsychological development level damage, and
 whether the postnatal iron nutrition status returns to normal cannot reverse this
 damage.

 2.1.2 To clarify whether GDM during pregnancy affects fetal fat synthesis and weight
 gain,further affects the weight and body symmetry of the children after delivery, and
 increasing the risk of physique growth deviation of the children.

 2.2 Significance The results of this study may provide a basis for the scientific
 judgment of the prognosis of the children of GDM mothers and the formulation of early
 intervention plans, as well as data support for further health policy formulation.

 3. Target 3.1 To clarify the influence of GDM on children's neuropsychological development
 level and progression; 3.2 To clarify the influence of GDM on children's physique
 growth; 3.3 To clarify the effect of GDM on Hb, MCV, MCHC, RDW%, and PLT in neonatal
 blood routines; 3.4 To understand whether GDM at different stages of pregnancy has
 different effects on the physique growth and neuropsychological development of the
 children, and whether it may have a predictive effect; 3.5 To understand whether the
 impaired neuropsychological development level of infants and preschool children in the
 GDM group with normal Hb, MCV, MCHC,RDW% and PLT has been repaired.

 4. Research Steps In the obstetrics department of the First People's Hospital of Chongqing
 Liangjiang New Area,China, the pregnant women diagnosed as GDM by IADPSG2010 standard
 and delivery children were enrolled into the GDM group, and the healthy pregnant women
 and delivery children in the same period were enrolled into the non-GDM group according
 to 1:1 ratio. To Collect data of pre-pregnancy, pregnancy and pregnancy outcomes of the
 two groups, and fill in the "Questionnaire", including the age of pregnant women,
 permanent residence, pre-pregnancy weight, pre-pregnancy weight, height, educational
 status, Number of pregnancies, number of births, pregnancy-related conditions, etc.
 Husband's age, educational status, weight, height, average monthly household income,
 etc. The physique growth index and blood routine were monitored at the age of 1 month,3
 months,6 months,12 months,24 months,36 months,48 months,60 months and 72 months,
 respectively. Physique growth indicators and blood routine were monitored. PDMS-2 was
 used to evaluate the motor development of infants at the age of 1 months,3 months and 6
 months, and the Gesell developmental scale was used to comprehensively evaluate the
 neuropsychological development of infants at the age of 6 months,12 months,24 months,36
 months,48 months,60 months and 72 months.

 5. The calculation formula of sample size is as follows:

 Nkeley =(（Z_(α/2)+Z_β ）^2 P(1-P)(γ+1))/〖γ(P_(0-) P_1)〗^2 p = (p_0+γp_1)/(γ+1) N＝The
 sample size of each group，α＝standard deviation，α=0.05，Zα/2=1.96，β=0.2，Zβ=0.842，r=1.It is
 ca6.lculated that each group needs 255 samples.

 6. Recruitment Process Since July 1, 2019, the subject recruitment was implemented in the
 obstetrics department of the First People's Hospital of Chongqing Liangjiang New Area,
 China. 255 pregnant women diagnosed with GDM by IADPSG2010 standard and their children
 will be enrolled into the GDM group, whereas, the same number of healthy pregnant women
 and their children will be enrolled into the project.

 7. Statistical Analysis Plan

 Excel software was used for data entry and SPSS 19.0 statistical software was used for
 data analysis. GDM was used as the exposure factor to analyze the differences between
 exposed group (study group) and unexposed group (control group).Specific analysis
 includes:

 7.1 Chi-square test was used to analyze the general demographic characteristics and
 other baseline characteristics between the two groups; 7.2 Chi-square test was used to
 analyze the feeding conditions, complementary food addition conditions, nursing
 conditions and main diseases between the two groups; 7.3 The height and weight values of
 the two groups were calculated according to the standard: LAZ, WAZ, WLZ and BMIZ, and
 the results were analyzed by student's t test.

 7.4 GMQ, FMQ and TMQ values in PDMS-2 motor development scale assessment results between
 the two groups were analyzed by nonparametric tests, while the development quotient (DQ)
 of the five area assessed by the Gesell developmental scale was analyzed using
 nonparametric tests.

 7.5 Student's t test was used to analyze the blood routine values between the two
 groups.

 7.6 Multiple linear regression analysis was used to analyze the factors affecting
 physical, motor and intellectual development between the two groups.

 7.7 Incomplete Data Disposal Method 7.7.1 Deletion of cases containing missing data:
 there are mainly simple deletion method and weight method. If the number of missing data
 is small, cases with missing data can be deleted or bias reduced by weighting the
 complete data. After marking cases with incomplete data, complete data cases are
 assigned with different weights, which can be obtained by logistic or probit regression.

 7.7.2 Fill in the missing data with the possible data

 Mean value interpolation:

 If the null value is numeric, the missing attribute value is filled in based on the
 average value of the value of the attribute on all other objects; If the null value is
 non-numeric, the value that the attribute takes the most times in all other objects
 (that is, the value with the highest occurrence frequency) is used to make up the
 missing attribute value according to the mode principle in statistics.

 7.7.3 Lost to follow-up to the processing method last observation carried forward(LOCF)
 and baseline observation carried forward(BOCF)

 8. Quality Control Plan Site quality control will be carried out regularly, at least once a
 month, to ensure that the plan is strictly followed, and the data collected are
 accurately recorded.

 8.1 Ethics This study has been approved by the Ethics Review Board of Children's
 Hospital of Chongqing Medical University.

 8.2 Selection of Research Subjects The person in charge of screening and enrollment must
 screen the subjects in strict accordance with the inclusion and exclusion criteria and
 maintain consistency of the inclusion and exclusion criteria Upon signing of the
 contract, screener will collect data of pre-pregnancy, pregnancy and pregnancy outcome
 of the two groups of mothers and have them fill out a questionnaire.

 8.3 Follow-Up Visits One researcher will keep track of follow-up visit, keep telephone
 numbers, provide health consultation, pay home visits, keep touch with the parents in
 any other possible forms and remind the parents of their appointments.

 8.4 Measures and Physical Evaluation One researcher will be responsible for physical
 measurements. This researcher will be trained on the standard physical measurement prior
 to the beginning of research, and the average value of three measurements will be taken.
 In terms of accuracy, two appraisers must go through the professional training of
 regular medical institutions and obtain the qualification certificate, and then begin
 the evaluation after the accuracy and consistency of the evaluation results.

 8.5 Data Collection Special personnel are assigned to collect and save paper data every
 day, and timely input the paper data into the computer for real and correct storage.

 8.6 Data Entry The research data are loaded into the electronic record form and cloud
 platform database timely, completely, correctly and clearly to ensure the authenticity
 and reliability of the content.

 9. Safety Evaluation There were no additional interventions in this study, so there was no
 additional risk to children beyond routine care.
Inclusion Criteria:

 1. term infant;

 2. Apgar score>=7 at birth；

 3. single birth;

 4. no obvious birth defects;

 5. no other perinatal diseases that seriously affecting growth and development;

 6. no congenital or genetic metabolic diseases that affect intelligence development;

 Exclusion Criteria:

 1. mother with type 1 or type 2 diabetes before pregnancy;

 2. the mother had no OGTT diagnosis results and was not diagnosed in strict accordance
 with the diagnostic criteria of GDM;

 3. the mother had suffered from severe acute and chronic infectious diseases;

 4. the mother has other pregnancy complications during pregnancy (hypertensionkidney
 disease,cardiovascular disease,liver disease,thyroid-related
 disease,cholestasis,severe anemia,etc.);

 5. Mother's age>35 years old;

 6. the infants developed diseases that severely affected metabolism or normal growth and
 development during the follow-up.