INTRODUCTION
The prevalence of obesity and metabolic diseases such as diabetes is increasing in the general population [1]. Gestational diabetes mellitus (GDM) is also increasing with the risk of developing pregestational diabetes mellitus (DM) affected by obesity in pregnant women [2,3]. GDM is defined as glucose intolerance or the diagnosis of diabetes for the first time during pregnancy [4]. Despite differences in ethnicity, diagnostic guidelines, and methods, approximately 10% of pregnant women develop GDM [5]. The well-known congenital anomalies include cardiac, neural, and urogenital anomalies. GDM also causes hypoglycemia, macrosomia, and birth injuries, including shoulder dystocia and brachial plexus injury [6,7].
In Korea, the prevalence of GDM is increasing and, as a result, the morbidity and mortality of neonates have changed. Given this background, the present study aimed to (1) examine the characteristics of pregestational DM and GDM in mothers; (2) compare congenital anomalies observed in babies from the two groups of mothers; and (3) explore the risk of cardiac anomalies in the two groups.
MATERIALS AND METHODS
1. Study population
This retrospective study used medical records from Bucheon St. Mary's Hospital between January 2013 and July 2021. The main inclusion criterion was the birth of infants to women with DM in this hospital. The control group included healthy infants, including sick babies, born at this hospital. We excluded infants with chromosomal anomalies, major congenital anomalies unrelated to glucose intolerance, and those born to mothers with non-typable DM.
2. Data collection
Due to some twin pregnancies, there were differences in the number of mothers and babies. The maternal characteristics examined included age, weight, body mass index (BMI; before pregnancy and at delivery), delivery type, in vitro fertilization, family history of DM, ethnicity, preeclampsia, glycated hemoglobin (HbA1c) in the third trimester, and DM treatment during pregnancy. A normal HbA1c range was defined as maintaining an HbA1c level ≤6.5% during pregnancy. Pregestational DM was defined as type 1 or 2 DM diagnosed before pregnancy. GDM was defined as DM diagnosed during pregnancy that was treated with diet or insulin therapy.
The neonatal characteristics examined included gestational age, Apgar scores at 1 and 5 minutes, birth weight, and sex. Intrauterine growth restriction was defined using the Delphi procedure as an estimated fetal weight or abdominal circumference less than the 3rd percentile of the gestational age during pregnancy provided by the obstetrician [8]. We included symmetric and asymmetric intrauterine growth restriction in the inclusion criteria.
Fetal distress and respiratory distress syndrome were also documented. Neonates diagnosed with respiratory distress syndrome were treated with a lung surfactant (Curosurf, Chiesi Farmaceutici). Respiratory distress required respiratory support such as O2 therapy or ventilatory care. Hyperbilirubinemia is defined as a sufficiently high bilirubin level that is required for phototherapy [9]. We also documented congenital anomalies such as congenital heart disease, neural tube defects, urogenital anomalies, gastrointestinal anomalies (gastroschisis), and limb anomalies. Echocardiography was performed in neonates born to pregestational DM mothers with a heart murmur due to maternal condition (e.g., systemic lupus erythematosus) and abnormalities in fetal sonography. Due to transfer to another hospital, loss to follow-up, or refusal of the parent, not all neonates underwent echocardiography in the pregestational group. Congenital heart disease is usually diagnosed at birth and is occasionally diagnosed using fetal sonography. We excluded patent foramen ovale, untreated patent ductus arteriosus (PDA), and peripheral pulmonary stenosis as congenital heart diseases.
3. Statistical analysis
Continuous variables are presented as mean±standard deviation, and categorical variables as values and percentages. Descriptive analyses were performed using the chi-square (χ2) test for categorical variables and analysis of variance for continuous variables. All statistical analyses, including propensity score matching, were conducted using SPSS version 28 software (IBM Co.). Statistical significance was defined as a twotailed P-value <0.05.
RESULTS
A total of 1,983 infants were born in the hospital during the study period, with 335 (16.7%) neonates from mothers with DM. Four infants were excluded: one with a chromosomal anomaly, one with CHARGE (Coloboma of the eye, Heart defect, Atresia of the choanae, Retardation of growth and development, Genital abnormalities, Ear anomalies, including deafness) syndrome, and two with hydrocephalus requiring a ventriculoperitoneal shunt.
The final sample of mothers with DM was 312, comprising 13 with type 1 DM, 58 with type 2 DM, 71 with pregestational DM, and 241 with GDM. Body weight and BMI were high in mothers with pregestational DM at delivery (P<0.001) (Table 1). The mean BMI was 28.8 kg/m2 in the GDM group and 32.2 kg/m2 in the pregestational DM group. The rate of preeclampsia in the DM group was higher than that in the control group, with 22.5% of the pregestational DM group diagnosed with preeclampsia. In contrast, 13.7% of the mothers with GDM had preeclampsia, and no significant difference was observed between the pregestational DM and GDM groups (P=0.072). The highest HbA1c level in mothers with pregestational DM was 7.1±1.6, which was higher than the value of 5.8±0.7 in mothers with GDM (P<0.001). The vast majority (97.2%) of mothers in the overt DM group were administered insulin therapy to control their blood glucose levels during pregnancy, compared with only 41.1% in the GDM group (P<0.001).
A total of 335 infants were included in the study: 76 were born to mothers with pregestational DM and 259 to mothers with GDM. The rate of preterm births was 25% in the overt DM group, which was significantly lower than that in the GDM group (38.6%, P=0.029) (Table 2). The rate of preterm births was higher in the DM group than in the control group (35.5% vs. 11.3%, P<0.001) (Table 2). The rate of hyperbilirubinemia was higher in the DM group than in the control group (20.6%, P<0.001) (Table 2). Furthermore, the cardiac anomaly rate was higher in the pregestational DM group than in the GDM and control groups.
The most commonly observed cardiac anomalies in this study included atrial septal defect (ASD), ventricular septal defect, hemodynamically significant PDA, and a prominent eustachian valve (Table 3). Figure 1 shows the 105 infants who underwent echocardiography at our hospital. The rate of neonates who underwent echocardiography in the pregestational DM, GDM, and control groups was 59.2%, 9.6%, and 2.1%, respectively. Fifty-five infants had a congenital heart disease. In the control, pregestational DM, and GDM groups, 23 (65.7%), 17 (37.7%), and 15 (60%) were diagnosed with congenital heart diseases. Other anomalies observed were hydronephrosis and hydrocele in five babies from mothers in the overt DM group, and multicystic dysplastic kidney, micropenis, and brachial plexus palsy in 13 babies from mothers in the GDM group.
We performed multivariate logistic regression analysis on 105 infants who underwent echocardiography. However, no significant risk factors for congenital heart disease were identified (Table 4).
DISCUSSION
In this study, we explored the characteristics of neonates born to mothers with DM. HbA1c levels, BMI, and body weight were higher in mothers with pregestational DM than in those with GDM. Furthermore, the premature birth rate was higher in the GDM group than in the pregestational DM group, and the results of multivariate logistic regression analysis revealed that DM and preterm delivery were risk factors for cardiac anomalies.
Globally, approximately 10% of pregnant women develop DM before and during pregnancy, an incidence similar to that observed in this study, and the rate of DM in pregnant women is increasing [10].
A population-based record review conducted in Sweden (2009 to 2012) [11] examined maternal characteristics in groups of mothers with pregestational DM and GDM, and without DM. That study reported that pregestational BMI was lower in type 1 DM than in type 2 DM, and that the BMI of the DM group was higher than that of the group without DM; however, the pregestational DM and GDM groups were not significantly different. Although the types of DM were not compared in the present study, the BMI of the DM group was significantly higher than that of the control group. Additionally, the BMI of the pregestational DM group was higher than that of the GDM group.
Preeclampsia, another maternal condition, is associated with maternal DM5, [12]. Van Zyl and Levitt [13] examined pregnancy outcomes in mothers with DM and reported that chronic hypertension was higher in pregestational DM than in GDM and that preeclampsia tended to be higher in pregestational DM. Similarly, in our study, the preeclampsia rate was higher in the DM group than in the control group; however, no significant difference was found between the pregestational DM and GDM groups. In addition, no significant differences in the risk factors of cardiac anomalies were found based on the results of multivariate analysis in the present study. These differing results may be due to the different diagnostic criteria and methods used to diagnose chronic hypertension and preeclampsia.
HbA1c is a predictive value for glycemic control during the last 3 months of pregnancy [14]. Although no significant differences in HbA1c levels were found in the present study, univariate analysis showed that HbA1c levels in the third trimester and the highest HbA1c levels were high in the pregestational DM group (P<0.001). In this regard, an earlier study [15] suggested that HbA1c levels at 29 to 30 weeks of gestation ≥6.1% and >5.6% were associated with adverse pregnancy outcomes among pregnant women with preexisting DM, including preterm delivery, neonatal hypoglycemia, increased cesarean section rate, large for gestational age, and neonatal respiratory distress. El-Ganzoury et al. [16] investigated whether poor glycemic control (HbA1c ≥7.0%) was associated with hypertrophic cardiomyopathy, a well-known cardiac complication in neonates. Similar to our study, Oben et al. [17] suggested an association between HbA1c levels and perinatal outcomes in mothers with GDM. HbA1c was not an independent factor affecting perinatal outcomes but was associated with increasing prematurity.
In pregestational DM, high glucose levels during the first trimester of pregnancy may affect organogenesis. Poor glycemic control can cause congenital anomalies in the fetus. In contrast, the risk of congenital anomalies is lower in GDM diagnosed at 24 to 28 weeks of pregnancy than in pregestational DM, because most organogenesis occurs during the first trimester [18,19]. A nationwide population-based study in the United States reported that both pregestational DM and GDM are associated with congenital anomalies, including cyanotic congenital heart disease, neural tube defects, urogenital anomalies (e.g., hypospadias and hydronephrosis), gastrointestinal anomalies (e.g., gastroschisis), and limb anomalies [20]. Another study in New York reported that birth defects were more common in the babies from mothers with DM than in those from mothers without DM. In addition, a higher prevalence of cleft lip and palate, cleft palate alone, hypospadias, and limb reduction defects was observed in the pregestational DM group than in the GDM group [21]. This result was similar to the findings of cardiac and other anomalies in the present study. In this study, the rate of anomalies was higher in the DM group than in the control group. In addition to congenital heart disease, the anomalies included hydronephrosis, multicystic dysplastic kidneys, and duplicated thumbs.
Previous studies have shown that maternal DM is associated with congenital heart anomalies [18,22-25]. Research in Canada [24] has suggested that the rate of congenital heart disease in babies of mothers with pregestational DM is 4.7 to 8 times higher than that in babies of nondiabetic mothers. Chen et al. [18] studied the phenotypes of congenital heart diseases associated with GDM. pregestational DM is a risk factor for congenital heart disease, and the most common phenotype is outflow tract defects. Among them, arterioventricular septal defects, tricuspid valve atresia, and tetralogy of Fallot were observed in the study. In the present study, the most common phenotype observed was ASD. Although ASD or VSD was usually closed during follow-up, serial echocardiography was required several times. Therefore, we included ASD, VSD, and hemodynamic PDA as congenital heart diseases. The rate of cardiac anomalies in the pregestational DM group was higher in our study than in other studies, which may be due to the small population size and/or low severity of this phenotype. From the study hospital, babies were transferred to a tertiary hospital for the treatment of congenital heart disease if an intervention was required.
pregestational DM is a predictive factor of cardiac anomalies. Several studies have shown that pregestational DM is a risk factor of cardiac anomalies [18,20,23,26]. However, in our study, no significant factors were found to increase the risk of congenital heart disease. Because of the low severity of congenital heart disease and the small population size for which echocardiography was performed, there seems to be a different result in multivariate logistic regression analysis.
This study had some limitations. First, this was a retrospective study that used medical records. Not all infants underwent laboratory evaluations or echocardiography. Second, the study population was small, and as the study hospital was a regional secondary hospital, there could be bias in our study population. Third, some data were not available for infants born to mothers without DM. To further identify anomalies associated with babies born to mothers with DM and to analyze the associated risk factors, a large prospective cohort study is needed.
In conclusion, pregnant mothers with DM exhibit specific characteristics. In pregnant women, DM is associated with congenital anomalies, including cardiac anomalies, in neonates. Therefore, the appropriate management of mothers with DM is important for the prognosis of their neonates.
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