Keywords pregestational diabetes - diabetes mellitus - hyperglycemia - congenital heart defects
Palavras-chave diabetes pré-gestacional - diabetes melito - hiperglicemia - defeitos cardíacos congênitos
Introduction
Congenital heart defects (CHDs), which affect 40,000 births per year in the United
States,[1 ] represent the most prevalent congenital defects.[1 ]
[2 ]
[3 ]
[4 ]
[5 ]
[6 ]
[7 ]
[8 ] In addition, they are a major cause of noninfectious death in infants[7 ] and convey an increase in healthcare costs,[9 ] so their prenatal diagnosis through fetal echocardiography is essential.[4 ]
[6 ]
It is described that, worldwide, ∼ 130 million women aged between 20 and 49 years
old are diagnosed with diabetes mellitus (DM) and ∼ 21 million births are complicated
by maternal diabetes (matDM).[7 ] Statistical data from Europe and the United States report that pregestational diabetes
(PGD) affects 0.3% of pregnant women.[5 ]
[10 ] In addition, there has been an increasing rise in its prevalence over time, especially
for type II diabetes.[2 ]
[4 ]
[8 ]
Pregestational diabetes is associated with an increased risk of congenital defects
and maternal and perinatal morbidity and mortality.[2 ]
[10 ] It threatens normal fetal cardiac development at several levels, which explains
the wide spectrum of associated CHDs, from small structural and/or functional defects
to major heart disease, with potential long-term sequelae.[7 ]
[9 ]
[10 ]
[11 ]
[12 ] Some studies point to a three times higher risk of CHD in the offspring of women
with PGD compared with the offspring of nondiabetic women.[4 ]
[7 ]
[8 ] Similarly, there is a higher prevalence for each CHD phenotype in this population.[1 ]
[3 ]
It is known that in pregnancies associated with prior matDM, hyperglycemia acts as
a primary teratogen.[2 ]
[4 ]
[7 ]
[9 ]
[11 ]
[13 ] Its presence in early stages of the embryonic development of the cardiovascular
system promotes the occurrence of embryopathies, culminating in cardiac defects.[1 ]
[3 ]
[7 ]
[10 ]
[12 ]
[14 ]
Despite the clear role of hyperglycemia, other factors inherent to matDM, namely placental
dysfunction, metabolic disorders such as obesity, and increased oxidative stress appear
to be players that also modulate the disturbance of cardiogenesis.[4 ]
[11 ]
[15 ]
Despite the apparent association between PGD as an environmental risk factor for CHDs,[1 ]
[3 ]
[5 ]
[7 ]
[8 ]
[9 ]
[13 ] there is still a long way to go in the investigation of this complex process and
the mechanisms by which matDM interferes with fetal cardiac development.[3 ]
[7 ]
[9 ]
[11 ]
[13 ]
Methods
The present bibliographic review was based on a literature search of articles published
between 2016 and 2021on the PubMed and Medline databases, restricted to articles written
in English. Experimental and observational studies involving humans or animals were
included. The keywords used were pregestational diabetes , diabetes mellitus , hyperglycemia , and congenital heart defects . From the analysis of the abstracts of the articles obtained, those that corresponded
to the objective of the review were selected and, additionally, a search of the references
of all the analyzed studies was performed to obtain additional information whenever
necessary ([Fig. 1 ]).
Fig. 1 . Flow diagram of the literature review.
Maternal Hyperglycemia and Fetal Cardiac Development
Maternal Hyperglycemia and Fetal Cardiac Development
The fetal environment in utero influences the development of the fetus during gestation,
impacting on the likelihood of developing lifelong disease. Fetal effects resulting
from deleterious conditions in utero appear to be proportional to the aggressiveness
of these conditions.[16 ]
During pregnancy, changes in glucose metabolism take place, in particular the increase
in maternal insulin needs and its resistance in the last trimester, as well as hormones
that inhibit its action, stimulating an increase in the amount of insulin supplied
by the pancreas.[17 ] In normal situations, there is the maintenance of a balance of the fetal blood glucose
level. At a late stage of gestation, there is a marked drop in glucose uptake in fetal
cardiac cells in order to promote proper embryonic cardiogenesis.[18 ]
Several studies highlight a strong correlation between matDM and a significantly increased
risk of CHDs in the offspring of affected pregnant woman.[4 ]
[7 ]
[8 ]
[19 ]
Hyperglycemia is the main teratogenic factor in diabetic pregnancies, and its presence
prior to conception and in the 1st trimester is associated with an increased risk of disturbed embryonic cardiac development.[7 ]
[17 ]
[20 ]
[21 ]
[22 ]
[23 ]
[24 ]
[25 ] Fetal hyperinsulinemia, inherent in pregnancies of diabetic mothers, is also thought
to underlie diabetic embryopathy.[26 ]
The spectrum of congenital cardiopathies associated with PGD involves looping, situs
anomalies, conotruncal, septal[7 ]
[22 ] and valvular malformations, transposition of great vessels, double-outlet right
ventricle, tetralogy of Fallot,[17 ]
[24 ]
[27 ] and aortic arch discontinuation.[20 ] Malformations of the cardiac outflow tract[21 ] and of the auriculoventricular septum[19 ] are particularly frequent.
Claudio Gutierrez et al.[23 ]
[27 ] found an association between the hyperglycemic environment during pregnancy and
the expansion of the ventricular compartment, decreased area of the ventricular myocardium,
and dilation of the ascending aorta in the late stages of pregnancy. Other studies
point to a correlation between PGD and hypertrophic fetal cardiomyopathy,[17 ]
[24 ]
[28 ]
[29 ] possibly due to the hyperinsulinemia that the fetus acquires in the context of maternal
hyperglycaemia.[17 ]
[28 ] An evident increase in the thickness of several cardiac structures is also described,
especially the interventricular septum, in pregnancies of diabetic mothers compared
with fetuses of normal pregnancies,[17 ]
[28 ] resulting in disturbed cardiac function.[17 ]
[24 ]
[28 ]
Several mechanisms have been implicated in this association between PGD and CHDs.[7 ] Hyperglycemia plays a role as a promoter of oxidative stress by increasing reactive
oxygen and nitrogen species,[7 ]
[22 ]
[23 ]
[27 ] which will promote the occurrence of genetic changes and abnormalities of the usual
pattern of apoptosis in cardiac cells,[23 ]
[27 ] particularly in the neural crest,[17 ] which is a key part in cardiac development.[7 ] On the other hand, in an hyperglycemic environment, the alteration of multiple signaling
pathways with repercussions in cardiac development is observed: (1) exacerbation of
the expression of transforming growth factor beta 1 (TGF-β1), originating an excessive
accumulation of extracellular matrix proteins in cardiac tissues;[27 ] (2) decreased levels of nitric oxide, which is essential for the proper functioning
of cardiac endothelial cells and whose reduction leads to inhibition of other signaling
pathways dependent on its effect;[22 ] and (3) excessive stimulation of nucleotide biosynthesis via pentose phosphate,
which is responsible for glucose metabolization, preventing proper maturation of cardiac
cells.[18 ] An association between high glucose levels and consequent placental vascular dysfunction
due to dysregulation of vascular endothelial growth factor, with a consequent impact
on cardiogenesis, has also been described.[17 ]
[19 ]
[20 ]
It is also known that the association between CHD and PGD does not change according
to the type of PGD[3 ]
[4 ]
[9 ] or to the type of treatment implemented in the context of diabetes.[3 ]
[9 ] In fact, even with optimal glycemic control, there is an increased risk of developing
CHD;[7 ]
[17 ]
[22 ]
[24 ]
[27 ]
[28 ] in clinical trials, it has been found that a negligible increase in glucose levels
in the mother is associated with defects such as tetralogy of Fallot in the offspring,[7 ]
[22 ] which presupposes that hyperglycemia is potentiated or interacts concomitantly with
other conditions in its teratogenic process.[22 ] Some studies point to a gene-environment interaction in which external factors inherent
to the fetal environment may act together with genetic predisposition in modulating
cardiac embryogenesis.[7 ]
[30 ]
In short, how the fetus reacts to maternal hyperglycemia is subject to several factors,
such as the developmental stage in which there was contact with maternal hyperglycemia
([Chart 1 ]), its severity, the presence of pathologies or concomitant risk factors, and genetic
background, inducing epigenetic changes and a complex interaction with repercussions
on fetal cardiogenesis.[7 ]
[22 ]
Chart 1
Spectrum of congenital cardiopathies associated with pregestational diabetes
Congenital cardiopathies associated with pregestational diabetes
Looping, situs, conotruncal, septal, and valvular anomalies
Transposition of great vessels
Double-outlet right ventricle
Tetralogy of Fallot
Aortic arch discontinuation
Hypertrophic fetal cardiomyopathy
Disturbed cardiac function
Placental vascular dysfunction
Effect of Pregestational Diabetes on Placental Function and Fetal Cardiac Function
in the 1st Trimester
Effect of Pregestational Diabetes on Placental Function and Fetal Cardiac Function
in the 1st Trimester
Placental development, which takes place in the 1st trimester, corresponds to a stage of marked susceptibility, so PGD may be a disruptive
factor.[31 ]
[32 ] The interface between the placental vascular system and fetal vessels exposes the
placenta to maternofetal endocrine imbalances, with possible harmful repercussions
on fetal development.[31 ] Fetuses exposed to the effects of hyperglycemia have a five-fold increased risk
of death in utero.[33 ] For this reason, diabetic women should be the target of a careful preconceptional
assessment and close monitoring from the 1st trimester in order to maintain a regular and balanced metabolic control, minimizing
the associated risks.[34 ]
[35 ]
[36 ]
[37 ]
Oxygen levels, and consequently reactive oxygen species, are known to increase significantly
in the placenta throughout the 1st trimester of pregnancy, especially in the presence of PGD, with potential consequences
on placental development. It is suggested that this increased oxygen tension amplifies
the effects of hyperglycemia at the trophoblast level, culminating in decreased trophoblast
proliferation during this period of gestation. As a result, the fetus will receive
a deficient nutritional intake, compromising its development. Thus, there seems to
be an association between PGD, deficient trophoblast proliferation, and disorders
such as fetal growth restriction, pre-eclampsia, and miscarriage.[38 ]
The higher propensity for congenital anomalies in pregnancies of diabetic mothers
associated with elevated maternal glucose levels early in gestation is notorious.[39 ] Maternal hyperglycemia is thought to convey changes in the blood flow established
between the mother, the placenta, and the fetus, which may have molecular effects
promoting CHD. Placental abnormalities seem to propitiate inflammation and oxidative
stress, with disruption of signaling pathways involved in fetal cardiac development.[7 ] Hyperglycemia is also known to impact proliferation and migration of neural crest
cell tissues.[40 ] These are important for an adequate evolution of fetal cardiac function throughout
pregnancy;[40 ] therefore, this interference in the 1st trimester interferes with organogenesis, promoting the appearance of CHDs.[33 ]
Russel et al. demonstrated a higher incidence of fetal cardiac function irregularities
in the 1st trimester in PGD compared with nondiabetic pregnancies. A deterioration of diastolic
function and global cardiac function is noted in this context, highlighting a decrease
in the ratio between passive and active ventricular filling and an increase in the
isovolumetric relaxation period and in the myocardial performance index.[41 ] Turan et al.[33 ] identified a shortening of the isovolumetric contraction period, failure of cardiac
contraction capacity, and deterioration of the ejection fraction. It was found that
the worse the maternal glycemic control, the greater the deterioration of fetal diastolic
function.[33 ] Sirico et al.[40 ] also described an increase in the mean 1st -trimester fetal heart rate in matDM compared with nondiabetic pregnancies. Some studies
seem to indicate that the structural cardiac abnormalities that occur in PGD are noticed
after the deterioration of cardiac function shown on ultrasound, raising the suspicion
that the latter may occur first.[41 ]
In summary, an adequate functional and structural cardiovascular development of the
fetus is determined by the interactions between the maternal, placental, and fetal
environments ([Chart 2 ]), which are closely dependent on maternal glycemic control in PGD, since glucose
levels in the mother influence multiple aspects of fetal cardiogenesis.[33 ]
Chart 2
Fetal cardiac dysfunctions in pregestational diabetes and methods for fetal heart
function assessment
Fetal cardiac dysfunctions in PGD
Fetal heart function assessment
Deterioration of diastolic function and global cardiac function
Fetal echocardiography
Decrease in the ratio between passive and active ventricular filling
Increase in the isovolumetric relaxation period and myocardial performance index
Shortening of the isovolumetric contraction period, failure of cardiac contraction
capacity, and deterioration of the ejection fraction
Increase in the mean 1st -trimester fetal heart rate
Abbreviation: PGD, pregestational diabetes.
Risk of Congenital Heart Defects in Offspring Exposed to Maternal Diabetes
Risk of Congenital Heart Defects in Offspring Exposed to Maternal Diabetes
Clinical trials have demonstrated an increased risk of CHDs in the offspring of diabetic
mothers compared with those of nondiabetic mothers.[42 ]
[43 ]
[44 ]
[45 ]
[46 ]
[47 ]
[48 ]
[49 ] What remains to be clarified is the extent of this association, something that differs
from study to study, as well as the relationship between matDM and particular subtypes
of CHDs,[1 ]
[10 ]
[42 ] since the spectrum of associated CHDs seems to encompass > 20 phenotypes.[42 ]
The literature shows that all types of PGD appear to be more likely to cause cardiac
malformations than gestational diabetes.[9 ]
[42 ] Similarly, there appears to be an increased risk for all phenotypes of CHDs in the
presence of matDM.[1 ] However, conotruncal defects, auriculoventricular septal defects, heterotaxy, ventricular
outflow tract obstruction, and double-outflow right ventricle[10 ]
[42 ]
[43 ] have been particularly identified.
It is estimated that the risk of CHD is about three times higher in pregnancies of
diabetic mothers compared with those of nondiabetic mothers.[2 ]
[8 ] It is also noteworthy that, among congenital anomalies associated with matDM, CHDs
correspond to the most frequent class.[2 ]
[9 ]
[36 ] Pregestational diabetes is, therefore, a modifiable risk factor for the incidence
of adverse pregnancy outcomes.[9 ]
It is known that the decisive period of fetal cardio genesis is between the 3rd and 7th weeks of gestation.[1 ]
[42 ] Thus, matDM, by promoting a hyperglycemic environment, generates imbalances in molecular
pathways crucial to cardiac embryogenesis, with consequent damage to it.[1 ]
[8 ]
[36 ]
[42 ] The inherent alterations in insulin resistance favour glucose transfer through the
placental interface, promoting a greater secretion of insulin by the pancreas, with
increased levels of fetal insulin.[12 ] Hyperglycemia and subsequent fetal hyperinsulinemia may have teratogenic effects
at this early stage of pregnancy. One of its apparent repercussions is myocardial
hyperplasia and hypertrophy through insulin receptors on the cardiac surface, which
mediate the increase in nutrient synthesis, with subsequent increase in cardiac muscle
mass.[10 ] It has been found that there is an intensification of the expression of these receptors
in the presence of poor glycemic control.[12 ] They are especially numerous in the interventricular septum, which is consistent
with the hypertrophy often found in this septum in the offspring of diabetic mothers.[10 ] Similarly, studies identify an association between interventricular septal thickness
and glycated hemoglobin (HgA1c) values.[12 ] Based on these findings, we conclude that the measurement of HgA1c at preconception
and in the 1st trimester is crucial for the surveillance of these pregnant women and for the assessment
of the risk of congenital malformations.[36 ]
Simultaneously, some authors argue that, following the oxidative stress intrinsic
to PGD, there is a decrease in cell proliferation and an increase in apoptosis, as
well as suppression of the expression of certain genes, blocking cardiomyocyte maturation
and differentiation, inhibiting embryonic cardiac development. Thus, the regeneration
potential of cardiac progenitor cells to restore injured cells is affected, which
ultimately may also lead to cardiac abnormalities.[50 ]
Although the extent of cardiac involvement is dependent on maternal glycemic control,[10 ] it has not yet been possible to quantify how current prenatal measures modulate
the risk of CHDs. Measures to reduce the risk of cardiac abnormalities in PGD include
strict control of blood glucose and body mass index[8 ] at preconception and in the early stages of pregnancy. In addition, early fetal
ultrasound monitoring allows the diagnosis of a part of the cardiac anomalies in the
1st half of pregnancy, making it possible to establish a timely course of action in the
course of pregnancy.[51 ]
The role of insulin analogues in 1st -trimester pregnancies of diabetic mothers is currently under evaluation. In fact,
there seems to be a decreased risk of CHDs in the offspring exposed to insulin analogues
as opposed to human insulin.[36 ] The feasibility of stem cell therapies in CHDs is also under discussion, since PGD
impairs the biological performance of progenitor cells and cardiac stem cells.[50 ]
In conclusion, the pathogenesis of CHDs remains unclear, but seems to involve multiple
players, with a crucial interaction between genetic and environmental factors.[8 ]
[42 ]
[52 ] These factors seem to lead to cardiac developmental disorders, both at morphological
and functional levels, conditioning a wide spectrum of CHDs.[11 ]
[12 ] Therefore, the study of glycemic control interventions in pregnant women is essential
to reduce the risk of these malformations.[36 ]
Pregestational Diabetes Mellitus and Obstetric Outcomes
Pregestational Diabetes Mellitus and Obstetric Outcomes
Pregnancies complicated by PGD present a greater association with unfavorable maternofetal
outcomes compared with pregnancies of nondiabetic mothers,[53 ]
[54 ]
[55 ]
[56 ] culminating in increased morbidity,[35 ]
[57 ]
[58 ] mortality, and hospitalizations.[56 ]
The complications resulting from matDM with greater emphasis in the literature encompass
fetal macrosomia, congenital anomalies (previously discussed), and miscarriage.[54 ]
[59 ]
[60 ]
[61 ]
[62 ] Also of note is the increased likelihood that the pregnant woman will suffer from
hypertensive disorders, such as pre-eclampsia, or that the fetus will develop complications
such as growth restriction,[35 ]
[54 ] jaundice, respiratory disorders, and neonatal hypoglycaemia.[63 ]
It seems that the damage inherent to each of these complications is greater the greater
the severity and duration of diabetes, pre-existing comorbidities, and glycemic control
in early pregnancy.[35 ]
[59 ]
[60 ] Interestingly, even in pregnancies of diabetic mothers with better blood glucose
levels, adverse outcomes continue to be recorded, and it remains unclear how much
glycemic control effectively mitigates the risks inherent to matDM. On the other hand,
maternal hypoglycemia also has the potential to generate adverse effects in pregnancy.
Its presence in a fetus usually with high glucose levels seems to be associated with
a greater threat of miscarriage.[60 ]
Therefore, the assessment of fetal well-being during pregnancy involves several factors,
and amniotic fluid volume is a key tool when we talk about diabetes in pregnancy.
In pregnancies of diabetic mothers, there is a correlation between poor glycemic control
and excessive accumulation of amniotic fluid (polyhydramnios).[61 ] The detection of this and other complications involves a multidisciplinary surveillance,
with analytical and echographic controls, whose frequency and most effective management
is still to be clarified, since all of them have limitations.[55 ]
[60 ]
[64 ]
[65 ]
Since the obstetric prognosis is largely influenced by the follow-up implemented in
diabetic mothers,[54 ] it would be ideal to initiate a line of preconception care. This would include closer
monitoring of diabetic women who are planning to become pregnant in the near future,
making efforts to control blood glucose values prior to pregnancy and implementing
a multidisciplinary approach to optimize care,[58 ]
[66 ] which should include the regular screening for nephropathy and retinopathy and the
verification of potentially teratogenic prescribed drugs, among other measures, in
order to reduce as much as possible the risk of complications during pregnancy.[58 ]
Despite advances in glycemic control and prenatal surveillance, improving obstetric
care in this population remains a challenge: not all patients have access to healthcare
and a large proportion do not use preconception care, missing a key window of opportunity
to institute effective disease control before pregnancy to prevent or mitigate adverse
outcomes ([Chart 3 ]).[66 ]
Chart 3
Some methods for the assessment of fetal well-being in pregestational diabetes
Methods for the assessment of fetal well-being in PDG
Analytical controls (glycaemia, serum levels of Pregnancy-Associated Plasma Protein
A [PAPP-A]…)
Fetal ultrasound monitoring
Amniotic fluid volume
Placental vascularization indices (uterine artery pulsatility levels…)
Abbreviation: PGD, pregestational diabetes.
Discussion
The incidence of CHDs is clearly higher in the offspring of mothers with PGD compared
with in the offspring of nondiabetic women,[1 ]
[3 ]
[4 ]
[7 ]
[8 ] with malformations of the cardiac outflow tract[21 ] and of the auriculoventricular septum[19 ] being particularly frequent. There is an association between PGD and fetal hypertrophic
cardiomyopathy,[17 ]
[24 ]
[28 ]
[29 ] with an evident increase in the thickness of cardiac structures such as the interventricular
septum,[17 ]
[28 ] leading to negative effects on long-term cardiac function.[17 ]
[24 ]
[28 ]
Hyperglycemia is identified as the primary teratogen in this relationship,[2 ]
[4 ]
[7 ]
[9 ]
[11 ]
[13 ] and its presence in the early stages of cardiac embryogenesis seems to favour the
occurrence of CHDs.[1 ]
[3 ]
[7 ]
[10 ]
[12 ]
[14 ] In addition, other factors inherent to matDM, such as placental dysfunction, increased
oxidative stress, and alteration of multiple molecular signaling pathways appear to
be players that also negatively modulate cardiogenesis.[4 ]
[11 ]
[15 ]
Thus, cardiac abnormalities in the context of matDM have a multifactorial basis, highlighting
the gene-environment interaction; that is, environmental factors, such as PGD, act
together with genetic predisposition in modulating cardiovascular development[7 ]
[30 ] ([Fig. 2 ]).
Fig. 2 Evidence points to an association between pregestational diabetes and a higher propensity
of the offspring to develop congenital heart disease (CHD). This correlation seems
to be justified, on the one hand, by the presence of fetal hyperglycemia and hyperinsulinemia
and, on the other hand, by a deficient placental development. Thus, the teratogenesis
of maternal diabetes will reside in the generation of reactive oxygen and nitrogen
species (oxidative stress), culminating in epigenetic and cell cycle changes, which
condition a defective cardiogenesis. Simultaneously, studies highlight the role of
genetic predisposition for abnormal fetal cardiac development, so that this interrelation
between fetal environment and genetic background will be at the basis of fetal heart
defects.
How the fetus reacts to maternal hyperglycemia depends on several factors, such as
the developmental stage in which it came into contact, its severity, the presence
of concomitant diseases, and genetic background. This interaction results in epigenetic
changes with considerable repercussions on fetal cardiogenesis.[7 ]
[22 ] Research in this area shows an important correlation between CHDs and maternal blood
glucose levels at an early stage of pregnancy; therefore, the risk of CHD increases
in pregnancies based on poor glycemic control or with repeated episodes of acute complications
of diabetes at an earlystage.[4 ]
[8 ]
[9 ]
Furthermore, pregnancies complicated by PGD are more associated with unfavorable maternal
and fetal outcomes[53 ]
[54 ]
[55 ]
[56 ] and higher fetal and maternal morbidity and mortality.[35 ]
[57 ]
[58 ] At the fetal level, complications involve macrosomia, congenital anomalies, miscarriage,[54 ]
[59 ]
[60 ]
[61 ]
[62 ] shoulder dystocia or contusions at delivery,[53 ]
[64 ] jaundice, respiratory disorders, and neonatal hypoglycaemia.[63 ] For the mother, there is a higher risk of hypertensive disorders[35 ]
[54 ] and higher rates of caesarean sections or perineal injuries.[53 ]
[64 ]
There are also several characteristics that, when present in pregnancies of diabetic
mothers, are imminently promoters of perinatal mortality, namely a low socioeconomic
status, smoking, advanced maternal age, obesity, or twin pregnancies.[31 ]
[61 ]
[67 ]
[68 ]
Early fetal ultrasound monitoring with a set of diagnostic and prognostic markers,
such as amniotic fluid volume assessment and fetal echocardiography, allows the identification
of some complications and some cardiac anomalies. This surveillance is essential to
define an appropriate course of action and to plan the eventual intervention required
after birth.[51 ]
The uterine environment experienced by the fetus clearly influences its development
during pregnancy and, possibly, will also have repercussions in adulthood. Thus, diabetic
women should receive individualized care, ideally from preconception, in order to
maintain regular metabolic control and minimize the associated risks.[34 ]
[35 ]
[36 ]
[37 ]
It is necessary to implement a continuous improvement of preconceptional and prenatal
care, since there are still women who do not benefit from it, losing the possibility
to prevent or mitigate deleterious outcomes.[66 ] In addition, it is necessary to continue to implement and improve surveillance and
intervention programs to address the complications that arise in the context of maternal
mortality, since the prevalence of PGD is increasing.[9 ]
Although various resources exist for the early diagnosis of some of the complications
of pregnancy in diabetic women, constant research into new markers is crucial, as
the current methods have limitations.[55 ]
[60 ]
[64 ]
[65 ]
There is still a significant list of answers to be found: why the teratogenesis associated
with hyperglycemia has a more profound impact on certain organs; why the risk of CHDs
in pregnancies of diabetic women does not equal the same risk in nondiabetic women,
despite optimal glycemic control; or what mechanisms explain the existence of pregnancies
in the context of matDM, which record much higher HgA1c values than what is considered
acceptable for a pregnancy without birth defects and that, despite this, follow a
normal course.[4 ]
In fact, the extent of cardiac impairment is found to be partly dependent on maternal
glycemic control,[10 ] but it is not yet possible to quantify how current prenatal measures modulate the
risk of CHDs in this setting.[8 ]
In this scenario, the question that arises is what should be the HgA1c threshold considered
adequate for a woman with PGD to become pregnant without increasing risks, which remains
unanswered.[4 ]
Further studies will be needed to understand how this gene-environment interface occurs
and why infants who have been exposed to teratogenic agents such as hyperglycemia
are vulnerable to fetal cardiac development disorders.[7 ] Genetic mechanisms that potentiate susceptibility to certain environmental factors
may be involved, something that will need to be clarified in future investigations.[7 ]
Some treatments for diabetic pregnant women are currently under investigation, such
as insulin analogues, which, compared to the use of human insulin, appear to have
a superior ability to maintain more adequate blood glucose levels. Future investigations
should test whether they effectively minimize the risk of CHDs in offspring exposed
to them.[36 ] New therapies under study include the use of stem cells, given the role of maternal
diabetes in cardiomyocyte development and repair; however, their efficacy has not
yet been proven.[50 ]
Conclusion
Pregestational diabetes has an irrefutable negative influence on pregnancy and fetal
cardiac development, even in women with adequate glycemic control. Given the increase
of women with this condition in recent years, a proactive attitude is imperative in
the information, prevention, and metabolic control of these patients in order to minimize
the associated disorders and complications. It is necessary to continue research in
this area in order to understand the various aspects of the association between maternal
diabetes and fetal cardiac anomalies so that we can have an early and effective intervention
in its development and prenatal detection.
