Types of malformations

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The congenital malformations of IDM and IGDM constitute a spectrum known as diabetic embryopathy (DE).21,24 This spectrum implies errors of morphogenesis which appear between the third and the seventh week of embryonic development (end of blastogenesis and organogenesis).25 Within this spectrum of DE, cardiac, skeletal, central nervous system (CNS), uro-genital, gastro-intestinal, facial and multiple malformations were repeatedly described (Table 23.1). Congenital malformations in IGDM and offspring of women with Type 2 diabetes affect the same organ systems that have been previously described in pregnancies with Type 1 diabetes.15 The most commonly affected organ systems were cardiac (37.6%), musculo-skeletal (14.7%), CNS (9.8%), and multiple malformations (16%).15

It has been debated whether maternal diabetes exerts a nonspecific teratogenic effect expressed in a universally increased risk of all congenital malformations or whether the disease should be regarded as a specific teratogen associated with a distinct pattern of congenital abnormalities.11 The spectrum in DE is large and highly variable; however, most studies have reported an increase of specific malformations especially involving the heart, the skeleton (particularly sacral agenesis), the kidneys and CNS.7 Regarding cardiac malformations, the strongest association with maternal diabetes was found in infants with defects of primary congenital cardiogenesis, whereas most abnormalities arising later in cardiac development were not associated with diabetes.9 Others found a strong teratogenic effect on four specific types of malformations: renal agenesis, obstructive urinary tract, cardiac and multiple abnormalities, as opposed to an unspecific increased general risk of congenital malformations.11

Types of malformations 175

Table 23.1 Congenital malformations in infants of diabetic mothers

Malformations

Organ system

Common

Rare, occasional

Cardiac

Corrected transposition Ventricular septal defect Coarctation Atrial septal defect Cardiomyopathy

Tetralogy of Fallot Hypoplastic left heart Single ventricle Double-outlet right ventricle Pulmonic stenosis Anomalous venous return

Skeletal

Sacral agenesis Vertebral and rib anomalies Limb reduction defects

Polydactyly Syndactyly Clinodactyly Clubfoot

CNS

Anencephaly Neural tube defects Microcephaly Hydrocephalus

Occipital encephalocele Holoprosencephaly Septo-optic dysplasia

Uro-genital

Hydronephrosis Renal agenesis Ureteral duplication Multicystic dysplasia Hypospadias

Hypoplastic genitalia Micropenis Ambiguous genitalia Megalo-urethera

Gastro-intestinal

Duodenal atresia Ano-rectal atresia Esophageal atresia

Malrotation Volvulus Omphalocele Gastroschisis Diaphragmatic hernia

Facial

Cleft lip Cleft palate Ears microtia anotia atresia of canal ear hairy ears hearing loss Eyes cataract coloboma optic nerve hypoplasia

Choanal atresia

Absent depressor anguli oris muscle Fused orbits

Others

Single umbilical artery

Laterality defects Tracheal stenosis Branchial arch anomalies

Cardiac malformations

Cardiac malformations are the most common congenital malformations of IDM, and they occur significantly more often in IDM than in infants of nondiabetic mothers.7,21 Rowland et al.26 reported a 4% prevalence of cardiac malformations in a series of 470 IDM, a 5-fold higher rate than in the general population (0.8%). Becerra et al.7 found that infants of mothers with gestational diabetes who required insulin during the third trimester of pregnancy were 20.6 times more likely to have major cardiovascular malformations than infants of nondiabetic mothers. No such difference was noted in infants of mothers with gestational diabetes who did not require insulin.7

Loffredo et al.,9 in a population-based case-control study of 4390 IDM and 3572 healthy infants, observed that pre-conceptional maternal diabetes was strongly associated with cardiovascular malformations of early embryonic origin (OR = 4.7) and cardiomyopathy (OR = 15.1), but not with obstructive and shunting defects (OR = 1.4). There was a strong association of cardiovisceral and cardiac chamber discordance, i.e. 'corrected' (levo-) transposition of the great arteries, but not with 'pure' transposition, i.e. intact ventricular septum or ventricular septal defect.9 Among outflow tract anomalies, the risk was strongly associated with normally related great arteries (OR = 6.6) but not with simple transposition. These findings imply a specific effect of maternal diabetes on certain subtypes of cardiac malformations and may have important clinical and preventive implications.9

Skeletal malformations

Maternal diabetes has been associated with sacral agenesis, also termed sacral dysgenesis or caudal regression.3 This is a complex malformation characterized by the absence or maldevelopment of the sacrum and coccyx, with or without hypoplastic femurs, dislocated hips, defects in tibias or fibulas, or other lower-limb malformations. Affected babies often have anomalies of other organ systems as well. Sacral agenesis occurs in about 0.2-0.5% of IDM, representing a 200- to 400-fold higher rate than in the general population.5,21

CNS malformations

Anencephaly is the most common CNS malformation associated with diabetic pregnancy, affecting 0.57% of IDM,21 which is 3-fold higher than the rate in the general population (0.19%).21 IDM also have a high prevalence of neural tube defects (1.95 vs. 0.2% in the general population).27 One study of experimental diabetes induced after the period of organogenesis noted no effect on the CNS of the offspring.21

Uro-genital malformations

Kucera3 was the first to report an increased rate of urological malformations in IDM. The most frequent renal malformations in IDM are renal agenesis, ureteral duplication, and hydronephrosis.1,11,24 Hypospadias is the most frequent genital malformation in IDM and IGDM.11,24

Gastro-intestinal malformations

The abdominal malformations shown to occur with a higher prevalence in IDM include ano-rectal, duodenal, and lower-intestine atresia.21,24 Malrotation, volvulus, and abdominal wall defects have also been described.

Facial malformations

Facial anomalies in IDM and IGDM have been described in only a small number of reports.7,16,28-31 The most frequent were oro-facial clefts7,16 and ear and eye abnormalities.1,7,29 Interestingly, some studies reported an association of maternal diabetes with certain facio-skeletal syndromes, such as femoral-facial syndrome and oculoauriculovertebral poly-topic field defect.29-32 Therefore, IDM and IGDM should be carefully evaluated for facial malformations.29-32

Other anomalies

A single umbilical artery occurs in about 6.4% of IDM, a 5fold higher rate than in the general population.21 This mild malformation might be associated with other, major, structural anomalies.

Multiple malformations

Many studies found a strong association between pre-gestational maternal diabetes and multiple-system malformations (not defined as a syndrome) in the offspring.4,11 For example, 27.5% of all malformed infants in the Collaborative Perinatal Project4 had multiple anomalies. Aberg et al.16 observed that 6% of their malformed IDM had more than one anomaly compared to 0.57% of the control group. They concluded that there is a clear-cut increase in the risk of multiple malformations in infants of mothers with pre-existing diabetes, but not of mothers with GDM.16 In the infants with multiple malformations, the same organ systems were affected as in the whole group of IDM, with highest rates for cardiac malformations, atresias, clefts, limb reduction, and hypospadias.

Mild malformations

Studies on mild malformations in IDM and IGDM are relatively scarce,33-35 and no randomized double-blind investigations have been performed to date. The results of the case-control studies are contradictory, with some showing significant differences but others not. No association was observed between the severity of the metabolic derangement (HbA1c) in the mother and the appearance of mild malformations in the offspring.34,35 This was also true for White's class, duration of diabetes, maternal age, and cigarette smoking.33

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