Interpretation of results and comparison with existing
literature
A number of studies have demonstrated that 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 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, Pateyet 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 Zablahet 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 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.