Keywords
gestational diabetes - fetal echocardiography - fetus - heart diseases - hypertrophic
cardiomyopathy
Palavras chave
diabetes gestacional - ecocardiografia fetal - feto - cardiopatias - miocardiopatia
hipertrófica
Introduction
Gestational diabetes mellitus (GDM) is defined as glucose intolerance with onset or
diagnosis during pregnancy. It affects ∼ 7% of all pregnancies, resulting in over
200 thousand cases per year.[1]
Previous studies have shown that maternal hyperglycemia may lead to fetal hypertrophic
cardiomyopathy (HCM)[2] and cardiac diastolic function impairment,[3] among other alterations.
Hypertrophic cardiomyopathy is characterized by an increased ventricular wall thickness,
which leads to a decrease in the left ventricular cavity size, to a potential reduction
in the ventricular systolic performance, and to the impairment of the diastolic function
because of the decreased ventricular filling. These alterations can lead to heart
failure and death.[4]
Cardiac complications due to congenital heart malformation and ventricular hypertrophy
are the major causes of morbidity and mortality in fetuses and newborns of mothers
with GDM.[5]
The incidence of HCM, especially interventricular septal hypertrophy (IVSH), varies
between 10% and 71%.[6]
[7]
[8] An increase in the ventricular wall thickness may also be involved in the cardiac
changes observed in fetuses of mothers with GDM, but septal hypertrophy is more studied
because of the higher number of insulin receptors in the septum of the heart.[9]
Prenatal HCM is diagnosed through intrauterine two-dimensional echocardiography, and,
based on the results, physicians may provide appropriate postnatal care and follow-up
for cardiac hypertrophy progression during the gestational period.[10] Some authors claim that fetal echocardiography should be recommended to all pregnant
women with GDM.[11]
The aim of the present study was to assess the prevalence of HCM in fetuses of pregnant
women with GDM before their treatment using fetal echocardiography.
Methods
The present cross-sectional study included 63 fetuses of mothers with GDM, and was
conducted before the mothers initiated their treatment in a public maternity clinic
at the southern region of Brazil between July 1 2013 and December 20 2013.
The study was conducted according to the local regulations for good clinical practices,
specifically those of the resolution of the Brazilian National Health Council (CNS,
in the Portuguese acronym, resolution no. 466/12), after approval from the Research
Ethics Committee (CEP011/12) of the institution. The principal researcher and collaborators
were responsible for providing information to the patients. None of the authors were
associated with the companies that provided the equipment or their competitors, and
did not receive any kind of support.
The study included singleton fetuses of pregnant women diagnosed with GDM, without
malformations and other diseases that could interfere with the fetal development.
The diagnosis of GDM was based on the criteria provided by the American Diabetes Association,
that is, blood glucose level ≥ 92 mg/dl (fasting), ≥ 180 mg/dl (1 hour after plasma
glucose) and ≥ 153 mg/dl (2 hours after plasma glucose), and an ultrasound was performed
between the 24th and 28th gestational weeks. Fetuses diagnosed with malformations
after their inclusion in the study were then excluded.
The fetal abdominal circumference (FAC) was determined as the average of three measurements
obtained at the stomach, umbilical vein, and liver levels. The FAC percentile for
the gestational age was calculated according to the method reported by Hadlock et
al.[12] Interventricular septum and left ventricular wall thickness were determined through
fetal Doppler echocardiography using two-dimensional sequential analysis for a longitudinal
transverse section at the left atrioventricular (bicuspid) valve tip level using the
M-mode.[13] The test was performed before the patients initiated the treatment for GDM.[14] Septum and/or left ventricular wall thickness values showing a standard deviation
of more than 2 according to the gestational age were considered abnormal, that is,
consistent with the findings of HCM.[15]
[16]
[17] The fetal echocardiographs were obtained by the same technician using the HD 7XE
(Philips®, Amsterdam, Netherlands) equipment.
The maternal data assessed were age, parity, pre-pregnancy body mass index (BMI = W/H2), and gestational age at the time of inclusion in the study. The fetal data assessed
were FAC percentile and interventricular septum and left ventricular wall thickness.
The primary and secondary outcomes assessed were the presence of HCM and FAC respectively.
All variables were descriptively analyzed, with quantitative variables expressed as
means and standard deviations.
Data were statistically analyzed using the Statistical Package for the Social Sciences
(SPSS, IBM-SPSS, Inc., Chicago, IL, EUA) software, version 21.0. Continuous (quantitative)
variables were expressed as means and standard deviations. Categorical (qualitative)
variables were expressed as absolute and relative frequencies. The 95% confidence
interval (95%CI) for the frequency was calculated using the one-sample t-test.
Results
Sixty-three pairs (pregnant woman and her fetus) were selected, and none was excluded.
The average age of the pregnant women was 32.32 (±6.2) years, and the average gestational
age at the time of the evaluation was 30.59 (±2.27) weeks. The majority of the pregnant
women had multiple gestations (66.66%), and a pre-pregnancy BMI > 25 kg/m2 (65.07%); the average BMI was 27.33 (±5.64) kg/m2. Maternal data are shown in [Table 1].
Table 1
Epidemiological data on pregnant women with gestational diabetes mellitus*
|
Maternal data
|
N
|
%
|
|
Pregnant women's weight
|
|
Normal
|
22
|
34.92
|
|
High
|
41
|
65.07
|
|
Total
|
63
|
100.00
|
|
Parity
|
|
Nulliparous
|
21
|
33.33
|
|
Multiparous
|
42
|
66.66
|
|
Total
|
63
|
100.00
|
Note: *Absolute number (N) and percentage (%).
The interventricular septum thickness showed a standard deviation of more than 2 in
50.8% of the fetuses, between 1 and 2 in 38.09% of the fetuses, and less than one
in 11.11% of the fetuses (95%CI: 38.1–63.5%). The left ventricular wall thickness
showed a standard deviation of more than 2 in 13 fetuses (20.6%) (95%CI: 11.1–30.2%),
and HCM was confirmed in 54% of the fetuses (95%CI: 41.3–65.1%). Only 2 (5.88%) of
the 34 fetuses with HCM exhibited alterations in the left ventricular wall, but none
of them exhibited alterations in the septum.
The FAC was normal (between the 10th and the 75th percentiles) in most fetuses (73.01%),
and it increased in 26.99% of them. There were no cases with a FAC below the 10th
percentile. Half of fetuses with normal abdominal circumferences exhibited HCM. The
majority of the fetuses (64.7%) with a FAC greater than the 75th percentile exhibited
HCM. Fetal data are shown in [Table 2].
Table 2
Fetal data on interventricular septum, left ventricular wall, and abdominal circumference
measurements*
|
Fetal data
|
N
|
%
|
|
Interventricular septum
|
|
< 1 SD
|
7
|
11.1
|
|
SD between 1 and 2
|
24
|
38.0
|
|
> 2 SD
|
32
|
50.8
|
|
Total
|
63
|
100.0
|
|
LV wall
|
|
> 2 SD
|
13
|
20.6
|
|
Fetal AC
|
|
Normal
|
46
|
73.0
|
|
Increased
|
17
|
27.0
|
|
Total
|
63
|
100.0
|
Abbreviations: AC, abdominal circumference; LV, left ventricular; SD, standard deviation.
Note: *Means and standard deviations, absolute numbers and percentages.
Discussion
Cardiomyopathies represent 8–11% of the cardiovascular abnormalities diagnosed during
pregnancy. After birth, cardiomyopathies are diagnosed in only 3% of newborns with
cardiovascular diseases, and diastolic dysfunction is associated with a higher risk
of postnatal mortality.[18]
In a previous study that used septal and left ventricular wall thickness measures
at birth as reference, it was reported that these values were increased in 69% of
the fetuses of mothers with GDM;[17] this value is slightly above the CI obtained in our study. In the present study,
we found that 54% (95%CI: 41.3–65.1%) of the fetuses evaluated before the treatment
for GDM were positive for HCM.
Hypertrophic cardiomyopathy affects the right ventricle and the posterior left ventricular
wall, but the septal hypertrophy is more evident because of the large number of insulin
receptors in the septum of the heart.[9]
[19]
[20] In our study, we observed that only 2 of the 34 fetuses with HCM exhibited alterations
in the left ventricular wall, but none of them exhibited alterations in the septum.
The fetuses of mothers with GDM are at a risk of developing HCM even when the mothers
exhibit good capillary glycemic control.[16]
[21] Other authors have also not found a relationship between the glycemic control detected
using maternal glycosylated hemoglobin and the presence of HCM.[22]
[23] These results show the limited existing knowledge about this disease.
Hyperinsulinemia is related to fetal macrosomia, and an increased FAC is directly
related to higher fetal weight, and fetal weight is related to HCM. Moreover, the
rate of HCM incidence in newborns that are large for their gestational age (LGA) can
reach 38%.[24] Considering that fetuses with FAC above the 75th percentile tend to be LGA, we found
a higher percentage of HCM (64.7%) in these fetuses.
In our study, the fetuses were evaluated before initiating the treatment for GDM.
Therefore, we do not know the effect of this treatment on HCM; a potential reduction
would justify an incidence decline from 54% to 20%[2] after delivery.
Hypertrophic cardiomyopathy was also observed in 50% of the fetuses with normal FAC,
which reflects the occurrence of interventricular septum alterations prior to FAC
alterations. This result also suggests the diagnosis of poor maternal glycemic control
even before FAC alterations.
Information on the postnatal consequences of HCM is insufficient in the current literature.[21] There are evidences for the effects of diabetes on the cardiac function of adult
patients.[25] The abnormalities and injuries studied in adults are not easy to assess in fetuses
because there is no evidence of the effects after the short period of exposure during
pregnancy.[26] Furthermore, a large majority of newborns is asymptomatic at birth, and if hypertrophy
is present, it spontaneously regresses in a few months.[18]
Routine referral to fetal echocardiography for pregnant women with a history of diabetes
mellitus has already been established according to some authors;[24] the severity of the disease has also been established in this group.[4] Some authors recommend that all pregnant women with GDM be submitted to fetal echocardiography
until a group with a higher risk for HCM is identified.[11]
Because of the small sample size of the present study, several inferences could not
be drawn from the results; however, the high prevalence and early occurrence of HCM
in this population indicate that this is one of the first effects of maternal diabetes
on fetuses. This observation justifies further assessments of this disease, including
its onset, manifestations, behavior during maternal treatment, and the perinatal and
adult repercussions.
