Early fetal growth delay detected by ultrasound marks increased risk of congenital malformation in diabetic pregnancy.

Ninety-nine insulin-dependent diabetic women with regular menstrual histories were examined by ultrasonic scanning in the seventh to 14th weeks of pregnancy. As judged by the crown-rump length 38 fetuses were smaller than normal. The term early growth delay is suggested for this phenomenon. Nine fetuses had major congenital malformations, and seven of them were smaller than normal in early pregnancy (p less than 0.02). The risk of fetal malformation in diabetic pregnancy increases with the severity of the diabetes. Early fetal growth delay is apparently another risk marker, in this series indicating a risk of 18% (7/38). The combination of severe maternal diabetes (White''s classes D and F) and early growth delay yielded a risk of major congenital malformation of 27% (6/22). These observations suggest a common mechanism behind early growth delay and induction of abnormal embryogenesis (and maybe even fetal death). The mechanism is unknown but probably influenced by the quality of regulation of diabetes.     

Early growth delay in diabetic pregnancy: relation to psychomotor development at age 4

Ninety nine consecutive insulin dependent and 101 non-diabetic pregnant women were examined by ultrasonograph to assess early fetal growth. In 42 of the diabetic mothers and three of the non-diabetic mothers the scan showed early intrauterine growth delay. At 4-5 years of age all children available for study were evaluated by the Denver developmental screening test. Only 23 of the 34 children of diabetic mothers with early intrauterine growth delay had normal test scores compared with 46 of the 50 children of diabetic mothers with normal intrauterine growth. The children failed in personal-social development, gross motor development, and particularly in language and speech development. Children of diabetic mothers with normal early fetal growth had scores very similar to those of the children of non-diabetic mothers, of whom 76 of the 86 tested had normal scores.This study suggests that children with a history of growth delay in early diabetic pregnancy should be screened for possible developmental impairment.     

Contribution of twin pregnancy to perinatal mortality and fetal growth retardation; reversal of growth retardation after birth.

A survey of factors associated with perinatal mortality in 511 twins and fetal growth retardation and its reversal in 262 twins is presented. The incidence of stillbirth was almost 50% higher in twins than in singletons and the neonatal mortality was six times as high. Eighty percent of the neonatal deaths occurred in infants born prior to or at 30 weeks of gestation; 93% of the deaths were in infants weighing less than 1500 g and 75% occurred within 48 hours of birth. Fetal malnutrition was the main cause of stillbirth, and respiratory distress syndrome and asphyxia neonatorum were the main causes of neonatal death. One quarter of the twins had fetal growth retardation, a prevalence 10 times that in singletons. In almost all, the growth retardation was reversed by high-energy feedings. Although twins represented only 1% of all pregnancies and 2% of live births, they composed 12% of infants with early neonatal death and 17% of growth-retarded infants. A program is suggested for reduction of twin mortality and morbidity.     

Autophagy contributes to retardation of cardiac growth in diabetic rats

Diabetes mellitus is a major predictor of heart failure, although the mechanisms by which the disease causes cardiomyopathy are not well understood. The purpose of this study was to determine whether prolonged exposure of cardiomyocytes to high glucose concentrations induces autophagy and contributes to cardiomyopathy. Interestingly, there were no differences in the autophagic activation produced by different glucose concentrations. However, cell viability was decreased by high glucose. In the diabetic rats, we found a higher level of microtubule-associated protein light chain 3 (LC3) expression and a reduction in the size of the left ventricle (LV) (P<0.05) caused by growth retardation, suggesting activated autophagy. Our in vitro findings indicate that hyperglycemic oxidative stress induces autophagy, and our in vivo studies reveal that autophagy is involved in the progression of pathophysiological remodeling of the heart. Taken together, the studies suggest that autophagy may play a role in the pathogenesis of juvenile diabetic cardiomyopathy.     

Mechanism of foetal growth retardation caused by smoking during pregnancy

In order to clarify the mechanism of retarded foetal growth in smoking pregnant women, foeto-placental function and maternal nutritional condition were assessed. Dehydroepiandrosterone sulfate (DHAS) loading test, measurement of cotinine which is a major metabolite of nicotine and pathohistological examination of placental villi were also made to know the effect of smoking on utero-placental circulation. In heavy smokers, urinary oestriol and serum hPL levels were lower than those in non-smokers while the maternal nutritional condition was not different from that in non-smokers. In the DHAS loading test, heavy smokers showed lower conversion of DHAS to oestradiol. In the non-stress test (NST), bradycardia and/or loss of variability of baseline foetal heart rate were noted after smoking. Levels of cotinine in maternal blood and umbilical cord blood in heavy smokers were markedly higher than those in non-smokers. Microscopic examination showed atrophic and hypovascular changes of placental villi obtained from smoking mothers. These results suggest that the retarded fetal growth in heavy smokers is due to the impairment of utero-placental circulation as a result of the vasoconstricting effect of nicotine.     

Intrauterine growth retardation and puberty in girls.

Some, albeit not all studies on the relationship between intrauterine growth retardation (IUGR) and female pubertal development have found an earlier and rapidly progressing puberty as well as concomitant disorders of related functional systems such as polycystic ovary syndrome and short stature. These pubertal changes are part of a growing list of IUGR-related diseases, which includes non-insulin dependent diabetes mellitus and coronary heart disease. A pulsatile release of gonadotropin releasing hormone is thought to be a conditio-sinne-qua-non for the initiation of puberty. In the absence of prospective studies on gonadotropin releasing hormone pulse patterns in IUGR-children other markers of pubertal development such as age at menarche have been deployed. From these studies it is not clear, however, whether the findings of an earlier onset of puberty in IUGR-girls merely reflect a more rapid progression of puberty. Both the role for IUGR and the mechanisms behind the onset of puberty are still elusive. Assuming a connection between IUGR and pubertal development, parallels can be drawn between hypotheses on the longterm consequences of IUGR and hypotheses on the initiation of puberty. For example, the somatometer concept proposes a role for fat mass in the initiation of puberty, which is compatible with the hypothesis on non-skeletal catch-up growth after IUGR. The debate on the origins of puberty and the role of IUGR mainly focuses on nature and nurture. Judgmentally, studies in mono- and dizygotic twins discordant for birth weight may be of particular help.     

Fetomaternal adrenomedullin levels in diabetic pregnancy.

We investigated whether maternal and fetoplacental adrenomedullin, a newly discovered hypotensive peptide involved in the insulin regulatory system, is modified in diabetic pregnancy. We studied its correlation with pregnancy complications associated with this disease. Thirty-six pregnant women with diabetes (13 with type I and 23 with gestational diabetes mellitus) and in 40 uncomplicated pregnancies were included. 10 out of 36 diabetic pregnancies were complicated by gestational hypertension. In each woman, adrenomedullin concentration in maternal and fetal plasma and in amniotic fluid was assessed by specific radioimmunoassay. We found that overall mean amniotic fluid adrenomedullin concentration was higher (p < 0.05) in diabetic (14.7 +/- 1.6 fmol/ml) than in uncomplicated pregnancies (10.8 +/- 0.9 fmol/ml), whereas no differences were present in maternal and fetal plasma adrenomedullin levels between diabetic and uncomplicated pregnant women. High levels of amniotic fluid adrenomedullin were found in both type I and gestational diabetes mellitus pregnancies (13.7 +/- 1.4 and 15.6 +/- 2.2 fmol/ml, respectively). Diabetic pregnancies complicated by gestational hypertension showed lower (p < 0.05) amniotic fluid adrenomedullin concentrations than normotensive diabetic patients. These findings suggest that placental adrenomedullin production is upregulated in diabetic pregnancy, and it may be important to prevent excessive vasoconstriction of placental vessels.     

Conservative management of pregnancy in diabetic women.

In 1979 the obstetric management of pregnancies in diabetic women in Cardiff was changed from elective delivery at 37-38 weeks to delivery at term. This change was facilitated by home monitoring of blood glucose concentrations and improved techniques for assessing fetal wellbeing. There were 35 pregnancies in insulin dependent diabetics in 1972-8 and 45 in 1979-82. The quality of diabetic control during pregnancy was equally good in both periods. The average gestation at final admission to hospital increased from 30 to 37 weeks. Amniocentesis to assess fetal pulmonary maturity was necessary in 26 patients (74%) in the first period of study and in only four (9%) in the second. Gestational age at delivery increased from 37.4 to 39.4 weeks after the change in policy. The proportion of mothers entering spontaneous term labour and delivering vaginally increased from 14.3% to 37.8%. The mean birth weight of live born, singleton infants increased from 3090 g to 3650 g, the feeding pattern improved, and respiratory problems were less common. Morbidity was reduced and perinatal mortality was not increased with conservative management of pregnancy in diabetic women.