Mary Higgins

A review of maternal and fetal growth factors in diabetic pregnancy.

Diabetes mellitus complicates 1-2% of all pregnancies but is associated with high perinatal morbidity and mortality. Gestational diabetes affects up to 4% of pregnancies and is associated with fetal macrosomia (large for dates). Fetal growth is a complex process influenced by determinants such as genetics, maternal factors, uterine environment and maternal and fetal hormones. Infants of pre-gestational diabetic mothers have an additional influence of maternal fluctuations in glycaemia. The purpose of this paper is to review maternal and fetal growth factors, including insulin, in the aetiology of macrosomia in diabetic pregnancy. Placental Growth Hormone is the major growth hormone secreted during human pregnancy. Leptin may have a role in satiety. Resistin was originally proposed as the link between obesity and diabetes but is now thought to have a more complex role. These hormones and their actions on human in-utero growth are reviewed in depth with particular reference to both pre-gestational (type 1 and type 2 diabetes) and gestational diabetes. Previously increased fetal weight in infants of diabetic mothers was thought to be as a result of maternal hyperglycaemia. It is now evident that control of fetal growth, in normal as well as diabetic pregnancies, is far more complex than previously thought.

Stereology of the placenta in type 1 and type 2 diabetes.

OBJECTIVE To assess by stereology the placental structure in type 1 (T1DM) and type 2 (T2DM) diabetic pregnancies compared to normal non-diabetic (ND) controls. STUDY DESIGN Prospective case control study. Placentae were sampled in a systematic random fashion. Stereological analysis was performed using a computerised stereology programme (Image Pro 6.2, Media Cybernetics, Inc, Silver Spring MD, USA). Participants were matched for gender of infant and mode of delivery. MAIN OUTCOME MEASURES Volume, length and surface area of placental components; clinical outcome. RESULTS Ten ND, eight T2DM and ten T1DM women consented to the study. There was no difference between the groups regarding maternal age, neonatal birth weight, or placental weight. On stereological examination, terminal villous volume was significantly increased in both diabetic groups compared to ND controls. Capillary volume and length was increased in T1DM pregnancies compared to ND and T2DM. Capillary length was increased in both diabetic groups compared to ND. When all diabetic groups were compared based on severity of glycaemia those with poor glycaemic control (HbA1c>7%) had higher placental capillary volume than those with good glycaemic control. CONCLUSIONS This study demonstrates an association between maternal diabetes and increased terminal villous volume. Additionally capillary volume and length is increased in the placentae of normally grown infants of T1DM diabetic mothers compared to non-diabetic controls. Maternal glycaemia appears to influence capillary, but not stromal, development. This suggests that factors other than glycaemia have a role in placental development in pre-gestational diabetes.

Fetal anterior abdominal wall thickness in diabetic pregnancy.

OBJECTIVE The purpose of this study was to investigate whether third trimester fetal anterior abdominal wall (AAW) thickness in diabetic pregnancy reflects glycaemic control and predicts macrosomia. STUDY DESIGN Prospective cohort study in a tertiary level maternity unit. One hundred and twenty-five diabetic mothers (71 pre-gestational and 54 gestational diabetics on insulin) underwent routine serial third trimester ultrasound examination with the additional measurement of AAW thickness. Pregnancy outcome was obtained. RESULTS 335 fetal AAW measurements were recorded in diabetic pregnancy from 30 to 38 weeks gestation. Third trimester AAW was significantly higher in macrosomic babies (5.4+/-1.4 mm vs. 4.7+/-1.4 mm, p<0.05). ROC derived cut off for AAW in the prediction of macrosomia was 3.5 mm at 30 weeks, 4.5 mm at 33 weeks and 5.5 mm at 36 weeks gestation. Using either a raised AAW measurement or an AC>90th centile, the prediction of birth weight greater than the 90th centile was better (88%) than with AC alone (70%). This improvement in sensitivity held even at earlier gestations in the third trimester. CONCLUSION Measurement of AAW in diabetic pregnancy may have a role in the prediction of macrosomia.

Clinical Associations with a Placental Diagnosis of Delayed Villous Maturation: A Retrospective Study

Delayed villous maturation (DVM) is a spectrum of placental disease characterized by decreased tertiary villus formation, reduced vasculosyncytial membrane formation, and, in its more severe forms, increased large bullous villi. In some series it has been associated with an increased risk of stillbirth in the late third trimester, but overall there are few data on its significance. The aim of this study was to assess perinatal factors associated with, and the clinical significance of, the finding of DVM on placental histology. This was a retrospective study investigating all pregnancies with DVM diagnosed on placental histology in a tertiary level unit between December 2001 and August 2006. Over a 6-year period, 2915 placentas were triaged for histopathological assessment, representing 6.1% of all 48 054 deliveries in this time period. One hundred ninety (6.3%) of these selected cases showed DVM. Fifteen placentas from infants with less than 34 completed weeks of gestation were excluded, leaving 175 for further analysis. When compared with controls matched for gestation and delivering within the same time period (n = 175), DVM was significantly associated with pregestational diabetes (8% vs 2.8%, P < .05; relative risk 2.8 [95% confidence interval 1.03–7.6]), gestational diabetes (8.6% vs 3.4%, P < 0.05; relative risk 2.5 [95% confidence interval 0.99–6.3]), and prenatal or intrapartum intrauterine death (8.6% vs 0%, P < 0.05). Delayed villous maturation is associated with both gestational and pregestational diabetes mellitus and with perinatal death.

Can Neonatal TSH Screening Reflect Trends in Population Iodine Intake

BACKGROUND The distribution of neonatal blood thyroid-stimulating hormone (TSH) concentrations has been used as an index reflecting population dietary iodine intake, with higher concentrations being indicative of lower iodine intake. We examined this distribution in neonates born in Ireland, where the pregnant population has shown a recent decline in urinary iodine (UI) excretion. Our objectives were to determine if any alteration was observed in the percentage of values > 5.0 mIU/L and whether a trend in neonatal blood TSH was apparent. METHODS Samples drawn from the National Neonatal Screening Programme were assessed during the years 1995-2006 from winter (January n = 35,079) and summer (August n = 37,940) months, respectively, in view of the known seasonal variation in Irish dietary iodine intake. RESULTS Apart from the first years studied (1995-1996), the proportion of individual blood TSH values >5.0 mIU/L did not exceed 3%, a value believed to be indicative of iodine deficiency. A significant declining trend in the proportion of blood TSH >5.0 mIU/L was observed in subsequent years (p < 0.01). While excluding severe iodine deficiency, these analyses failed to detect the slight but highly significant (p < 0.001) tendency toward increasing blood TSH within the 0-5.0 mIU/L interval in the study population between 1999 and 2006, which was greater in summer than in winter months (p < 0.001). CONCLUSIONS These data support a link between fetal thyroid function and a fall in maternal iodine intake. While the findings of the proportion of blood TSH values >5.0 mIU/L exclude severe maternal or fetal iodine deficiency, a trend toward increasing TSH may provide an early indication of impending iodine deficiency. The findings assume greater importance in the context of declining UI reported from many developed countries even where the proportion of blood TSH values >5.0 mIU/L is <3%, thus excluding severe maternal and fetal iodine deficiency.

Real increasing incidence of hysterectomy for placenta accreta following previous caesarean section.

OBJECTIVE Placenta accreta, morbid adherence to the uterus to the myometrium, is commonest in association with placenta previa in women previously delivered by caesarean section (CS). It has become proportionally a greater cause of major maternal morbidity and mortality as the frequency of other serious obstetric complications has declined. The aim of this study was to examine the incidence of placenta accreta in the context of a rising caesarean delivery rate. STUDY DESIGN Retrospective review of the incidence of placenta accreta in parous women during the 36 years 1975-2010. Cases were identified from hospital records and then correlated with pathological reports. The incidence of placenta accreta was analysed in the context of women previously delivered by CS. RESULTS During the 36-year period in our unit, 157,162 multiparous women delivered, of whom 15,151 (9.6%) had a previous CS scar. The institutional incidence of CS rose from 4.1% in 1975 to 20.7% in 2010. Twenty-five parous women, all with a previous CS, had placenta accreta requiring hysterectomy. The overall incidence of placenta accreta was 1.65 per 1000 parous women with a previous CS, but was low (1.06/1000) until 2002. From 2003 to 2010 the incidence rose to 2.37/1000 previous CS deliveries (OR 2.2; 95% CI 1.05-5.1). CONCLUSION The frequency of placenta accreta correlated steadily with the CS rate until 2000. Since then, the incidence has nearly doubled in women with previous CS scars, suggesting an additional causative influence on risk.

Troponin T and Pro-B-Type Natriuretic Peptide in Fetuses of Type 1 Diabetic Mothers

OBJECTIVE Cardiomyopathy is noted in up to 40% of infants of diabetic mothers, and the exact mechanisms are unknown. The aim of this study was to determine whether fetal serum markers of cardiac function differ between normal and type 1 diabetic pregnancies and to examine the relationship between these markers and fetal cardiac structure and function. RESEARCH DESIGN AND METHODS This was a prospective observational study of 45 type 1 diabetic pregnancies and 39 normal pregnancies. All participants had concentrations of fetal pro–B-type natriuretic peptide (proBNP) and troponin-T (TnT) measured at the time of delivery. All patients with type 1 diabetes had Doppler evaluation of the umbilical artery, middle cerebral artery, and ductus venosus in the third trimester, and a subset (n = 21) had detailed fetal echocardiograms performed in each trimester. RESULTS Fetal proBNP and TnT concentrations were higher in the diabetic cohort than in the normal cohort (P < 0.05). ProBNP correlated positively with interventricular septum thickness (P < 0.05) but not with cardiac function indexes in the third trimester. In patients with poor glycemic control, there was a significant positive correlation (P < 0.05) between fetal TnT and the third trimester umbilical artery pulsatility index. There were also increased levels of fetal TnT in infants with poor perinatal outcome (P < 0.05). CONCLUSIONS Biochemical markers of cardiac dysfunction are elevated in infants of diabetic mothers, especially those with cardiomyopathy or poor perinatal outcome. Hyperglycemia in early pregnancy may affect myocardial and placental development, thus contributing to the susceptibility to hypoxia seen in these infants.

Maternal and fetal placental growth hormone and IGF axis in type 1 diabetic pregnancy.

Aim Placental growth hormone (PGH) is a major growth hormone in pregnancy and acts with Insulin Like Growth Factor I (IGF-I) and Insulin Like Growth Hormone Binding Protein 3 (IGFBP3). The aim of this study was to investigate PGH, IGF-I and IGFBP3 in non-diabetic (ND) compared to Type 1 Diabetic (T1DM) pregnancies. Methods This is a prospective study. Maternal samples were obtained from 25 ND and 25 T1DM mothers at 36 weeks gestation. Cord blood was obtained after delivery. PGH, IGF-I and IGFBP3 were measured using ELISA. Results There was no difference in delivery type, gender of infants or birth weight between groups. In T1DM, maternal PGH significantly correlated with ultrasound estimated fetal weight (r = 0.4, p = 0.02), birth weight (r = 0.51, p<0.05) and birth weight centile (r = 0.41, p = 0.03) PGH did not correlate with HbA1c. Maternal IGF-I was lower in T1DM (p = 0.03). Maternal and fetal serum IGFBP3 was higher in T1DM. Maternal third trimester T1DM serum had a significant band at 16 kD on western blot, which was not present in ND. Conclusion Maternal T1DM PGH correlated with both antenatal fetal weight and birth weight, suggesting a significant role for PGH in growth in diabetic pregnancy. IGFBP3 is significantly increased in maternal and fetal serum in T1DM pregnancies compared to ND controls, which was explained by increased proteolysis in maternal but not fetal serum. These results suggest that the normal PGH-IGF-I-IGFBP3 axis in pregnancy is abnormal in T1DM pregnancies, which are at higher risk of macrosomia.

Delayed villous maturation of the placenta: quantitative assessment in different cohorts.

Placental villous maturation is maximal in the 3rd trimester, with an abundance of terminal villi. Delayed villous maturation (DVM) of the placenta is associated with chromosomal abnormalities, gestational diabetes, and an adverse outcome. This study compares quantitative assessment of vasculo-syncytial membranes (VSM) in cases of liveborn infants, perinatal deaths, and controls. Cases were selected as follows: (1) liveborn infants with a qualitative diagnosis of DVM (n = 15); (2) controls matched for gestational age whose placentas did not have DVM (n = 15); (3) stillbirths (SB)/neonatal deaths (NND) showing DVM (n = 13); and (4) SB from autopsies in which DVM was felt to be the cause of death (COD) (n = 12). Vasculo-syncytial membranes were counted in 10 terminal villi in each of 10 consecutive high-power fields on 3 slides. Data analysis was carried out using SPSS. Liveborn cases with DVM showed statistically significantly less VSM than controls (mean 1.01 vs 2.42, P < 0.0001). The SB/NND group also showed significantly less VSM than the control group (mean 0.46 vs 2.42, P < 0.0001) and less than the liveborn DVM group (mean 0.46 vs 1.01, P = 0.001). The COD group was significantly different from the control group (mean 0.42 vs 2.42, P < 0.0001) and the liveborn DVM group (mean 0.42 vs 1.01, P < 0.0001) but not significantly different from the SB/NND group. There is a quantitative reduction in VSM in cases of DVM compared to controls.

Heart rate variability in neonates of type 1 diabetic pregnancy.

BACKGROUND Cardiomyopathy is a common finding in offspring of pre-gestational type 1 diabetic pregnancy. Echocardiographic and biochemical evidence of fetal cardiac dysfunction have also been reported. Studies suggest that offspring of diabetic mothers (ODM) undergo a fetal programming effect due to the hyperglycaemic intrauterine milieu which increases their risk of cardiovascular morbidity in adult life. Decreased neonatal heart rate variability (HRV) has been described in association with in-utero growth restriction, prematurity, sudden infant death syndrome and congenital heart disease. The effect of in-utero exposure to hyperglycaemia in diabetic pregnancy on neonatal HRV is unknown. AIMS Our aim was to determine if neonatal HRV differs between normal and diabetic pregnancy. STUDY DESIGN AND SUBJECTS This was a prospective observational study of 38 patients with pregestational type 1 diabetes and 26 controls. HRV assessment was performed using Powerlab (ADI Instruments Ltd). OUTCOME MEASURES Heart rate variability assessment and cord blood sampling for pH and glucose were performed for all neonates. Maternal glycaemic control was assessed via measurement of glycosylated haemoglobin in each trimester in the diabetic cohort. RESULTS Neonates of diabetic mothers had evidence of altered heart rate variability, with increased low frequency to high frequency ratio (LF: HF), suggestive of a shift towards sympathetic predominance (p<0.05). This altered HRV was significantly related to fetal acidaemia, cord blood glucose values and maternal glycaemic control during pregnancy (p<0.05). CONCLUSION Neonates of pregestational diabetic pregnancy have altered HRV which is related to maternal hyperglycaemia, fetal acidaemia and fetal glycaemia. Exposure of the developing heart to fluctuations in maternal glycaemia with subsequent alterations in HRV may explain why infants of diabetic mothers are at greater risk of cardiovascular disease in later life.