Maternal Cardiovascular and Metabolic Function Before Conception and Subsequent Development of Gestational Diabetes Mellitus

doi:10.21203/rs.3.rs-4906324/v1

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Maternal Cardiovascular and Metabolic Function Before Conception and Subsequent Development of Gestational Diabetes Mellitus

https://doi.org/10.21203/rs.3.rs-4906324/v1

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Aims

To determine if maternal cardiovascular and metabolic indices before conception were different in women who in a subsequent singleton pregnancy developed gestational diabetes mellitus (GDM), compared to those without GDM.

Methods

This was a prospective observational study in women attending for infertility treatment in an in vitro fertilization clinic. This visit included recording of maternal demographic characteristics and medical history, assessment of maternal cardiovascular function by echocardiography and examination of metabolic profile. The inclusion criteria were attendance of the infertility clinic before the onset of treatment and subsequent singleton pregnancy delivering a non-malformed live birth. The pre-pregnancy results in women who developed GDM were compared to those without GDM.

Results

The study population of 287 women included 75 (26.1%) who developed GDM. In the GDM, compared to the non-GDM group, there was a higher mitral valve E/e’ (6.24[5.93, 6.55] vs 5.83[5.69, 5.93], mean intima media thickness(0.51[0.51,0.51] vs 0.49[0.49, 0.49] mm and left ventricular global longitudinal systolic strain (-19.9[-20.4, -19.6] vs -20.8[-21.1, -20.6]% and lower apolipoprotein A (113[105, 121] vs 136[121,134]mg/dl). In multivariable analysis, after accounting for differences in maternal characteristics, there was persistence of significant differences in E/e’ and apolipoprotein A. However, the performance of screening for GDM achieved by the use of maternal risk factors was not improved by the addition of cardiovascular and metabolic indices.

Conclusion

Women at risk to develop GDM during pregnancy have an adverse risk factor profile before conception. Further studies are needed to confirm whether optimization of cardiovascular and metabolic risk factors prior to conception might be beneficial in reducing the risk for subsequent development of GDM.

Cardiovascular function

Gestational diabetes

Metabolic profile

Pregnancy

Maternal cardiovascular and metabolic dysfunction before conception precedes the development of gestational diabetes mellitus. #GDM #Cardiovascular profile #Metabol-ic profile

Women with gestational diabetes mellitus (GDM) have a constellation of adverse cardiovascular risk factors and show abnormal cardiovascular responses during pregnancy compared to women with uncomplicated pregnancy. However it remains unclear whether these findings reflect a fragility of maternal cardiovascular system before conception or these reflect maladaptation to volume loading during pregnancy.

What is the key question?

Is there pre-existing cardiovascular and metabolic dysfunction in women at risk for GDM.

What are the new findings?

Women destined to develop GDM, compared to those without GDM, have a higher body mass index and higher incidence of family history of diabetes.
After accounting for differences in maternal characteristics, in the GDM group there were higher diastolic filing pressures and lower apolipoprotein A levels.

How might this impact on clinical practice in the foreseeable future?

It is necessary to determine whether optimization of risk profile prior to conception might reduce the risk for subsequent development of GDM.

Gestational diabetes mellitus (GDM) is characterized with increased glucose levels and develops for most after 20 weeks gestation (1). Although the condition resolves with delivery, epidemiological studies have consistently demonstrated that women with history of GDM have increased risk of developing type 2 diabetes and adverse cardiovascular outcomes within a decade after the index pregnancy (2, 3). Interestingly, the increased cardiovascular risk of these women cannot be attributed exclusively to the development of type 2 diabetes (2).

Our group and others have shown that women at risk for GDM often have a constellation of adverse cardiovascular risk factors ie increasing age, weight (4–8). In addition, metabolic abnormalities including dyslipidemia and increased inflammation have also been reported (9). We have also demonstrated that prior to development of GDM women at risk have deranged cardiac remodeling during pregnancy with mild reduction in left ventricular systolic and diastolic function and these cardiac alterations are accentuated with increasing gestation(5, 7, 8). However it remains difficult to decipher whether these changes reflect a pre-pregnancy fragility of maternal cardiovascular system which is unable to adapt to volume loading during pregnancy.

The objective of this study was to determine if maternal cardiovascular indices and metabolic profile before conception were different in women who during a subsequent singleton pregnancy developed GDM from those without GDM and to evaluate whether pre-pregnancy cardiovascular assessment can assist in risk prediction for development of GDM.

Study design and participants

This was a prospective observational study in women attending for infertility treatment in Genesis Athens Clinic, Athens, Greece between January 2022 and December 2023. This visit included recording of maternal demographic characteristics and medical history, assessment of maternal cardiovascular function and collection of blood for determination of biochemical profile. The women gave written informed consent to participate in the study, which was approved by the Local Research Ethics Committee (Approval File Registry 182/18-12-2021). The inclusion criteria were attendance of the infertility clinic before the onset of treatment and subsequent singleton pregnancy delivering a non-malformed live birth. We excluded multiple pregnancies and those with major fetal abnormalities.

Maternal cardiovascular assessment

All participants were studied by 2-dimensional and Doppler transthoracic echocardiography at rest in the left lateral decubitus position and data were acquired during unforced expiration. The examinations were carried out by cardiologists. The protocol included standard parasternal and apical views acquired with EPIQ ELITE ultrasound (Philips Bothell, WA, USA) as per American Society of Echocardiography (EAE/ASE) guidelines (10). Echocardiography was performed by four cardiologists who were trained in echocardiography.

Left ventricular systolic function was assessed by calculating left ventricular ejection fraction using M-mode of the left ventricle in the parasternal long axis view and by global longitudinal systolic strain using speckle tracking. The latter was calculated as a composite of the four, three and two chamber views. The more negative values denote increased strain, thus better systolic function.

Left ventricular diastolic function was assessed by measuring Doppler inflows at the mitral valve using pulse Doppler. The mitral peak early (E) and late (A) diastolic flow velocities were measured, and the E/A ratio was calculated. Pulsed tissue Doppler recordings were obtained at the septal and lateral aspects of basal left ventricle at the junction with the mitral valve annulus in the apical four-chamber view. Using tissue Doppler the E/e’ ratio was calculated using the mean value between septal and lateral peak e’ waves. This measure provides estimate of the left ventricular filling pressure. The higher the values the lower the left ventricular diastolic function.. Left atrial area was calculated in end-systole from the four-chamber view.

Myocardial performance index was calculated as a marker of global left ventricular function from the sum of the isovolumic contraction and relaxation time divided by ejection time. Left ventricular mass was calculated with the Devereux formula using measurements of the anatomical M-mode applied in the parasternal long axis. Hemodynamic parameters which were assessed were cardiac output and peripheral vascular resistance. Cardiac output was calculated from stroke volume (derived from the left ventricular outflow tract velocity-time integral) multiplied by heart rate. Peripheral vascular resistance was calculated from the formula (mean arterial pressure*80/ cardiac output)

Intima media thickness

Carotid intima-media thickness (cIMT) testing is an easily performed, cost effective and accurate method for the noninvasive assessment of atherosclerosis (11). The thickness of the inner two layers of the common carotid artery; the intima-luminal and media- adventitial was measured by a 18 − 4 MHz linear array using the EPIC ELITE Philips Bothell, WA, USA ultrasound machine. All measurements were calculated by the Phillips QLAB software The cIMT of both left and right common carotid artery were calculated during the end -diastole and measurements with ≥ 95% success rates were documented.

Biochemical measurements

In all women we obtained 10mL of venous blood which was used for measurement of HbA1c, interleukin-6 (IL-6), tumor necrosis factor-a (TNF-alpha), high sensitivity c-reactive protein and lipid profile (total cholesterol, low density lipoprotein, apolipoproteins A and B and lipoprotein A). Measurements of IL-6 and TNF-alpha were performed using ELISA, whereas the other biochemical measures were assessed using a Biochemical Analyzer (Roche Cobas Integra 400 Plus).

Outcome measure

The outcome measure was GDM which was diagnosed on the basis of results of the oral glucose tolerance test (OGTT) with administration of 75-g glucose, which was performed in all women at 24–28 weeks’ gestation; the diagnosis was made if the fasting plasma glucose level was ≥ 5.6 mmol/L and/or 2-h plasma glucose level was ≥ 7.8 mmol/L (12).

Statistical analysis

Data were expressed as median (interquartile range [IQR]) for continuous variables and n (%) for categorical variables. Students t-test and χ2-square test or Fisher’s exact test, were used for comparing outcome groups for continuous and categorical data, respectively. Cardiovascular and metabolic indices were summarized between the GDM and no-GDM groups by mean and 95% confidence intervals and compared using students t-test.

In order to assess the additive value of each individual cardiovascular or metabolic index over and above the prior risk of GDM from the FMF GDM history model [ref] logistic regression models were fitted with prior risk as an offset. Firstly, cardiovascular and metabolic indices were adjusted for maternal characteristics and medical history to compute multiple of the median (MoMs) of difference from the mean (Deltas). Secondly, logistic regression models were fitted with GDM as the outcome, prior risk of GDM as an offset and each individual cardiovascular or metabolic index as a covariate. Effects and p-values from these models were assessed. Performance of prediction of GDM from history alone, plus each of the individual cardiovascular or metabolic indices was assessed by detection rates for fixed screen positive rates of 10% and 20%.

As this is an exploratory study, rather than a formal trial, no adjustments for multiple testing were made. The statistical software package R was used for data analyses (13)

Study participants

The study population of 287 women with singleton pregnancies conceived by in vitro fertilization, included 75 (26.1%) who developed GDM. In the GDM, compared to the non-GDM group, the maternal weight and body mass index were higher and there was a higher incidence of first or second degree relative with diabetes mellitus (Table 1).

Table 1

Characteristics of the study population.
Characteristic	No GDM (n = 212)	GDM (n = 75)	p-value
Maternal age (years)	41.0 (38.0, 44.0)	41.0 (38.0, 45.5)	0.303
Maternal weight (kg)	62.5 (57.0, 70.0)	66.0 (58.5, 78.5)	0.026
Maternal height (cm)	166 (162, 170)	164 (160, 169)	0.031
Body mass index (kg/m²)	22.6 (20.7, 25.5)	24.9 (21.8, 28.5)	0.002
Chronic hypertension, n(%)	3 ( 1.42)	3 ( 4.00)	0.381
Smoking n(%)	52 (24.53)	26 (34.67)	0.164
Family history of diabetes n(%)*	8 ( 3.77)	18 (24.00)	< 0.0001
Parity			0.151
Nulliparous, n(%)	192 (90.57)	65 (86.67)
Parous, previous GDM, n(%)	6 ( 2.83)	6 ( 8.00)
Parous, no previous GDM, n(%)	14 ( 6.60)	4 ( 5.33)
Values are given in median (interquartile range) and n (percent)
GDM, gestational diabetes mellitus.
* First or second degree relative.

Maternal cardiovascular and metabolic indices

The maternal pre-pregnancy cardiovascular and metabolic indices in the study population are summarized in Table 2. In the GDM, compared to the non-GDM group, there was a higher mitral valve E/e’, mean intima media thickness and global longitudinal strain and lower apolipoprotein A and hemoglobin A1c, but there were no significant difference between groups in lipid profile and maternal hemodynamics including cardiac output, peripheral vascular resistance and mean arterial pressure.

Table 2

Cardiovascular and metabolic profile of the study population.
Measurements	GDM (n = 75)	No GDM (n = 212)
Hemodynamic parameters
Mean arterial pressure (mmHg)	89.0 (86.9, 91.3)	86.7 (85.4, 87.9)
Heart rate (beats/minute)	74.6 (72.1, 77.2)	75.8 (74.2, 77.4)
Peripheral vascular resistance (PRU	1754 (1661, 1847)	1703 (1651, 1754)
Left ventricular cardiac output (L/min)	4.2 (4.0, 4.5)	4.2 (4.1, 4.3)
Left ventricular diastolic function
Mitral valve E/A	1.38 (1.27, 1.43)	1.41 (1.37, 1.45)
Mitral valve E/e’	6.24 (5.93, 6.55)*	5.83 (5.69, 5.98)
Left atrial area (cm2)	12.4 (11.7, 13.0)	11.7 (11.4, 12.1)
Left atrial volume (mL³)	27.5 (25.5, 29.7)	25.3 (24.1, 26.5)
Left ventricular systolic function
Myocardial performance index	0.52 (0.50, 0.55)	0.50 (0.49, 0.51)
Global longitudinal systolic strain (%)	-19.9 (-20.4, -19.6)*	-20.8 (-21.1, -20.6)
Ejection fraction – biplane (%)	62.4 (61.3, 63.6)	62.7 (62.1, 63.2)
Mitral valve s (cm/s)	41.2 (40.3, 42.1)	39.9 (39.2, 40.6)
Relative wall thickness (cm)	0.36 (0.35, 0.37)	0.36 (0.35, 0.36)
Structural marker
Left ventricular mass indexed *	66.9 (64.2, 69.5)	63.1 (61.4, 64.9)
Mean intima media thickness (mm)	0.51 (0.51, 0.51)*	0.49 (0.49, 0.49)
Right ventricular systolic function
Tricuspid annular plane systolic excursion (mm)	25.2 (24.5, 25.9)	25.0 (24.6, 25.5)
Metabolic profile
Hemoglobin A1c (%)	5.56 (5.26, 5.85)	5.74 (5.56, 5.92)
High density lipoprotein (mg/dl)	52.5 (47.4, 57.7)	52.1 (50.0, 54.2)
Low density lipoprotein (mg/dl)	151 (141, 161)	156 (150, 161)
Triglycerides (mg/dl)	176 (166, 186)	181 (174, 189)
Total.cholesterol (mg/dl)	238 (229, 247)	244 (239, 249)
Lipoprotein A (mg/dl)	26.8 (24.5, 29.0)	26.2 (24.8, 27.5)
Apolipoprotein A (mg/dl)	113 (105, 121)*	136 (121, 134)
Apolipoprotein B(mg/dl)	144 (134, 154)	143 (137, 148)
C-reactive peptide (mg/dl)	4.89 (4.04, 5.74)	4.88 (4.47, 5.29)
Interleukin – 6 ( ng/ml)	14.2 (12.3, 16.1)	15.3 (14.3, 16.4)
Tumor necrosis factor – a (ng/ml)	1.88 (1.67, 2.09)	1.82 (1.68, 1.96)

Following multrivariable analysis, accounting for differences in maternal characteristics, the higher mitral valve E/e’ and lower apolipoprotein A levels persisted in the GDM group, compared to those without GDM (Table 3). The performance of screening for subsequent development of GDM by a combination of maternal characteristics and medical history with pre-pregnancy cardiovascular and metabolic indices, expressed as detection rate (DR) at 10% and 20% false positive rates is shown in Table 4. The results indicate that there is no significant improvement in DR from the addition of cardiovascular and metabolic indices.

Table 3

Cardiovascular and metabolic indices adjusted for maternal characteristics.
Cardiovascular profile	Estimate	95% CI	p-value
Hemodynamic parameters
Mean arterial pressure log10(MoM)	2.509	-3.870 to 8.888	0.441
Heart rate log10(MoM)	-2.438	-6.679 to 1.803	0.260
Peripheral vascular resistance delta	0.0003	-0.0004 to 0.001	0.363
Left ventricular cardiac output log10(MoM)	-0.242	-2.937 to 2.453	0.860
Left ventricular diastolic function
Mitral valve E/A log10(MoM)	-0.331	-3.284 to 2.621	0.826
Mitral valve E/e’ log10(MoM)	4.247	0.509 to 7.985	0.026
Left atrial area log10(MoM)	2.551	-0.872 to 5.974	0.144
Left atrial volume log10(MoM)	1.545	-0.591 to 3.681	0.156
Left ventricular systolic function
Myocardial performance index log10(MoM)	2.789	-1.088 to 6.666	0.159
Global longitudinal systolic strain delta	1.931	1.632 to 2.230	0.117
Ejection fraction - biplane delta	0.002	-0.057 to 0.061	0.941
Mitral valve s delta	0.025	-0.036 to 0.086	0.422
Right ventricular systolic function
Relative wall thickness log10(MoM)	0.314	-4.313 to 4.941	0.894
Structural marker
Left ventricular mass indexed *delta	0.018	-0.002 to 0.038	0.076
Tricuspid annular plane systolic excursion delta	0.012	-0.081 to 0.104	0.801
Mean intima media thickness delta	4.014	-0.732 to 8.760	0.097
Metabolic profile
Hemoglobin A1c delta	-0.322	-0.614 to -0.031	0.030
High density lipoprotein delta	0.003	-0.021 to 0.026	0.823
Low density lipoprotein delta	-0.009	-0.018 to 0.0002	0.055
Triglycerides delta	-0.005	-0.012 to 0.002	0.192
Total cholesterol delta	-0.009	-0.017 to 0.00001	0.050
Lipoprotein A delta	0.0006	-0.034 to 0.035	0.973
Apolipoprotein A delta	-0.827	-1.630 to -0.025	0.043
Apolipoprotein B delta	-0.002	-0.012 to 0.007	0.613
C-reactive peptide delta	0.008	-0.109 to 0.125	0.893
Interleukin – 6 delta	-0.014	-0.057 to 0.028	0.505
Tumor necrosis factor – a delta	0.052	-0.321 to 0.426	0.785

Table 4

Performance of screening for gestational diabetes mellitus by maternal history plus cardiovascular and metabolic marker, presented as detection rate (DR) at 10% and 20% false positive rates (FPR).
Method of screening	DR at 10% FPR	DR at 20% FPR
Maternal history	16.0 (8.6–26.3)	32.0 (21.7–43.8)
+ Cardiovascular markers
+ Mean arterial pressure	14.7 (7.6–24.7)	36.0 (25.2–47.9)
+ Heart rate	17.3 (9.6–27.8)	34.7 (24.0–46.5)
+ Peripheral vascular resistance	16.4 (8.8–27.0)	32.9 (22.3–44.9)
+ left ventricular cardiac output	16.4 (8.8–27.0)	32.9 (22.3–44.9)
+ Mitral valve E/A	16.0 (8.6–26.3)	33.3 (22.9–45.2)
+ Mitral valve E/e’	16.0 (8.6–26.3)	38.7 (27.6–50.6)
+ Left atrial area	20.3 (11.8–31.2)	36.5 (25.6–48.5)
+ Left atrial volume	18.9 (10.7–29.7)	36.5 (25.6–48.5)
+ Myocardial performance index	17.3 (9.6–27.8)	33.3 (22.9–45.2)
+ Global longitudinal systolic strain	18.3 (10.1–29.3)	35.2 (24.2–47.5)
+ Ejection fraction	15.7 (8.1–26.4)	31.4 (20.9–43.6)
+ Mitral valve s	16.0 (8.6–26.3)	34.7 (24.0–46.5)
+ Relative wall thickness	16.0 (8.6–26.3)	33.3 (22.9–45.2)
+ Left ventricular mass indexed *	20.0 (11.6–30.8)	34.7 (24.0–46.5)
+ Tricuspid annular plane systolic excursion	14.7 (7.6–24.7)	33.3 (22.9–45.2)
+ Mean intima media thickness	16.0 (8.6–26.3)	34.7 (24.0–46.5)
+ Metabolic markers
+ Hemoglobin A1c	17.1 (9.2–28.0)	40.0 (28.5–52.4)
+ High density lipoprotein	15.7 (8.1–26.4)	32.9 (22.1–45.1)
+ Low density lipoprotein	18.6 (10.3–29.7)	34.3 (23.3–46.6)
+ Triglycerides	15.7 (8.1–26.4)	35.7 (24.6–48.1)
+ Total.cholesterol	18.6 (10.3–29.7)	35.7 (24.6–48.1)
+ Lipoprotein A	15.7 (8.1–26.4)	32.9 (22.1–45.1)
+ Apolipoprotein A	17.1 (9.2–28.0)	31.4 (20.9–43.6)
+ Apolipoprotein B	18.6 (10.3–29.7)	35.7 (24.6–48.1)
+ C-reactive peptide	15.7 (8.1–26.4)	32.9 (22.1–45.1)
+ Interleukin − 6	15.7 (8.1–26.4)	34.3 (23.3–46.6)
+ Tumor necrosis factor - a	15.7 (8.1–26.4)	32.9 (22.1–45.1)

The main findings of the study are that women who develop GDM, compared to those without GDM, have before conception an adverse risk factor profile with higher body mass index and higher incidence of first or second degree family history of diabetes, lower apolipoprotein A serum levels and mild reduction in left ventricular systolic and diastolic function and higher intima media thickness. After accounting for differences in maternal characteristics higher mitral valve E/e’ continued to be associated with higher risk of GDM development. The extent to which optimization of maternal risk factors prior to conception might be beneficial in reducing the development of GDM during pregnancy needs to be determined.

Previous studies have demonstrated that GDM identifies women at increased risk for development of both type 2 diabetes and premature cardiovascular disease within 10 years postpartum (2, 3) Similarly, findings from the CARDIA study (Coronary Artery Risk Development in Young Adults) support that GDM is another distinct diabetes-related hazard to cardiovascular health in women(14). This risk may be attributable to the effects of placental hormones or increased release of inflammatory cytokines during pregnancy that increase insulin resistance and may promote atherogenesis(14). In the current study, we measured lipids and inflammatory markers in all women. We showed that women who subsequently developed GDM do not have evidence of increased inflammation but have lower apolipoprotein A levels. Although absolute HDL levels were not significantly different between the GDM and non-GDM groups, the lower apolipoprotein A levels suggest different texture of HDL lipoprotein in women with GDM. The role of HDL in cardiovascular risk reduction has been extensively studied in large epidemiological studies (15). The higher HDL and apolipoprotein A levels have been consistently associated with reduction in cardiovascular risk. Therefore, the lower apolipoprotein A levels imply an increased cardiovascular risk in women at risk for GDM.

Previously, we have demonstrated that women at risk for GDM during pregnancy have increased aortic stiffness whilst only few demonstrate increase in peripheral vascular resistance including women with severe GDM or co-existence with hypertensive disorders (6). In the current study we measured aortic intima media thickness, a well-established prognostic marker of atherosclerotic risk to establish the a priori atherosclerotic risk of these women. Although aortic intimal media thickness was increased in women at risk for GDM, this association did not persist after accounting for differences in maternal characteristics and this further emphasizes the need for optimal risk factor management for optimal cardiovascular prevention. In addition, we assessed maternal haemodynamics. We showed that cardiac output and peripheral vascular resistance as well as blood pressure before conception were not significantly different between those who subsequently developed GDM, compared to those without GDM.

In the current study we elected to study women who embark on IVF treatment and assess their cardiovascular profile prior to getting pregnant whilst continuing to monitor them after conception for development of pregnancy complications. We performed detailed cardiac functional analysis and demonstrated mild reduction in left ventricular systolic and diastolic function in women at risk for development of GDM during pregnancy. From various measurements the mitral valve E/e’ remained an important determinant of GDM development. During pregnancy a mild increase in E/e’ is expected due to the volume loading of pregnanc (16)y. Our results suggest that women at risk to develop GDM have already a fragile cardiovascular phenotype prior to conception which is potentially aggravated with the volume loading of pregnancy.

In a previous study of 73,334 women with singleton pregnancies examined at 11–13 weeks’ gestation, independent prediction for subsequent development of GDM was provided by increasing maternal age and weight, first and second degree relative with diabetes mellitus, black and Asian ethnicity, conception by use of ovulation induction drugs and previous pregnancy affected by GDM (17). In our study, in which all women were of white ethnicity and conceived by in vitro fertilization, in the GDM compared to the non-GDM group there was a significantly higher maternal weight and body mass index and higher incidence of family history of diabetes mellitus; the lack of an association with maternal age and previous history of GDM may be a consequence of the small number of affected pregnancies in our study. We also assessed whether cardiovascular assessment before conception can be a useful strategy for risk stratification of women at risk for GDM. The results of our study would argue against such strategy considering the small detection rates identified.

Strengths and weaknesses

This is the first study to examine maternal cardiovascular and metabolic profile prior to conception and determine the factors which predispose to development of GDM in a subsequent pregnancy. Considering that most pregnancies are unplanned we elected to study women who are embarking on IVF treatment to conceive. However, this approach has some limitations, because the participating women tend to be older and have a higher infertility risk. Although our results may not be generalizable to all unplanned pregnancies, they provide strong evidence that adverse maternal risk factor profile is associated with higher risk of GDM development. In addition, women in the current study were all of white ethnicity and therefore our results may not be applicable to non-white populations.

In conclusion, the results of our study suggest that optimization of maternal risk factors might be an optimal approach for women who are planning to get pregnant as a preventative measure to reduce both CV risk as well as risk for development of GDM during pregnancy. In addition, our results would argue against a routine cardiovascular assessment prior to pregnancy as a risk stratification strategy for development of GDM. However interventional trials will be needed to confirm or refute our hypothesis.

Conflict of interest
None of the authors has any conflict of interest.

Funding

The study was supported by a grant from the Fetal Medicine Foundation (Charity No: 1037116). The ultrasound machines and probe for the ophthalmic artery studies were provided free-of-charge by Philips. The biochemical studies were funded by Genesis Athens Clinic, Greece. These bodies had no involvement in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

Author Contribution

M.C. and K.H.N. conceived the idea and wrote the first draft of the manuscript. A.W performed the data analysis. K.S., K.P., A.P. and V.P. recruited and examined the patients. All authors approved the final version of the manuscript. M.C. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Data Availability

Anonymized data can be available upon request and institutional approval.

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No competing interests reported.

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Maternal Cardiovascular and Metabolic Function Before Conception and Subsequent Development of Gestational Diabetes Mellitus

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Abstract

Aims

Methods

Results

Conclusion

Twitter summary

What is already known about this subject

INTRODUCTION

RESEARCH DESIGN AND METHODS

Study design and participants

Maternal cardiovascular assessment

Intima media thickness

Biochemical measurements

Outcome measure

Statistical analysis

RESULTS

Study participants

Maternal cardiovascular and metabolic indices

DISCUSSION

Strengths and weaknesses

Declarations

Conflict of interest
None of the authors has any conflict of interest.

Funding

Author Contribution

Data Availability

References

Additional Declarations

Status:

Version 1

Maternal Cardiovascular and Metabolic Function Before Conception and Subsequent Development of Gestational Diabetes Mellitus

Status:

Version 1

Abstract

Aims

Methods

Results

Conclusion

Twitter summary

What is already known about this subject

INTRODUCTION

RESEARCH DESIGN AND METHODS

Study design and participants

Maternal cardiovascular assessment

Intima media thickness

Biochemical measurements

Outcome measure

Statistical analysis

RESULTS

Study participants

Maternal cardiovascular and metabolic indices

DISCUSSION

Strengths and weaknesses

Declarations

Conflict of interest None of the authors has any conflict of interest.

Funding

Author Contribution

Data Availability

References

Additional Declarations

Status:

Version 1

Conflict of interest
None of the authors has any conflict of interest.