Association Between the Early or Late Onset of Gestational Diabetes Mellitus with Neonatal Adverse Outcomes: A Retrospective Cohort Study

doi:10.21203/rs.3.rs-3347019/v1

Download PDF

Research Article

Association Between the Early or Late Onset of Gestational Diabetes Mellitus with Neonatal Adverse Outcomes: A Retrospective Cohort Study

https://doi.org/10.21203/rs.3.rs-3347019/v1

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

Background

The significance of timing in diagnosing hyperglycemia during pregnancy and its association with adverse outcomes for the newborn is controversial. The literature has been evolving in standardizing gestational diabetes mellitus (GDM) diagnosis and terminology. we aimed to investigate the association between early-onset GDM and adverse outcomes in newborns and neonates, comparing it with the late-onset GDM model.

Methods

It was a retrospective cohort study at the Perinatal Diabetes Research Center-Assis affiliated nucleus from Botucatu Medical School-UNESP, Brazil, between 2016–2019. The group composition were, early-onset concerning participants with fasting glucose ≥ 92 mg/dL and < 126 mg/dL before 20 weeks of gestation or late-onset participants with negative first-trimester screening and positive 75g-OGTT at 24–28 weeks. The maternal baseline characteristics included: pre-pregnancy body mass index (BMI; Kg/m²); the pregnancy weight gain (Kg) calculated by the difference between final pregnancy weight (36 gestational weeks or more) and pre-pregnancy maternal weight and classified according to the pre-pregnancy BMI (8). In addition, the perinatal outcomes evaluated in this study were: gestational age (GA), birth weight (BW), and BW status according to GA as adequate, large or small, Apgar scores at the first and 5th minutes.

Results

Eight hundred eighty pregnant women were selected, 203 (23.07%) presenting GDM were eligible from December 2016 to December 2021. According to the timing onset of GDM, 89 (43.84%) were in the early-onset group and 114 (56.16%) in the late-onset group. the FPG values at the first trimester were higher in the early-onset group. The 75grams-OGTT values were higher in the late-onset group. The final BMI was higher in the late-onset group. A univariate linear regression was performed in order to determining relation between late-onset according different outcomes (Table 3), no significant relation was detected.

Conclusions

Pregnants with early-onset of GDM showed higher BMI during pregnancy, but there was no difference between the early or late-onset of GDM concerning neonatal adverser outcomes.

Gestational diabetes mellitus

newborn

adverse complications

The significance of timing in diagnosing hyperglycemia during pregnancy and its association with adverse outcomes for the newborn is controversial (1). The literature has been evolving in standardizing gestational diabetes mellitus (GDM) diagnosis and terminology (2). Over the past years, studies have demonstrated that the GDM diagnosis strategy considers either first-trimester hyperglycemia or second-trimester 75g oral glucose tolerance test (75g-OGTT) screening and diagnosis (3, 4). Currently, there is no consensus for the preferred testing approach or diagnostic glycemic thresholds for early GDM (5).

Recognizing the pregnancy risk factors related to the timing of GDM diagnosis may have a positive impact on the health of both the fetus and the newborn, mainly because there are divergences for in GDM screening and diagnosis protocols (1). However, insufficient data exist reporting the extent to which the first-trimester recognition of hyperglycemia or the conventional 24–28 weeks of gestation diabetes screening during pregnancy lead to unequal newborn adverse outcomes (6).

Therefore, we aimed to investigate the association between early-onset GDM and adverse outcomes in newborns and neonates, comparing it with the late-onset GDM model. We hypothesize that the early onset of hyperglycemia during pregnancy may lead to worse neonatal outcomes.

It is a retrospective cohort study at the Perinatal Diabetes Research Center-Assis affiliated nucleus from Botucatu Medical School-UNESP, Brazil, between 2016–2019. Pregnant women were followed during pregnancy and the neonatal period. The original study design was based on the primary goal of developing a predictive model for postpartum UI in women who had had GDM during their pregnancy (7). This ongoing study protocol includes all pregnant women who receive prenatal care in the obstetric and maternal-fetal medicine clinics at PDRC. We decided to retrospectively investigate the newborn outcomes in the GDM group in this cohort according to the onset period of hyperglycemia.

The current study is an ancillary analysis of GDM and the postpartum maternal and neonatal outcome of an ongoing cohort study entitled "Diamater" from PDRC, financially supported by FAPESP (São Paulo Research Foundation-São Paulo - Brazil). (7) Diamater's study was reviewed and approved by the Institutional Review Board -Botucatu (Letter of approval 1.048.565 issued on Apr 28, 2015) and by the Institutional Review Board (IRB-Assis number 1.716.895). Before enrollment, each woman was fully explained about the study and signed an informed consent form.

The inclusion criteria: patients from the antenatal care service submitted to the GDM screening and diagnosis from WHO guidelines. The exclusion criteria: multiple pregnancies, fetal loss before 22 weeks of gestation, stillbirth, loss to follow-up before collecting data during the pregnancy or neonatal period, severe maternal or fetal comorbidities during pregnancy or perinatal period and not related to the GDM status, pre-pregnancy DM. Patient follow-up: According to WHO guidelines, all women included started prenatal care before 20 weeks of gestation and underwent a universal screening with fasting glucose (FG) in the first prenatal visit, and for those with negative screening, the 75g-OGTT in the second trimester (24–28 weeks of gestation), except those previously submitted to bariatric surgery. For this specific group, the screening was made with FG in the second trimester.

The group composition were:

Early-onset: Patients with FG ≥ 92 mg/dL and < 126 mg/dL before 20 weeks of gestation.

Later-onset: Patients with negative first-trimester screening and positive 75g-OGTT at 24–28 weeks.

The outcome of interest: pre-term or term birth, fetal weight in grams, mode of delivery, the fetal weight adequacy for the gestational age at the birth, the Apgar score at first and the 5th minute, the Apgar Score less than 7; the adverse outcomes in the newborn requiring hospitalization in the first 28 days of the childbirth. Women in this study received prenatal care in our hospital's obstetric and maternal-fetal medicine clinics. Pregnant with GDM received nutritional counseling through a centralized office where they were given instructions regarding their diet and recommended weight gain based on their pre-pregnancy BMI. Self-monitoring of plasma glucose was recommended four times daily, and targets for plasma glucose included a fasting value of less than 95 mg/dL and two-hour post-meal values of less than 130 mg/dL. In addition, incomplete or missing antenatal and perinatal data were recovered from the institutional medical record.

The maternal baseline characteristics included: age, parity, Caucasian or non-Caucasian ethnicity, higher or non-higher educational level; previous bariatric surgery, physical activity during pregnancy (considered positive when more than 150 minutes per week during the gestational period); pre-pregnancy body mass index (BMI; Kg/m2); the pregnancy weight gain (Kg) calculated by the difference between final pregnancy weight (36 gestational weeks or more) and pre-pregnancy maternal weight and classified according to the pre-pregnancy BMI (8). In addition, the perinatal outcomes evaluated in this study were: gestational age (GA), birth weight (BW), and BW status according to GA as adequate, large or small, Apgar scores at the first and 5th minute; presence or not of neonatal complications until 28 days. All reference parameters were used following the clinical protocol of the local perinatal unit.

The outcome of interest was the gestational age at the delivery, newborn weight, the adequacy of newborn weight according to the gestational age, the Apgar score at 1st and the 5th minute, the Apgar score less than seven at the 5th minute, and the necessity of neonate hospitalization during the first 28 days.

For the sample size, we assumed that the risk of an outcome event equal to 0.20 among the group with a prior diagnosis, increased risk of an event outcome to 0.35 in the group with a late diagnosis, ratio of the number of participants in the group with no and with previous obesity equal to 1:1, type I and II errors equal to 0.05 and 0.20, respectively, and the presence of a maximum of three other variables in the adjusted models, and it was estimated that 170 participants per group were necessary.

Confound variables considered: maternal age, parity, previous vaginal or C-section, ethnicity, educational level, physical activities during and after pregnancy, maternal weight, previous bariatric surgery, pre-pregnancy BMI, and final BMI at delivery. Data collection procedures and statistical analysis: According to the predefined period and the inclusion and exclusion criteria, data were input into a specific software spreadsheet, audited, and consistency checked.

The Mann-Whitney test for numerical variables and the Chi-square test for categorical variables were used to compare groups according to the outcomes. Univariate logistic regression was conducted to estimate the relative risks (RR) and their respective 95% CI for the newborn outcomes according to the clinical and demographic characteristics. Finally, multivariate regression analysis was performed to identify which factors were independently associated with the newborn adverse outcomes and estimate the adjusted RR (adj RR).The variables were individually inserted, and those with a P-value under .05 were maintained. Lost to follow-up occurred entirely at random and were excluded. In addition, the missing data were sparse and occurred randomly, and the imputation method treated the few cases statistically. The SPSS version 23.0 (IBM, New York) was used for analysis. All statistical significances were two-sided and accepted at P < .05.

Table 1

Baseline characteristics according to the timing GDM onset.
	Early-onset (n = 89)	Late-onset (n = 114)
Variables	Med (IQR)	Med (IQR)	p*
Number of gestations	2.0 (1.0–2.0)	2.0 (1.0–2.0)	.196
Number of vaginal delivery	0.0 (0.0–0.0)	0.0 (0.0–0.0)	.996
Number of C-sections	0.0 (0.0–1.0)	0.0 (0.0–1.0)	.496
Maternal age (years)	30.0 (26.0-34.5)	29.5 (25.0-33.3)	.609
First trimester FPG (mg/dL)	95.0 (93.0–97.0)	85.0 (80.0–89.0)	.000
75g OGTT (mg/dL) – fasting	83.0 (78.0-86.5)	91.7 (80.0–96.0)	.000
75g OGTT (mg/dL) − 1h	134.0 (113.0-150.0)	167.5 (144.0-184.0)	.000
75g OGTT (mg/dL) − 2h	117.0 (100.0-130.0)	140.0 (121.0-159.0)	.000
BMI (kg/m²) pre-pregnancy	27.5 (24.1–32.1)	26.5 (23.8–29.7)	.202
BMI (kg/m²) gestation	31.5 (28.1–36.8)	30.0 (27.4–33.7)	.036
Weeks of gestation	38.1 (37.3–38.9)	38.2 (37.4–38.9)	.732
Newborn weight at birth (grams)	3170 (2830–3490)	3150 (2855–3400)	.728
1-minute Apgar score	9.0 (9.0–9.0)	9.0 (9.0–9.0)	.765
5-minutes Apgar score	9.0 (9.0–10.0)	9.0 (9.0–10.0)	.182
n: sample; g: mg/dL: miligrams per deciliter; FPG: fasting plasma glucose; 75g OGTT: 75 grams oral glucose tolerance test; BMI: Body Mass Index; Data are presented in: Med (IQR): Median (interquartile range); p-values are based on *Mann–Whitney U. Significance p < 0.05.

Table 2

Baseline characteristics according to the GDM onset.
	Early-onset (n = 89)	Late-onset (n = 114)
Variables	n (%)	n (%)	p*
Non-Caucasian	14 (15.7%)	13 (11.4%)	.409
Higher educational level	55 (61.8%)	73 (64%)	.771
Previous bariatric surgery	0 (0%)	1 (0.9%)	1.000
Obesity pre-pregnancy	30 (33.7%)	26 (22.8%)	.113
Pre-term birth	12 (13.5%)	12 (10.5%)	.662
C-section	88 (98.9%)	112 (98.2%)	1.000
Fetal growth restriction	7 (7.9%)	8 (7%)	1.000
Adverse neonatal outcome	10 (11.2%)	12 (10.5%)	1.000
5-minutes Apgar < 7	1 (1.1%)	3 (2.6%)	.633
Data are presented in n(%): absolute frequency (n) and percentage (%); p-values are based on *Chi-square test. Significance p < 0.05.

According with the results disposed in Table 1, the FPG values at the first trimester were higher in the early-onset group. The 75grams-OGTT values were higher in the late-onset group. The final BMI was higher in the late-onset group.

According to Table 2, the baseline characteristics did not differ between groups the timing of onset GDM in all studied variables.

A univariate linear regression was performed in order to determining relation between late-onset according different outcomes (Table 3), no significant relation was detected. It indicates that there is no difference regarding mother outcomes as gestational age on delivery, weight gain, c-section between the participants with late or early-onset of GDM. The same occurred related with newborn outcomes as weight on birth, apgar > 7, pre-term birth and fetal growth restriction.

Table 3

Univariate linear regression according different models, regarding gestational age, weight gain, weight on birth and Apgar > 7.
Variables	Β	95% CI	p*
	Investigation Model (Gestational Age)
Late-onset GDM	-0.16	(-0.62-0.30)	.502
	Investigation Model (Weight Gain)
Late-onset GDM	-22.18	(-157.46-113.09)	.748
	Investigation Model (Weight on birth)
Late-onset GDM	-22.18	(-157.46-113.09)	.748
	Investigation Model (Apgar > 7)
Late-onset GDM	8.16	(0.16-417.97)	.296
	Investigation Model (Pre-term birth)
Late-onset GDM	0.81	(0.36–1.85)	.617
		Investigation Model (C-section birth)
Late-onset GDM	1.00	(0.75–1.33)	.976
	Investigation Model (Fetal growth restriction)
Late-onset GDM	.94	(0.33–2.62)	.899
GDM: Gestational Diabeltes Mellitus; BMI: Body Mass Index; Data are presented in: β: Standardized regression Coefficient; SE: Standard error; 95% CI: 95% Coeficient Interval; p-values are based on *Univariate linear regression significance for investigation model p < 0.2.

Our findings indicated that from the 203 GDM women, 43.84% were screened positive in the early-onset group and 56.16% in the late-onset group. The results are consonant with other similar studies. The GDM incidence in HAPO study cohort ranged from 9.3–25.5% depending on study site (9).

Early-onset of hyperglycemia during pregnancy refers to the occurrence of elevated blood glucose levels, typically indicative of gestational diabetes mellitus (GDM), in the early stages of pregnancy, usually during the first trimester. In this context, "early-onset" suggests that the condition develops relatively early in the course of pregnancy, as opposed to later stages, such as the second or third trimester.

We observed in the early-onset GDM, a significant higher difference in the BMI calculated at the end of the prenatal care, compared with the late-onset group. We did not find diferences among the other variables studied. The relationship between early-onset GDM and obesity is complex. Obesity is a known risk factor for developing GDM, and individuals who are obese before becoming pregnant are at a higher risk of developing GDM during pregnancy. In fact, Weiss et al reported that the GDM risk was increased 3 to 4 fold in women with obesity (10).

Pregnant individuals with obesity are at a higher risk of experiencing complications during pregnancy and childbirth. These complications can sometimes affect the newborn's immediate health and Apgar score. For example, obese individuals are more likely to have babies with macrosomia (excessive birth weight), which can affect muscle tone and respiration in the newborn. Although our findings did not showed different between groups according timing of GDM diagnosis, it is important to consider this information for further studies.

It is essential to highlight the new emphasis on early GDM diagnosis to prevent perinatal morbidity and mortality and identify potential long-term maternal complications. Our results evokes the importance of the concern that GDM is a clinical entity starting before pregnancy, and the crutial early-onset diagnosis may be critical for reducing adverse outcomes.

Limitations include reduced precision due to the sampling design and implementation. We also assume that did not controlled how the disease and exposure variables were ascertained and recorded precisely in the pregnancy-span.

Although GDM is an entity with high prevalence worldwide and recognized association with adverse neonatal period, we can not fully generalize the results for different populations regarding ethnicity, socioeconomic status, parity, mode of delivery, and the plurality of variables influencing the outcome. No obstant, besides our parochial results, the presented results are critical to evoke new studies and discussions envolving the screening, diagnosis and treatment for the GDM during the entire pregnancy span.

Pregnant with early-onset of GDM showed higher BMI during pregnancy, but there was no difference between the early or late-onset of GDM concerning neonatal adverse outcomes.

Author contributions

Conceptualization: Fabiana Vieira Duarte de Souza Reis, Carlos Izaias Sartorao-Filho, Luis Sobrevia, Bruna Bologna, Luana Favaro Iamundo, Luis Takano, Raissa Escandiussi Avramidis, Rafael Guilen de Oliveira, Marilza Vieira Cunha Rudge, Angelica Mercia Pascon Barbosa

Formal analysis: Fabiana Vieira Duarte de Souza Reis, Carlos Izaias Sartorao-Filho, Caroline Baldini Prudencio, Marilza Vieira Cunha Rudge, Angelica Mercia Pascon Barbosa

Writing – original draft: Fabiana Vieira Duarte de Souza Reis, Caroline Baldini Prudencio,

Writing – review & editing: Luis Sobrevia, Bruna Bologna, Luana Favaro Iamundo, Luis Takano, Raissa Escandiussi Avramidis, Rafael Guilen de Oliveira, Marilza Vieira Cunha Rudge, Angelica Mercia Pascon Barbosa

Diamater Study Group – data collection and analysis.

Ethics approval and consent to participate

Study was reviewed and approved by the Institutional Review Board -Botucatu (Letter of approval 1.048.565 issued on Apr 28, 2015) and by the Institutional Review Board (IRB-Assis number 1.716.895). Before enrollment, each woman was fully explained about the study and signed an informed consent form.

Consent for publication

All authors assert that there are no undisclosed conflicts of interest (both personal and institutional) regarding specific financial interests that are relevant to the work conducted or reported in this manuscript. I have had full access to all the data in the study and thereby accept full responsibility for the integrity of the data and the accuracy of the data analysis

Acknowledgments

The authors would like to thank the pregnant women who participated in this study.

Data Availability

The authors confirm that all data underlying the findings are fully available without restriction. All relevant data is on the present manuscript .

Funding

The authors received a grant from Fapesp 2016/01743-5

Competing interests

The authors declare no competing interests.

Financial disclaimer

Supported by Sao Paulo Research Foundation protocol number 2016/01743-5 and 2021/10665-6. Brazilian Federal Agency for Support and Evaluation of graduate Education/SD (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, CAPES/DS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Sweeting A, Wong J, Murphy HR, Ross GP. A Clinical Update on Gestational Diabetes Mellitus. Endocr Rev. 2022 Sep;43(5):763–93.
González-González NL, González-Dávila E, Megía A, Pintado P, Vega B, Padrón E, et al. The NDDG criteria versus the IADPSG or the ADA criteria for diagnosing early-onset gestational diabetes mellitus or abnormal glucose tolerance. Int J Gynecol Obstet. 2023;160(3):906–14.
Djelmis J, Pavić M, Mulliqi Kotori V, Pavlić Renar I, Ivanisevic M, Oreskovic S. Prevalence of gestational diabetes mellitus according to IADPSG and NICE criteria. Int J Gynecol Obstet. 2016 Dec;135(3):250–4.
Erjavec K, Poljičanin T, Matijević R. Impact of the Implementation of New WHO Diagnostic Criteria for Gestational Diabetes Mellitus on Prevalence and Perinatal Outcomes: A Population-Based Study. J Pregnancy. 2016;2016:1–6.
Immanuel J, Simmons D. Screening and Treatment for Early-Onset Gestational Diabetes Mellitus: a Systematic Review and Meta-analysis. Curr Diab Rep. 2017 Oct;17(11):115.
Most OL, Kim JH, Arslan AA, Klauser C. Maternal and neonatal outcomes in early glucose tolerance testing in an obstetric population in New York city. J Perinat Med. 2009 Mar;37(2):114–7.
Rudge MVC, Souza FP, Abbade JF, Hallur RLS, Marcondes JPC, Piculo F, et al. Study protocol to investigate biomolecular muscle profile as predictors of long-term urinary incontinence in women with gestational diabetes mellitus. BMC Pregnancy Childbirth [Internet]. 2020 Dec 19;20(1):117. Available from: https://bmcpregnancychildbirth.biomedcentral.com/articles/10.1186/s12884-020-2749-x
Martin KE, Grivell RM, Yelland LN, Dodd JM. The influence of maternal BMI and gestational diabetes on pregnancy outcome. Diabetes Res Clin Pract. 2015 Jun;108(3):508–13.
Sacks DA, Coustan DR, Hadden DR, Hod M, Maresh M, Oats JJN, et al. Frequency of gestational diabetes mellitus at collaborating centers based on IADPSG consensus panel-recommended criteria: the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. Diabetes Care. 2012 Mar;35(3):526–8.
Weiss JL, Malone FD, Emig D, Ball RH, Nyberg DA, Comstock CH, et al. Obesity, obstetric complications and cesarean delivery rate--a population-based screening study. Am J Obstet Gynecol. 2004 Apr;190(4):1091–7.

Download PDF

Editorial decision: Major revision
18 Nov, 2023
Reviewers agreed at journal
22 Oct, 2023
Reviewers invited by journal
15 Oct, 2023
Editor assigned by journal
12 Sep, 2023
First submitted to journal
11 Sep, 2023

You are reading this latest preprint version

Association Between the Early or Late Onset of Gestational Diabetes Mellitus with Neonatal Adverse Outcomes: A Retrospective Cohort Study

Status:

Version 1

Abstract

Background

Methods

Results

Conclusions

Introduction

Method

Results

Discussion

Conclusion

Declarations

References

Status:

Version 1