The Diabetes In Pregnancy Dilemma 2nd ed. Oded Langer

Chapter 30. Epidemiology and Prenatal Diagnosis of Congenital Malformations in Diabetic Embryopathy

Zhiyong Zhao, PhD

E. Albert Reece, MD, PhD, MBA

Practice doesn’t make perfect Practice reduces imperfection

Key Points

 Pregestational diabetes is a risk factor for birth defects and perinatal mortality.

 With rapid growth of the diabetic population, the number of the infants born with birth defects is projected to increase.

 Maternal glycemic control and adequate perinatal care can reduce the infant mortality rate. However, the rate of birth defects in infants of women with diabetes remains higher than that in the general population.

 The poor outcome of diabetic pregnancies in developing countries may be due to inadequate clinical care rather than racial background.

 Ultrasound is a reliable and commonly used diagnostic tool for detection of fetal abnormalities in diabetic pregnancies. Molecular biomarkers can be used as supplementary indicators in diagnosis.

INTRODUCTION

Although diabetes mellitus dates back to the beginning of humanity, encompassing centuries and various civilizations, the association between maternal diabetes and birth defects and perinatal mortality was not determined until the late 19th century.12 Aggressive glycemic control and intensive perinatal care of pregnant women with diabetes have dramatically reduced the rate of fetal mortality. However, the rate of birth defects remains as high as 10%.3-5 Making matters worse, the incidence of diabetes among women of childbearing age has increased over the past four decades, with no signs of leveling off or declining.6 According to the recent report by the Centers for Disease Control and Prevention, nearly 26 million individuals at 20 years of age or older were diagnosed having diabetes in the United States, including 13 million women.7 These data suggest that approximately 8000 babies will be born each year in the United States with maternal diabetes-associated congenital malformations.Moreover, rapid increases in the number of diabetic individuals in developing countries have become a global concern in public health.8,9

Diabetes mellitus in pregnant women can occur prior to or during gestation. The former is referred to as pregestational (or preexisting) diabetes mellitus.10,11 The latter is known as gestational diabetes, which may be a direct consequence of the altered maternal metabolism due to the changing hormonal milieu.12,13 Pregestational diabetes can affect embryos at early developmental stages, and, thus, is more likely to result in higher perinatal mortality and structural malformation rates (Table 30-1).10,14,15 It is estimated that the frequency of pregestational diabetes complicating pregnancies in the United States is 2%-5%.16,17 Gestational diabetes, on the other hand, often is associated with newborn macroso- mia and preterm birth (Table 30-1).12 The incidence of gestational diabetes in the United States is nearly 5% of all pregnancies.16,17

Under maternal hyperglycemic conditions, embryos and fetuses are exposed to highly stressful environments generated by abnormal maternal metabolism. Although increased ketone bodies18 and triglycerides19 have been found to be associated with embryonic malformations, a strong correlation between hyperglycemia and high rates of birth defects has been demonstrated.20-22 It is generally believed that hyperglycemia is the major teratogenic factor for birth defects. Therefore, early detection of diabetes in pregnant women is important for reducing fetal complications. In clinics, the level of glycosylated hemoglobin A (HbA1c), which is expressed as percentage of total hemoglobin A, is used as an integrated retrospective index of glycemic status in pregnant women.23,24 The introduction of HbA1c has permitted investigators to monitor and confirm the presence of hyperglycemia during very early stages of gestation.24,25 The oral glucose tolerance test also is useful for screening gestational diabetic status in the population.24,25

TABLE 30-1 Fetal Malformations in Diabetic Pregnancy

Gestation Stage

Abnormality

Preimplantation

 

Cell death

 

Failure in implantation

First trimester

 

Severe structural malformations

 

Growth retardation

 

Early spontaneous abortion

Second trimester

 

Mild structural malformations

 

Growth retardation

 

Polyhydramnios

 

Erythremia

 

Spontaneous abortion

Third trimester

 

Macrosomia

 

Respiratory stress

 

Intrauterine demise

EPIDEMIOLOGY

Prior to widespread use of insulin to manage pregnant women’s glucose levels, the maternal diabetes-associated perinatal mortality rate was as high as 70%, and maternal mortality reached 30%- 40%.26,27 After the introduction of insulin, maternal mortality decreased dramatically, while perinatal mortality reduced slowly and has reached the current rate of 4%-13%.28-34 The decline of maternal and perinatal mortality is believed to be the result of insulin administration along with clinical care and aggressive perinatal and neonatal management.20,29,35-37 Unfortunately, the rate of developmental defects has not changed, and the reasons for this are still not completely understood.

During the past decades, efforts have been made to investigate the epidemiology of birth defects of infants of diabetic mothers in developed and developing counties around the globe. In Europe, a number of studies conducted in the early 20th century have shown that birth defect rates in infants of diabetic mothers were 10%—18%. The studies show declines in fetal malformation rate to 8%-9%, and include a number of large scale surveys by the Academic Hospital Groningen and Isala Clinics of the Netherlands,38 a German group,39 groups in Great Briton,40,41 the Gestation and Diabetes in France Study Group,42 the Spanish Collaborative Study of Congenital Malformations,43,44 and the Centers for Disease Control and Prevention.45

Retrospective examinations of clinical records in Australia and New Zealand show higher perinatal mortality rates in the offspring born to mothers with preexisting diabetes mellitus (5.4%- 7.5%) than that of infants born to women with gestational diabetes (1.4%-1.6%).46-48 It is noted that the perinatal mortality declined to 3.9% after the 1980s, due to successful control of hyperglycemia in the women. However, the prevalence of congenital malformations has remained as high as 9%—13%.46-48

In North America, perinatal mortality rate and fetal malformation rate were also as high as 17% in the early 20th cen- tury,31,45,49,50 but declined markedly to 6%-7% by the latter half of the 20th century, according to large scale epidemiological studies, including the U.S. Centers for Disease Control and Prevention Study (1940-1988),45 Atlanta Birth Defects Case-Control Study (1968-1980),51 Baltimore-Washington Infant Study,52 Parkland Hospital Study in Dallas, Texas (1991-2000),53 and National Birth Defects Prevention Study (1997-2003).5

In Africa and Asia, available data have shown various types of adverse outcomes of diabetic pregnancies with high perinatal mortality of up to 12%-20% in the last century.54-63 Because many deliveries take place in nonclinical settings where no medical records are kept, it is impossible to obtain reliable birth defect rates from some countries. However, a study conducted in Singapore, one of the developed Asian countries, reported a 15.5% malformation rate in infants of diabetic mothers.64

The poorer outcomes of diabetic pregnancies in developing countries may be due to reduced availability and substandard quality of perinatal care.64 Whether there also is an underlying difference in the prevalence of diabetes among racial/ethnic groups in these countries is still not clear. A number of reports have shown a high prevalence of diabetes and poor pregnancy outcomes in Asian and African women, compared with Caucasian women, even in the developed countries.65-69 However, other studies found no difference in pregnancy outcomes between Caucasian and Indo-Asian women.70

MECHANISMS OF DIABETIC EMBRYOPATHY

Developmental malformations in infants of diabetic mothers exhibit a great diversity, ranging from congenital structural defects, to functional defects, to lower birth weight, to macrosomia.14,30,71,72 Because maternal diabetes can adversely affect almost every aspect of embryonic development and maternal-fetal interaction, the frequency and severity of abnormalities appear to be correlated with the gestational stages at which the embryo or fetus begins to be exposed to hyperglycemia (Table 30-1).73-75The first trimester is the critical period of embryonic development, in which organ formation undergoes morphogenesis.73,78 In the first trimester, maternal hyperglycemia can cause congenital anomalies, growth retardation, and spontaneous abortion.20,76,77 In the second and third trimesters, maternal hyperglycemia usually leads to functional defects, fetal hyperinsulinemia, fetal respiratory stress, and fetal excessive growth.74,75

Structural abnormalities caused by maternal diabetes can occur in many organ systems. The mechanisms by which maternal hyperglycemia induces embryonic malformations have not been fully understood. Studies using animal models have shown that hyperglycemia affects various cells and tissues in the embryo.78-80 The extraembryonic tissue (yolk sac) plays an important role in early embryogenesis by transporting nutrients and exchanging gases.81 The yolk sac functions as an early route of nutrition for the embryo, characterized by Reece et al. (Figure 30-1).82 In diabetic embryopathy, the extraembryonic tissue’s functions are severely impaired by maternal hyperglycemia, manifested by shorter microvilli, swollen mitochondria, reduced number of rough endoplasmic reticulum (ER), and lipid droplets in the endothelial cells.83,84

The most common and severe abnormalities in diabetic embryopathy are seen in the central nervous and cardiovascular systems (CNS and CVS).5,71 The development of the CNS begins with formation of the neural tube, a process known as neurulation. On the dorsal region of the embryo, the neural plates differentiate from the ectoderm and develop dorsal-laterally into the neural folds.85,86 The neural folds further grow, bend, and eventually fuse at the midline along the anterior-posterior body axis to form the neural tube (Figure 30-2).87 Most of the anomalies in the CNS result from abnormal development of the embryonic neural tube and are known as neural tube defects (NTDs).11,12,14

Abnormalities in the CVS are associated with aberrant development of various processes, including cardiac chamber formation, myocardial development, cardiac septation, and valve formation.88-91 Cardiac septal defects are the most common heart abnormalities in diabetic embryopathy, and are associated with the endocardial cushions in the atrioventricular junction and outflow tract. The endocardial cushions are bulbous structures composed of an endocardial (endothelial) cell layer and acellular cardiac jelly within the heart tube.92 The endocardial cells differentiate into mesenchymal cells, a process referred to as epithelial-mesenchymal transformation, and migrate into the cardiac jelly to promote the endocardial cushions growing toward each other and eventually fusing together to form continuous septa (Figure 30-3).92,93

Associated with the dysmorphogenesis of the embryonic structures, programmed cell death (apoptosis) and cell proliferation (mitosis)are increasedanddecreased,respectively.7980889094 Cellmigration, another important cellular activity in organogenesis, has also been shown to be suppressed by maternal hyperglycemia. This includes the migration of neural crest cells that contribute the development of the craniofacial structures and outflow segment of the heart,95-97 and the migration of endocardial cells, which is required for the development of the endocardial cushions and cardiac septation.89,98

The aberrant cellular activities seen in diabetic embryopathy are the consequences of disrupted intracellular signaling. Under hyperglycemic conditions, glucose influx into the embryonic cells perturbs normal glucose metabolism, producing metabolites that change intracellular conditions and modify proteins, such as glycosylation, to alter their activity.94,99 These abnormal intracellular changes have a profound impact on expression of genes that encode proteins which control cellular activity and embryonic morphogenesis.100,101

Maternal diabetes alters the molecular activities in embryonic cells. Although some of the molecular pathways and intermediates have been widely studied, while others have yet to be confirmed, Figure 30-4 depicts a very plausible hypothetical model of the underlying etiological mechanisms of diabetes-induced birth defects. Maternal hyperglycemia stimulates the expression of inducible nitric oxide (NO) synthase (iNOS), the only member of the NOS family (iNOS, neuronal NOS, and endothelial NOS) that sensitively responds to environmental stimulations.102 Upregulation of iNOS leads to overproduction of NO, which alters protein activity via cysteine nitrosylation and tyrosine nitration, generating so-called nitrosative stress.103,104

Hyperglycemia disturbs the function of organelles such as the ER and mitochondria.105,106 Dysfunction of the ER compromises the folding and processing of newly synthesized polypeptides, causing retention of proteins in the ER lumen and resultant ER stress.107 Under stress conditions, cells activate a number of molecular signaling pathways, known collectively as the unfolded protein response (UPR), which express chaperone proteins to resolve the protein folding crisis, modify proteins to block translation, inhibit cell division, and trigger apoptosis to eliminate the abnormal cells.108 Hyperglycemia also disrupts the functions of mitochondria, including the generation of adenosine triphosphate via the electron transfer chain.109 Disruption of electron transfer generates high levels of reactive oxygen species (ROS).110 With the depletion of endogenous antioxidants and downregulation of antioxidative enzymes, such as superoxide dismutases, the imbalance of ROS levels and antioxidative buffering generates oxidative stress (Figure 30-4).111 Interaction between these two pathways remains to be delineated.

Oxidative and ER stress alter gene expression, protein activity, and intracellular signal transduction, leading to inhibited cell mitosis and promoted apoptosis. Studies in animal models of diabetic pregnancies have revealed that members of the protein kinase C and mitogen-activated protein kinase families are involved in hyperglycemia-induced apoptosis.79,112 These kinases regulate apoptotic factors in the Bcl-2 and caspase families, which have been shown to play a role in diabetic embryopathy.113,114

Understanding the mechanisms underlying embryonic malformations in diabetic pregnancies sheds light on the development of effective interventions to prevent birth defects in infants of diabetic mothers. For example, oral treatment with an iNOS inhibitor can decrease NTD rate in the embryos of diabetic ani- mals.115 Treatments with antioxidants, such as vitamins E and C, A-acetylcysteine, and lipoic acid, can reduce NTD rates in animal models and in animal embryos cultured in high concentrations of glucose.79,112 It is highly conceivable that, with further basic research to understand the mechanisms of diabetic embryopathy, effective interventions will be developed to protect embryos from maternal hyperglycemic insult within the near term.

ANOMALIES AND DIAGNOSIS

Fetal Growth

Lower birth weight, premature birth, and gross hypoplasia (such as caudal regression) are frequently seen in the newborn infants of mothers with pregestational diabetes.116 Macrosomia is often associated with gestational diabetes mellitus.117,118 Ultrasound has been widely used to monitor fetal development and detect structural abnormalities,119 and is proven to be an important approach in diagnosing maternal diabetes-associated fetal anomalies and assessing fetal growth.120-122

Because fetal growth is one of the most common developmental aspects affected by maternal diabetes mellitus, early detection of abnormal growth benefits the birth outcomes of diabetic pregnancies. Measuring the crown-rump length, the long axis of the embryo, is the most accurate method of fetal growth assessment and estimating gestational age in the early period of preg- nancy.123,124 However, after 12 weeks of gestation, this measurement becomes less accurate because of variable degrees of fetal flexion.125 In the second trimester, measurements of the biparietal diameter (BPD) are reasonably accurate (±7-10 days) for gestational age estimate.125-127 In addition to the BPD the occipitofrontal diameter, the distance from the mid echogenic plane of the occipital bone to the mid echogenic plane of the frontal bone, should also be measured.128,129 By knowing the biparietal and occipitofrontal diameters, the head circumference can be calculated.128,129

Other fetal growth measurements include transverse cerebellar diameter (TCD), abdominal circumference (AC), and fetal long bones. The TCD has been used to evaluate the growth of the fetal head and body.128-130 Because the posterior fossa is not affected by external pressure, the measurements of TCD are independent of the fetal head and provide more precise and accurate information about fetal growth than other measurements of the fetal head.128-130

The AC can be used to predict birth weight and fetal growth in diabetic pregnancy.131,132 Because the fetal liver is the organ most affected by maternal diabetes, the level of the fetal liver should be chosen as the plane for the AC measurement. Gestational age and fetal growth can also be estimated from the measurements of the fetal long bones such as the femur, humerus, tibia, and ulba.122,133,134

Macrosomia is the most frequent phenotype of gestational diabetes, ranging from 20%-32%. It is defined as a fetal weight in excess of 4000 g or a birth weight above the 90th percentile for gestational age.135,136 Prenatal diagnosis of macrosomia utilizes BPD versus AC, and head versus chest dimensions.118,120

Central Nervous System

The most common fetal abnormalities in diabetic embryopathy are present in the CNS (Table 30-2).14,71,78,80 These malformations can be reproduced in diabetic rodent models, allowing experimentation to delineate the underlying mechanisms (Figure 30-5).79,80,94,112

TABLE 30-2 Major NTDs in Diabetic Embryopathy

Region

Defect

Brain

Anencephaly

 

Excencephaly

 

Arhinencephaly

 

Holoprosencephaly

 

Microcephaly

Spinal cord

Spina bifida

Anencephaly

Anencephaly is an anomaly in the forebrain, which occurs when the neural tube fails to close completely at the cranial pole during fusion of the neural folds.137,138 The cerebral hemispheres are usually absent, whereas the brain stem and portions of the midbrain are present (Figure 30-6). In association with this forebrain defect, the cranial vault is absent, although portions of cranial bones may be present.137,139 Fetuses with anencephaly also can have spina bifida, cleft lip or palate, clubfoot, omphalocele, and polyhydram- nios.137-139 Prenatal diagnosis of anencephaly is possible in the first trimester, but is usually not obvious until 12 weeks of gestation. The phenotype can be recognized when the fetal brain appears flat in ultrasound images.125,140 In the second trimester, anencephaly can be recognized by the poorly formed cranial bones and the symmetric absence of the calvarium.125,137,140

Holoprosencephaly

Holoprosencephaly is a relatively rare group of brain defects. It is the result of incomplete separation of the cerebral hemispheres.141 Based on the degree of hemispheric nonseparation, holoprosencephaly is categorized into alobar, semilobar, and lobar types, with alobar being the most severe malformation.141,142

Holoprosencephaly can be diagnosed as early as 14 weeks’ gestation, although diagnosis at the 20th week anomaly scan is more common.143-145 Alobar and semilobar holoprosencephaly can be detected by the complete or partial absence of the midline echo within the fetal head.144,146 Because of the defect in cleavage of the two hemispheres, the anterior cerebral artery runs along the internal side of the frontal bone. The sign of a “snake under the skull” in the sagittal view of the brain in a sonograph is commonly used as a marker for all the three types of holoprosencephaly.146,147

Microcephaly

When the head circumference of the fetus is below the third to fifth percentile, the fetus can be considered as having a microcephalic defect.148 However, this standard does not apply to all children falling in this range because a number of factors can contribute to smaller brain sizes in fetuses who may be normal such as intrauterine growth restriction and irregular growth during gestation.140 In severe cases of irregular growth, the head circumference can be more than three standard deviations less than the mean.140 The diagnosis can be suspected in utero when the BPD is discrepant by more than five weeks from the menstrual dates.128 It is necessary to measure the head circumference in relation to other biometric parameters such as fetal bone length and head/body ratio. Because microcephaly is difficult to definitively diagnose using ultrasound, magnetic resonance imaging may be used to confirm this condition.140

Spina Bifida

Spina bifida, characterized as a failure in neural tube closure in the dorsal midline, occurs at a high frequency among fetuses of women with diabetes.31,137 In the coronal plane, the fetal spinal column appears as three parallel lines, with the central line representing the vertebrae.149-151 In the transverse plane, the neural canal appears as a closed circle. In many cases of spina bifida, there is “splaying” of the laminae, which creates a picture of a V-shaped spinal configuration on transverse scan or of a longitudinal scan in the area of the defect. A detailed diagnosis of the spine can prove a formidable task when the fetus is very active or in a less than suitable position.150,152

Peripheral Nervous System

Maternal diabetes also affects the development of the peripheral nervous system.80,153 For example, the cranial ganglia fail to fully develop in fetuses of diabetic animals.95,154 This may be due to impaired migration of the neural crest cells,153,155 which are vulnerable to hyperglycemic insult.95,155

Functional Abnormalities

Functional defects in the infants of diabetic mothers have been described and are correlated with the abnormal development of the nervous systems. Defects include marked delay of in utero movement of fetuses, compared with nondiabetic pregnancies.156 Children of diabetic mothers can have abnormal patterns in movement and sleep cycle, as well as memory deficiencies.157-159 A wide spectrum of neurologic and psychological defects, including cerebral handicap, mental retardation, reading disability, speech disturbance, behavior disturbance, psychosis, and deafness, have been found to be associated with maternal diabetes mellitus.160-162 Some of these problems may be caused by birth trauma because infant macrosomia and shoulder dystocia can lead to damage to the head and neck or hypoxic necrosis.163,164 Nevertheless, a strong correlation has been established between some of these defects and maternal hyperglycemic insults to the fetuses.

Cardiovascular System

Cardiovascular defects in fetuses of diabetic mothers are present in all the cardiac structures, including the atria, ventricles, septa, outflow tracts, and valves (Table 30-3).5,71,72,116 Most of the abnormalities have been recapitulated in animal models (Figure 30-7).88,97,153,165

Formation of the cardiac defects largely occurs in embryos exposed to hyperglycemia in the early first trimester (>7 weeks of gestation),73 which has also been demonstrated experimentally in an animal model.89 When hyperglycemia occurs during the late gestational period, after the cardiovascular structures have formed, there is an increased risk of myocardial hypertrophy.166 The myocardial hypertrophy seen in the infants of diabetic mothers includes larger heart, thickened myocardium, thickened interventricular wall, and asymmetric hypertrophic valves.167,168

TABLE 30-3 Major CVS Defects in Diabetic Embryopathy

Cardiac Structure

Defect

Ventricles

Hypoplastic left heart

Hypoplastic right heart

Septa

Atrial septal defects

Ventricular septal defects

Atrioventricular septal defects

Outflow tracts

Transposition of the great arteries Double-outlet right ventricle Coarctation of the aorta Aortic stenosis Truncus arteriosus

Valves

Pulmonic valve atresia Pulmonary valve stenosis

Complex defects

Tetralogy of Fallot

In a normal fetal heart, left ventricular fractional and circumferential shortening is greater than that of the right ventricle. However, the fetuses of diabetic mothers with hypertrophic heart have decreased biventricular myocardial fractional shortening, smaller left ventricular stroke volume, and diminished left ventricular output (Figure 30-8).169,170 The hypertrophic phenotype is believed to be a result of fetal hyperinsulinemia.171

Because abnormalities of the cardiovascular system involve structural and functional defects, fetal echocardiography is the primary diagnostic tool used to assess fetal cardiac structure.172,173 With this technology, accurate assessment of cardiovascular structure can be obtained with two-dimensional real-time analysis. Pulse-time and continuous-wave Doppler can be used to evaluate intra- and extracardiac flow qualitatively and quantitatively. A complete fetal echocardiographic examination should incorporate the following standard views: (1) the four-chamber view; (2) the left ventricular long-axis view, with visualization of the aortic outflow tract; (3) the short-axis view, with visualization the pulmonary outflow tract and ductus arteriosus; and (4) the longitudinal view of the aortic arch. These views will provide details of the intracardiac anatomy and evaluation of the conotruncus and left ventricular outflow tract. The scan should also include an evaluation of the relationship of the great arteries to one another. A normal crossing relationship virtually excludes the possibility of transposition of the great arteries.125

The echocardiographic features of the fetus with diabetic hypertrophic cardiomyopathy include restricted ventricular filling, dynamic left or right ventricular outflow tract obstruction, and global myocardial hypertrophy. Some of or all these findings may be present in any individual fetus and to varying degrees.168,174 M-mode and real-time two-dimensional echocardiography can be used to measure the ventricular septum. The normal thickness of the septum should be less than 6 mm during the third trimester.175 The measurements should be taken just below the atrioventricular valves from the long- axis view of the left ventricle. During systole, the anterior leaflet of the mitral valve may be seen to be closely opposed to the interventricular septum, a phenomenon known as systolic anterior motion.

Color flow Doppler mapping, which can assess functional stenosis or dynamic obstruction, has been utilized in combination with the fetal echocardiography to make more accurate diagnoses of cardiac anomalies. For example, when applied to a two-dimensional image or M-mode image, color flow Doppler mapping can precisely detect the point in the cardiac cycle when turbulence begins. Pulsewave Doppler is used to examine ventricular inflow patterns in the fetuses that have evident hypertrophic or hypoplastic cardiomyopathy (Figure 30-8). Left ventricular outflow tract obstruction and conotruncal abnormalities are commonly seen in fetuses of diabetic mothers. Assessment of these abnormalities can be made with both pulse-wave and directed continuous-wave Doppler techniques.125

The growth of the head of the fetus is an indication of potential microtia. Measurement of the size of the head using twodimensional and three-dimensional ultrasound have been applied to diagnose hemifacial microsomia and microtia.180,181 More precise measurements of the forehead length, forehead height, and forehead area can be obtained by drawing a line from the apex of the philtrum to the nasion across the anterior forehead.181 These data are used to calculate the forehead index. Diagnosis of these craniofacial anomalies is achieved by comparing the forehead index of the subject with that of normal fetuses at the same gestation stage.181

To diagnose cleft lip or cleft palate, a combination of coronal and axial scans using two-dimensional ultrasound is commonly used. Cleft lip can be easily recognized from coronal scan images. In cases where cleft lip extends into the palate, the axial scan of the maxilla can provide the image of the defects.180 The cases of lateral cleft lip/palate often present so-called maxillary pseudomass visualized in two-dimensional sonographs.182

SKELETAL SYSTEM

The skeletal anomalies that most frequently occur in the infants of diabetic mothers include sacral agenesis and hypoplasia, hypoplastic limbs, and pes equinovarus.30,71,72,183 Hallucal polydactyly is also seen in the newborns of diabetic mothers.184 Fused cervical vertebrae and agenesis of ribs has also been reported in humans and animal models.177

GASTROINTESTINAL ABNORMALITIES

The most common gastrointestinal anomalies in the fetuses of diabetic mothers are small bowel atresia, left colon syndrome, and imperforate anus.185 Duodenal atresia is a common form of small bowel obstruction and can be diagnosed by sonography. Sonographic findings in small bowel atresia are characterized by dilated sonolucent “masses” that occupy the fetal abdominal cavity. The “double-bubble” phenomenon in duodenal atresia can be seen in jejunal atresia.186 Because the double-bubble picture is not always present before 24 weeks’ gestation, ultrasound examination may result in false-negative diagnoses in the second trimester. Therefore, it is necessary to perform ultrasound diagnosis during the third trimester. Determination of disaccharidase activity in the amniotic fluid before the 22nd week of gestation also can be helpful in making the diagnosis.186 Colonic atresia can be detected as enlarged echo-free colonic loops in the lower abdomen with active peristalsis. Polyhydramnios is less frequent than with proximal lesions.187

CRANIOFACIAL REGIONS

In the craniofacial regions, the most common anomaly is hemifacial microsomia and microtia in newborns of diabetic mothers.176,177 Cleft palate/lip also occurs in relatively high fre- quency.16,178 Hearing impairment in the children has been found to be associated with diabetic pregnancy.176,177,179 Some of the cases are likely due to the defects in the inner and middle ears.179 It has been observed that maternal hyperglycemia alters the development of the Meckel’s cartilage, which gives rise to the auditory bones in the middle ear.153

GENITOURINARY ABNORMALITIES

Structural defects in the genitourinary system are seen frequently in the newborn infants of diabetic mothers.31,73,188 The malformations include renal agenesis, uterine agenesis, ureteral duplication, hydronephrosis, renal cysts, oligohydramare, hypoplastic vagina, hypoplastic testes, and ambiguous genitals.15,31,188 These anomalies are occasionally associated with caudal regression syndrome, but more often occur independently.15,189 Fetal kidneys can be observed in embryos around 12 weeks of gestation using high-resolution and high-frequency ultrasonography, making diagnosis of renal agenesis and abnormalities possible from this stage.125,190 In many cases, diminution in amniotic fluid occurs. The absence of the amniotic fluid “window” makes the visualization of kidneys very difficult. The problem can be even more complicated if the fetal adrenal undergoes hypertrophy, creating the phenomenon that a structure seems present in the area where the kidneys usually reside. Duplication of ureter can be detected as a cystic structure adjacent to the kidney.125

CAUDAL REGRESSION SYNDROME

Caudal regression syndrome, also known as caudal dysplasia, is characterized by the absence or hypoplasia of caudal struc- tures.183,191 It is a relatively rare condition that complicates 1 in 200 to 1 in 500 diabetic pregnancies. The anomaly may result from a defect in the mid posterior axis mesoderm of the embryo occurring before the fourth week postconception.183,192 Caudal regression syndrome can be diagnosed by noting a shortened spine and abnormal lower limbs, and can be detected in the fetus as early as second trimester.

MOLECULAR MARKERS FOR DIAGNOSIS

Biomolecules in maternal circulation have been found to be associated with fetal abnormalities. These biomarkers include a-fetoprotein, human chorionic gonadotropin, maternal serum unconjugated estriol, and Inhibin-A.125,193-195 Because mechanisms underlying the molecule-anomaly correlation are still not clear, biomarkers can only be used as supplementary indicators to ultrasound examinations. To increase the reliability of the molecular indication, multiple markers are usually used.194,195 In addition to protein markers, maternal circulating noncoding RNAs have been explored as potential biomarkers for NTDs.196 Further research is needed to validate the reliability of the RNA markers for future application in diagnosis.197 Not only does the reliability of biomarkers in diagnosis need to be improved but also the sensitivity of biomarkers must be enhanced to achieve the goal of early diagnosis (ideally before eight weeks of gestation), as most biomarkers are only detectable in the second trimester.194,198

SUMMARY

Diabetes mellitus in early pregnancy increases the risk of birth defects in infants, as well as perinatal mortality. Although aggressive glycemic control and perinatal care have markedly reduced these complications, the birth defect rate in diabetic pregnancies (10%) remains much higher than that in the general population (3%). Hyperglycemia disturbs intracellular metabolic homeostasis to generate nitrosative, oxidative, and ER stress in the embryo, leading to decreases in cell proliferation, increases in programmed cell death, and, eventually, malformations. Fetal structural defects are seen in almost every organ system. Diagnosis of the abnormalities largely relies on sonography, with molecular biomarkers as supplementary references; however, early detection of fetal anomalies (<10 weeks) is still a challenge.

Diabetic embryopathy is a global public health issue. Although pregestational screening for maternal diabetes, perinatal care, and postnatal management are available for most pregnant women in developed countries, the rate of birth defects in infants of diabetic mothers remains high. With the prevalence of type 2 diabetes in the general population on the rise, especially among women of childbearing age, diagnosing and managing diabetic pregnancies pose significant challenges for the medical community. In developing countries the rates of birth defects and mortality are high because of unavailable and inadequate care for pregnant women, statistics which are compounded by an increasing prevalence of diabetes in these countries. Therefore, it is vital to develop effective interventional approaches to prevent embryonic malformations in diabetic pregnancies such as dietary multinutrients.

Modern technology provides powerful tools for an early diagnosis of fetal abnormalities at the morphological and molecular levels. However, because hyperglycemia insults on embryo occur at very early pregnancy, detection of diabetes in women prior to pregnancy is also crucial to achieve the goal of preventing birth defects in diabetic pregnancies. Screening for diabetes in childbearing age women and medical counseling before pregnancy should be essential components of perinatal care.

ACKNOWLEDGMENTS

We thank Drs. Christopher R. Harman and Shifa Turan at Department of Obstetrics, Gynecology and Reproductive Sciences of University of Maryland School of Medicine for the ultrasonic images. We also thank Dr. Julie Wu at University of Maryland School of Medicine for critical reading, commenting, and editing.

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