Develop. Med. Child Neurol. 1970, 12, 145-152
A Syndrome of Congenital Malformations possibly due to Maternal Diabetes
D. A . J . Williamson
THE relationship between diabetes mellitus during pregnancy and congenital mal- formations in the resulting infants has interested paediatricians and obstetricians for many years. Many workers claim that the risk of congenital abnormality is significantly increased for babies born to diabetic mothers, although there is a con- siderable discrepancy among the published figures (Table I). To some extent the con- fusion is due to the difficulty in defining just what is understood by a congenital abnormality; somc workers include every minor blemish as an abnormality while others consider only major or lethal deformities. Pedersen et al. (1964), taking major malformations only, found an incidence of 5.2 per cent in the infants of diabetic mothers, compared with 1 -2 per cent in a control series, but there was no increase in the incidence of minor abnor- malities. Analysis of Farquhars (1965) cases shows that 10 (6.6 per cent) of 152 liveborn infants of diabetic mothers had major congenital abnormalities, but he claims that this proportion is no higher than that in his series of carefully matched controls. It is, however, three times greater than the overall incidence of 2.3 per cent given by McKeown and Record (1960).
All types of malformations have been described among infants of diabetic mothers and most authors do not suggest that there is any particular pattern in this group; however Herre and Horky (1964) and Roszkowski and Kietlinska (1965) have reported a relatively high incidence of central nervous system abnormalities and Pedersen et a/. (1964) mention that several of their cases had severe bony abnormalities of the limbs. Lenz and Maier (1964) have drawn attention to a number of uncommon abnormalities which they claim may be particularly related to maternal diabetes. Reporting 2 cases with femoral aplasia and other deformities of the legs, they note that 7 of the cases reported by Pedersen et a/. (1964) were similarly affected. In a subsequent review of the literature, Kucera et al. (1965) collected the records of 31 infants born to diabetic mothers whose major abnormality was either aplasia or hypo- plasia of the femora, agenesis of the lower vertebrae, or both. They refer to this as the Syndrome of Caudal Regression, as described by Duhamel (1 961), and they point out that among the 50 cases of sacral agenesis reported by Blumel et al. (1959), 6 were the offspring of diabetic mothers. Further examples of this syndrome have
Southampton Childrens Hospital, Winchester Road, Southampton SO9 4WR.
DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY. 1970, 12
TABLE I Incidence of Congenital Abnormalities among (he Infants of Diabetic Mothers
Peel and Oakley (1950) . . Hargbard e t a / . (1959) . . Pitt (1962) .- .. Pedersen et a/ . (1984, . . Herre and Horky (1964) . . Farquhar ( I 965) .. Hubbell et a / . (1965j . . Breidahl(l966) . . . . Watson (1968) . . . . Barashnev (1968) . . . .
Dunn (1964) ..
Total No. of Infants Centre
London .. .. Stockholm .. New Zealand . . Birmingham .. Copenhagen .. Karlsburg . . . . Edinburgh .. Boston . . . . Melbourne .. London .. .. Moscow .. ..
I 4 2 514 1 I 3 69
853 143 I 5 2 413 200 197 -
Overall Incidence of Congenital Abnormalities
McKeown and Record ( I 960) Birmingham . . I 51,160
6 . 3 7 . 6 4 .4 1 . 5 5 . 2 6 . 8 6 . 6
13 .0 2 0 . 0 10.7 5 . 0
been reported by Aubertin et al. (1964), Stern el al. (1965), Rusnak and Driscoll (1966), Frantz and Aitken (1967) and Hiertonn et al. (1967), but so far no British cases have been described.
Case-Records Case 1 (Fig. 1)
This first-born female infant was delivered by caesarean section at 36 weeks gestation, weighing 2,460 g. At birth she was noticed to have micrognathia, cleft lip and palate, and a small upright tongue. The neck was short and there was a Sprengels deformity of the left shoulder. The left femur was considerably shorter than the right and there was bilateral metatarsus varus deformity of the feet. After considerable difficulty with feeding due to glossoptosis, the child made good progress. She has had a number of corrective operations and can now walk well. Her intelligence is normal.
Her mother, who was 23 at the time of Fig. 1
the pregnancy, had been treated for Case 2 (Fig. 2) diabetes since the age of 16. Throughout This female infant was delivered by the pregnancy there had been little medical caesarean section at 38 weeks gestation, supervision and the diabetes was known weighing 3,150 g. She was noted to have a to have been poorly controlled with lente markedly Cushingoid facies, and the insulin. lower half of her body was grossly
D. A. J. WILLIAMSON
abnormal. There was marked shortening of both legs with fixed abduction and external rotation of the hips and flexion of the knees. The feet were abnormally small and had varus deformities. The upper arms also seemed to be shorter than normal. X-rays confirmed the shortening of all the long bones of the legs and also of the humeri. Agenesis of the vertebrae from L.4 downwards was demonstrated with consequent collapse of the pelvis (Fig. 3). The infant subsequently developed con- gestive heart failure and was found to have cardiac enlargement and a systolic murmur. She never thrived and eventually died at the age of five weeks. Post-mortem examination showed the heart to be grossly abnormal with severe pulmonary stenosis and post-stenotic dilatation of the pulmonary artery. A widely patent ductus arteriosus joined the aorta just distal to a severe coarctation. The left ventricle was
hypoplastic and there was a small ventri- cular septal defect. In addition, she had multiple spleneculae and a malrotation of thecolon.The tongue was small andupright.
The infants mother was 24 at the time of pregnancy and had been a known diabetic since the age of 15. Two previous and one subsequent pregnancy produced normal babies. Her diabetes had been well con- trolled with lente insulin throughout the pregnancy.
Cuse 3 (Fig. 4) This male child was delivered by
caesarean section. At birth he had gross abnormalities of the lower half of the body. The abdominal musculature was very poor and there were large bilateral herniae. There was bilateral dislocation of the hips. The left tibia was hypoplastic and the upper end of the right tibia was not expanded. The left knee-joint was grossly abnormal. There were six toes on each foot. In addition, there was shortening of the right forearm. The ears were pointed. He was later found to have a systolic murmur, believed to be due to a small ventricular septal defect. He has under- gone numerous operations, including an
DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY. 1970, 12
amputation of the left leg at the knee-joint. At the age of 12 years he is now remarkably fit and attends a normal school.
His mother, who was 33 at the time of the pregnancy, had been diabetic for 8 years. During the first trimester her diabetes had been poorly controlled and she had been in hypoglycaemic coma several times.
Case 4 (Fig. 5 ) This male infant was born at 36 weeks
gestation, weighing 6 lb. 10 oz. He had severe abnormalities of the lower half of the body. Shortly after birth he developed hypoglycaemia, requiring treatment with intravenous glucose. The legs were abnormally short, with very little muscular development below the knees. The feet were small, and movement at the ankle and tarsal joints was much restricted. Extension of the knees was also somewhat limited. There was a diffuse swelling it1 the sacral region and two marked dimples over the buttocks. X-rays confirmed the hypoplasia of the long bones of the legs and revealed agenesis of the vertebrae from L.3 down-
D. A. J. WILLIAMSON
wards with consequent collapse of the pelvis (Fig. 6).
His mother was 32 at the time of the pregnancy. She had had two previous pregnancies; the first was normal but the second resulted in a full-term stillborn infant weighing 109 lb. During the third pregnancy she was found to be diabetic at the fourth month and was treated with 24 units of soluble insulin daily. Since delivery, however, it has been possible to control her diabetes with dietary treatment only.
Discussion The collection of a group of patients
having in common reduction defects of the legs with or without agenesis of the lower segments of the spinal column involves a degree of selection, but the resulting clinical picture is sufficiendy unusual and
striking to warrant the use of the term syndrome. In only a minority of the recorded cases of caudal regression has maternal diabetes been noted, but this may well be due to the authors failure to appreciate the significance of this feature. Conversely, many other abnormalities have been observed in infants with the caudal regression syndrome born to diabetic mothers. Table I1 sets out the pattern of associated defects described in the recorded cases. This list is probably incomplete, as many of the case-reports in the literature are very brief. It will be seen that certain malformations, particularly those of the upper limbs, mouth, palate and heart, occur frequently. How far it is possible to include these other abnormalities in the syndrome must be a matter of opinion, but it would seem that the term Syndrome of Caudal Regression may be too circumscribed.
TABLE I1 Abnormalities found in 43 cases of Diabetic Embr