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\begin{document}

\title{Cardiac function in gestational diabetes mellitus: A longitudinal study
from fetal life to infancy}



\author[1]{Marietta Charakida}%
\author[2]{Kypros Nicolaides}%
\author[3]{Janina Semmler}%
\author[2]{Jesica Aguilera}%
\author[1]{Huijing Zhang}%
\author[1]{Santiago Anzoatgui}%
\affil[1]{King's College London Faculty of Life Sciences and Medicine}%
\affil[2]{Fetal Medicine Institute}%
\affil[3]{King’s College Hospital}%


\vspace{-1em}



  
  \date{May 14, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
Objective: To determine whether cardiac functional and structural
changes in fetuses of mothers with gestational diabetes mellitus (GDM)
persist in the offspring beyond the neonatal period. Design:
Longitudinal study Setting: Fetal Medicine Unit in a UK teaching
hospital Population: 73 women with GDM and 73 women with uncomplicated
pregnancy were recruited and fetal cardiac scans were performed at 35-36
weeks' gestation. Repeat echocardiogram was performed in their offspring
during infancy. Main outcome measures: Fetal and infant cardiac
functional and structural changes Results: Fetuses of mothers with GDM,
compared to controls, had more globular right ventricles (sphericity
index 0.7, IQR 0.6/0.7 vs 0.6, IQR 0.5/ 0.6, p\textless{}0.001) and
reduced right global longitudinal systolic strain (-16.4, IQR
-18.9/-15.3 vs -18.5, IQR -20.6/-16.8, p=0.001) and left global
longitudinal systolic strain (-20.1, IQR -22.5/-16.9 vs -21.3, IQR
-23.5/-19.5), p=0.021). In the GDM group, compared to controls, in
infancy there was higher left ventricular E/e' (8.7, IQR 7.3/9.7 vs 7.9
IQR, 6.8/8.9 p=0.011) and lower left ventricular global longitudinal
systolic strain (-21.0, IQR -22.5/-19.4 vs -22.3, IQR -23.5/-20.7,
p=0.001) and tricuspid annular plane systolic excursion (13.8, IQR
12.7/16.1 vs 15.2, IQR 13.8/16.8, p=0.003). These differences remained
following multivariable analysis. Conclusion: GDM is associated with
alterations in fetal cardiac function and structure compared to controls
and persistent cardiac changes in infancy.%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION}

Epidemiological studies have shown that children of women with
gestational diabetes mellitus (GDM) have increased risk to develop early
cardiovascular disease in childhood and young adulthood (1, 2). We and
others have shown that GDM is associated with fetal cardiac
morphological and functional changes which are mostly noted in the right
ventricle, which is consistent with the dominance of the right heart
late in gestation (3-5). However, it remains unknown whether these
cardiac changes persist in postnatal life and they identify the subgroup
of children who are at increased long-term cardiovascular risk. To date
only few studies have carried out postnatal assessment in offspring of
mothers with GDM but these studies were confined to the neonatal period
(5, 6).

The objective of this study is to determine whether cardiac functional
and structural changes in fetuses of mothers with GDM persist in the
offspring beyond the neonatal period.

\textbf{METHODS}

\textbf{Study population- Study design}

This is a prospective longitudinal study in which women with singleton
pregnancies with GDM and an equal number of control women with
uncomplicated pregnancies were recruited at the time of their routine
fetal ultrasound scan at 35-36 weeks' gestation. Women with prior known
cardiovascular disease, pregestational diabetes, gestational or
pre-existing hypertensive disorder, fetal structural defects or
chromosomal abnormalities were not eligible to participate in this
study. Mothers were asked to bring their children for a repeat
cardiovascular assessment at around six months after delivery. Women
provided written informed consent to participate in the Advanced
Cardiovascular Imaging Study which received ethical approval (REC No
18/NI/0013, IRAS ID:237936). The prenatal data from this study
constitute part of data included in a previous publication from our
group (3).

\textbf{Maternal characteristics}

We recorded information on maternal age, racial origin (White, Black,
Asian and mixed), medical history, parity (parous and nulliparous if
there was no previous pregnancy with delivery at [?]24 weeks\selectlanguage{ngerman}´ gestation).
Weight and height were measured and body mass index calculated at their
clinical visit. The diagnosis of GDM was made by performing the two-step
approach at 24-28 weeks' gestation recommended by NICE guidelines; a
result from the 75 mg oral glucose tolerance test (OGTT) was considered
to be positive if the fasting plasma glucose was \selectlanguage{english}[?]5.6 mmol/L or the
2-hour plasma glucose level was \selectlanguage{english}[?]7.8 mmol/ (7). Management of GDM was
based on target glucose ranges and insulin or metformin were used when
dietary management failed. Glycemic control was assessed by home
self-monitoring and use of a glycometer for daily measurement of the
fasting and 1-hour post-prandial capillary blood glucose level; the
normal values for fasting blood glucose are 3.9-5.3 mmol/L and for
1-hour post-prandial blood glucose are 5.0-7.8 mmol/L. The records of
each patient were reviewed by an endocrinologist at the time of the
clinical visit and based on the results the method and dose of treatment
were adjusted appropriately to ensure good glycemic control.
Postnatally, all patients with GDM were offered a fasting plasma glucose
test 6-13 weeks after birth to exclude the presence of diabetes
mellitus. Data on pregnancy outcome were collected from hospital
delivery records or the general medical practitioners. Birth weight for
gestational age was converted to a Z-score based on the Fetal Medicine
Foundation fetal and neonatal weight chart (8).

\textbf{Fetal cardiac assessment}

The methodology was described in detail previously (2, 3). Essentially,
fetal heart was assessed using Canon Aplio i900 machines equipped with a
convex transducer (10C3 and i8CX1). Left and right ventricular
sphericity indices were measured on images from an apical 4-chamber view
at end-diastole. Left myocardial performance index was obtained using
pulsed wave Doppler. Systolic functional assessment included tricuspid
annular plane systolic excursion (TAPSE) using M-Mode, isovolumic
contraction (IVCT) from Doppler waveforms of blood flow. Diastolic
function was assessed with Doppler waveforms of blood flow and tissue
Doppler. Measurements included E/A ratio, E/e', isovolumic relaxation
time (IVRT). Myocardial deformation of the left and right ventricle was
measured in the apical 4-chamber view. All images were acquired at
100-160 frames per second as per recent guidelines (14) and analysed
using special speckle tracking software (Vitrea, Canon) as previously
described (3). Global longitudinal strain (GLS) and diastolic peak
strain rate (E and A), from the right and left ventricle, were measured.

\textbf{Childhood cardiovascular assessment}

Conventional and tissue Doppler echocardiography was performed using a
Canon Aplio i900 machine (PST-50BT neonatal transducer) according to the
guidelines of the American Society of Echocardiography (9). Measures
which were assessed were indices of systolic and diastolic left
ventricular function, including peak systolic mitral annular tissue
velocity and midwall fractional shortening and peak mitral annular
velocities in early diastole (e'), a measure of diastolic relaxation.
The ratio of early diastolic transmitral flow velocity E/E' was
calculated. Left ventricular mass (LVM) measurements were normalized to
body surface area as indexed LVM (LVMI). Speckle tracking analysis was
also performed to calculated left ventricular global longitudinal
systolic function. Right ventricular systolic function was also assessed
by tricuspid annular plane systolic excursion.

\textbf{Statistical analysis}

Normally distributed continuous variables are presented as mean (+-
standard deviation) and variables not following normal distribution as
median (25\textsuperscript{th} - 75\textsuperscript{th} percentile).
Nominal variables are summarized as counts and absolute percentages.
Distribution of continuous variables was graphically assessed by
histograms and quantile-quantile plots. Cardiac measurements were
compared between GDM and controls with the independent samples Student's
T Test or the Mann-Whitney U Test and the chi-squared test for
continuous and categorical variables, respectively. General linear
regression models were used to assess the association between GDM and a
range of echocardiographic parameters.

To facilitate the comparison of changes in echocardiographic parameters
before and after pregnancy for the two groups of interest, we used
linear mixed models with two random effects (random intercept and random
slope) and an unstructured variance-covariance matrix. Cardiac
parameters which were used as outcome variables included E/A, E/E',
global longitudinal strain, and myocardial performance index. An
interaction term (GDM yes/no*time interval between prenatal and
postnatal assessment) was introduced in linear mixed models to evaluate
the potential differential effect of GDM on changes in cardiac
measurements before and after delivery. Analysis was further adjusted
for a pre-specified set of confounders, including maternal age, race,
time elapsed from delivery to postnatal visit and change in infant
weight from birthweight. Statistical analysis was conducted with STATA
package, version 13.1 (StataCorp, College Station, Texas USA). We deemed
statistical significance at p \textless{}0.05. All tests were 2-tailed.

\textbf{RESULTS}

\textbf{Participant characteristics}

We studied 73 women with GDM and 73 women with uncomplicated pregnancy.
Women with GDM, compared to controls, were older and were more of Black
racial origin but there was no difference in weight and body mass index
between the groups (Table 1). In the GDM group, 23 women were on diet,
24 on metformin and 26 were on insulin alone or insulin and metformin.
Women with GDM delivered approximately one week earlier compared to
controls. There was no difference in birthweight z score between the two
groups.

\textbf{Comparison of fetal cardiac parameters in GDM and controls}

Fetal heart rate was similar in GDM and controls. Fetuses of mothers
with GDM, compared to controls, had more globular right ventricles
(sphericity index 0.7, IQR 0.6 - 0.7 vs 0.6, IQR 0.5 - 0.6,
p\textless{}0.001) and reduced right and left ventricular systolic
function (Table 2), but, there was no significant difference in
diastolic functional indices (Table 3).

\textbf{Comparison of postnatal cardiac indices in GDM and controls}

Postnatal assessment was carried out at 7+-2.3 months in the offspring of
women with GDM and at 11+-2.7 months in the controls. Infant weight and
height were lower in GDM compared to controls. In the GDM group,
compared to controls, there was higher left ventricular E/e' (8.7, IQR
7.3/9.7 vs 7.9, IQR, 6.8/8.9, p=0.011) and lower left ventricular global
longitudinal systolic strain (-21.0, IQR -22.5/-19.4 vs -22.3, IQR
-23.5/-20.7, p=0.001) and tricuspid annular plane systolic excursion
(13.8, IQR 12.7/16.1 vs 15.2, IQR 13.8/16.8, p=0.003) (Table 4). These
differences remained following multivariable analysis (Table 3). There
was no significant interaction between GDM and time interval from fetal
cardiac assessment. There was no difference in postnatal cardiac
functional and structural indices within the GDM group according to
diabetic treatment in pregnancy (Supplementary Table 1)

\textbf{DISCUSSION}

\textbf{Main findings}

In this longitudinal study we demonstrated that first, fetuses of
mothers with GDM, compared to controls, had more globular hearts and
reduced biventricular systolic function; second, diastolic and systolic
ventricular function remained reduced beyond the neonatal period; and
third, these associations were not modified by maternal diabetic
treatment. These findings suggest that maternal GDM may have prolonged
adverse influence on the cardiovascular health of the offspring.

\textbf{Interpretation of results and comparison with existing
literature}

A number of studies have demonstrated that \emph{in utero} exposure to
hyperglycaemia can adversely affect the fetal heart (3, 4, 10).
Consistent with this, in our study, we showed that fetuses exposed to
GDM have altered heart morphology with more globular hearts compared to
that seen in controls and the difference in shape were driven by changes
in the right ventricle. By using a variety of echocardiographic
modalities we also showed that fetuses of mothers with GDM, compared to
controls, have subtle functional cardiac changes which can be identified
only by using more advanced imaging modalities. Right and left
longitudinal myocardial deformation were reduced in fetuses exposed to
GDM compared to controls but diastolic indices were similar between the
two groups when analysis was adjusted for differences in maternal
characteristics, estimated fetal weight and heart rate. Similar results
have been reported before, in some studies (11, 12) but not in all (13).
For example, Miranda \emph{et al} in a combined group of 76 women with
pregestational diabetes and GDM demonstrated biventricular diastolic
dysfunction in their fetuses (4). Although measurements of diastolic
function commonly precede systolic functional changes, these are more
difficult to accurately assess in fetal life. In our study, we used
speckle tracking analysis to assess the rate of change in the right and
left myocardial deformation as well as conventional and tissue Doppler
imaging. We followed a strict protocol for image acquisition using high
frames per rate as per recent guidelines(14) and performed the analysis
without compromising our temporal resolution. It is possible therefore
that the noted discrepancies are due to differences in the study
population ie inclusion on pregestational diabetic women in Miranda's
study as well as differences in the software used for speckle tracking
analysis (15).

The influence of GDM, however, might not be limited to fetal life as
observational data suggest that maternal diabetes before or during
pregnancy is associated with increased rate of early onset
cardiovascular disease from childhood to adulthood (1,2). To date, only
few studies have assessed offspring of diabetic mothers spanning from
fetal to neonatal life and provided conflicting results about the
presence of persistent cardiac changes (6, 16, 17). For instance,
Patey\emph{et al,} in a group of 21 neonates of mothers with
pregestational diabetes or GDM, compared to controls, demonstrated
persistent alterations in left ventricular chamber geometry in the
perinatal period (5) and Zablah\emph{et al,} in a retrospective study
reported that 75 neonates who were exposed to pregestational diabetes or
GDM, compared to controls, had decreased left ventricular systolic and
diastolic function in the first week of life (17). In contrast, Mehta
\emph{et al,} documented in 50 newborns of mothers with pregestational
diabetes or GDM, that early cardiac changes such as reduced diastolic
ventricular function and myocardial hypertrophy are transient and
resolve in the first month of life (6). However, cardiac assessment in
the neonatal period is also affected by changes in loading conditions,
which relate to closure of cardiac shunts and the change from a parallel
circulation to one in series as part of the physiological adaptation to
postnatal life and this may obscure small differences to become apparent
in offspring of women with GDM compared to controls. Therefore, to
minimize this confounding effect, in our study we elected to study
children after the first few months of life. We showed that infants
exposed prenatally to GDM have increased diastolic functional indices
and reduced biventricular systolic function compared to controls,
whereas no differences in left ventricular mass was noted. Cardiac
changes were seen in both ventricles but more apparent in the left
ventricle and remained after accounting for differences in maternal
characteristics, infant weight gain and interval of cardiac assessment
since birth. However, it remains to be established whether the noted
cardiac functional changes persist in childhood and contribute to the
reported increased cardiovascular disease risk noted in offspring of
diabetic mothers.

In the management of GDM, insulin therapy is often added when diet or
oral pharmacological treatments fail to establish good glycemic control.
Although insulin may have growth stimulating effects on the myocardium
(18) this does not cross the placenta and is unlikely to affect directly
the fetal heart (19). However, from different hypoglycaemic treatments,
it is well described that metformin crosses the placenta and concerns
were raised regarding long term programming effects on fetal metabolism
as well as its impact on fetal heart with sustained effects in childhood
(20, 21). In our study, there was no difference in cardiac indices both
in fetal or postnatal life between the treatment groups thus our results
would not support such a hypothesis.

\textbf{Possible pathophysiological mechanisms}

Few studies have provided mechanistic insights about the link between
maternal diabetes and increased cardiovascular disease in the offspring.
It is well established that glucose crosses the placenta and fetal
hyperglycaemia leads to insulin production, increase in hepatic glucose
uptake and glycogen synthesis in the fetus (22). These metabolic changes
are associated with glycogen uptake from myocardial cells and
development of myocardial hypertrophy, which may vary in severity
depending on glycaemic control during pregnancy. Animal studies have
also shown that intrauterine exposure to hyperglycaemia can induce fetal
myocardial hyperplasia and myocardial remodelling which can account for
differences in morphology and endocardial deformation noted between
fetuses of mothers with GDM and controls. In addition, experimental
studies have indicated that fetuses of mothers with GDM may experience
hypoxaemia, which can lead to myocardial cell damage, myocyte death and
impaired ventricular function (23-25). Finally, depending on the timing
of \emph{in utero} exposure to the hyperglycaemic stimulus changes to
critical developmental pathways can occur as a result of altered gene
expression (26).

\textbf{Strengths and limitations}

Strengths of our study include, first, longitudinal cardiovascular
assessment in pregnancies affected only by GDM without the confounding
effect of pregestational diabetes, which could potentially affect early
embryonic development and alter cardiac morphogenesis and placental
development. Second, by performing detailed cardiac functional
evaluation from fetal to postnatal life, we were able to detect subtle
fetal cardiac functional changes and track these through the first year
of life. Cardiac measurements were performed using advanced
echocardiographic modalities and following strict imaging protocols.
Third, trained fellows blinded to maternal characteristics performed
analysis to avoid any bias in the results. The main limitation of the
study is that fetal speckle tracking analysis was performed using one
analysis platform and as such the measurements may not be generalizable
to those generated by other software(15). Another limitation was that
although we aimed to have the same interval after delivery for postnatal
cardiac assessment for the GDM and controls, this was not achieved and
there was a mean difference of 4 months between the groups; however, we
accounted for this discrepancy in the multivariable analysis.

\textbf{Conclusion}

The study demonstrates that GDM is associated with reduction in fetal
cardiac function and that cardiac functional changes persist in infancy.
Further studies with longer follow up are needed to determine whether
the fetuses and children of women with GDM that demonstrate such cardiac
changes are the ones who will be at increased long term cardiovascular
risk.

\textbf{Acknowledgement:} This study was funded by a grant from the
Fetal Medicine Foundation (Charity No: 1037116). The ultrasound machines
for fetal echocardiography and the software for speckle tracking
analysis were provided free-of-charge by Canon Medical Systems Europe
BV, ZOETERMEER, The Netherlands. 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.

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