David A. Abell

FETAL GROWTH RETARDATION AND PRE‐ECLAMPSIA

In a series of 2434 patients with pre‐eclampsia, the prevalence of fetal growth retardation was 8.7 per cent compared with 8.6 per cent in the total hospital population. The prevalence was increased in early‐onset pre‐eclampsia (18.2 per cent) (P <0.001) and reduced in late‐onset pre‐eclampsia (5.6 per cent) (P <0.00l). In patients who later developed early‐onset pre‐eclampsia with fetal growth retardation, the prevalence of subnormal oestriol excretion was significantly increased (79.5 per cent) (P <0.001) as was the prevalence of hypoglycaemia (33.3 per cent) (P <0.001) suggesting that fetal growth retardation in these pregnancies preceded the clinical signs of pre‐eclampsia. The prevalence of placental abruption (8.3 per cent) and the prevalence of perinatal deaths (28.7 per cent) were both significantly higher in pregnancies with early‐onset pre‐eclampsia and fetal growth retardation (P <0.001).

Mortality and Morbidity of Fetal Growth Retardation

Summary: This study reports the fetal outcome in 500 pregnancies when the baby weighed less than the 10th centile for gestational age at birth, compared with that in a series of 500 pregnancies where there was a normal weight for gestation. Fetal growth retardation (0‐9th centile) had a significant positive association with perinatal mortality (5.2% versus 1.2%, P > 0.001) and low oestriol excretion (42.4% versus 15%, P > 0.001), but not with major fetal malformations or fetal asphyxia. In the study group, 20 of the 26 perinatal deaths were associated with subnormal oestriol excretion. When severe fetal growth retardation was considered (less than the 5th centile), the associations with perinatal mortality (19%) and subnormal oestriol excretion (63%) were stronger and a significant correlation with major malformations emerged (17%, P > 0.001). Detection of subnormal oestriol excretion allows identification and appropriate treatment of severe fetal growth retardation which should improve survival and neurological development in these infants. This study confirms that birth‐weight below the 10th centile is an appropriate definition of fetal growth retardation in terms of perinatal mortality and morbidity.

Fetal growth and placental function assessed by urinary estriol excretion before the onset of pre-eclampsia

In a series of 1,316 patients with pre-eclampsia 744 had urinary estriol excretion measured before and 366 after the onset of clinical signs of the disease. Low estriol excretion had a highly significant association with fetal growth retardation and perinatal death both before and after the onset of clinical signs (p less than 0.001). As assessed by the incidences of low estriol excretion, fetal growth retardation, and perinatal wastage, pre-eclampsia of early onset (before 37 weeks) was a malignant disease in comparison with pre-eclampsia of late onset (after 37 weeks). Patients destined to develop early-onset pre-eclampsia had a high incidence of subnormal estriol excretion (25.4%; p less than 0.001). Although further deterioration of placental function occurred after the onset of clinical signs (41.3%; p less than 0.01), fetal growth and prognosis were already determined.

The association between abnormal glucose tolerance (hyperglycemia and hypoglycemia) and estriol excretion in pregnancy

In 2,000 consecutive patients having glucose tolerance tests in pregnancy hyperglycemia (greater than or equal to ninety-fifth percentile) was associated with increased placental weight (p less than 0.01) but not with increased fetal birth weight. Patients with hypoglycemia (less than or equal to fifth percentile) were more likely to have small-for-dates babies (p less than 0.01). Perinatal death was related to maternal glucose tolerance, being reduced from 1.3% in the total series to 0.6% when normoglycemia was present (p less than 0.05); it was significantly increased in the presence of maternal hyperglycemia (p less than 0.001) and hypoglycemia (p less than 0.01). A combination of abnormal glucose tolerance and subnormal estriol excretion detected pregnancies with significantly higher incidences of fetal and placental growth retardation, major fetal malformations, and perinatal deaths. Moreover, the combination of normoglycemia and normal estriol excretion (62.3% of patients) was associated with a very favorable pregnancy outcome (0.4% perinatal death rate). Hypoglycemia was at least as significant as hyperglycemia in terms of unfavorable pregnancy outcome, especially when associated with subnormal estriol excretion.

The significance of abnormal glucose tolerance (hyperglycaemia and hypoglycaemia) in pregnancy.

Maternal hypoglycaemia (plasma glucose below 5th centile) had a highly significant association with fetal growth retardation, and perinatal mortality was significantly increased in the presence of both hypoglycaemia and hyperglycaemia (plasmaglucose above 95th centile) when pregnancy outcome was analyzed in 5000 consecutive patients who had a glucose tolerance test performed during the third trimester of pregnancy. This study confirms the significance of abnormal glucose tolerance as a causative factor of feto‐placental dysfunction. The flat glucose tolerance test pattern had no significance beyond the presence of associated hypoglycaemia, but reactive hypoglycaemia, and persistent abnormalities of plasma glucose levels during the test, were associated with higher incidences of complicated outcome. Hypertonic dextrose therapy administered to the patient with persistently subnormal urinary oestriol excretion was less likely to cause a favourable response in oestriol excretion if glucose tolerance was abnormal, perhaps because the adverse influences of abnormal glucose tolerance were not reversible by the third trimester of pregnancy. Hypoglycaemia and hyperglycaemia, additional to diabetes mellitus, are significant factors in the aetiology and diagnosis of abnormal pregnancy, and point to the need to investigate therapeutic measures.

The Effects of Hypoglycaemia and Hyperglycaemia on Pregnancy Outcome

Summary: A 50 g 3‐hour oral glucose tolerance test was performed on 5,000 consecutive patients during the third trimester of pregnancy. An increased incidence of complicated pregnancy outcome was seen when there was hypoglycaemia and hyperglycaemia (fifth and ninety‐fifth percentiles respectively for plasma glucose levels). Hypoglycaemia had a significant association with subnormal urinary oestriol excretion (P<0.05), fetal and placental growth retardation (P<0.001), and increased perinatal mortality (P<0.05). When there was hyperglycaemia, placental growth was stimulated (P<0.01) and perinatal mortality was increased (P<0.001). When urinary oestriol excretion was persistently subnormal and glucose tolerance was normal the perinatal mortality rate was 2.0%, whereas in the presence of hypoglycaemia this was 12.7% (P<0.001) and when there was hyperglycaemia the rate was 12.8% (P<0.001). Therapeutic measures applied to the patient who is hypoglycaemic, especially when there is subnormal oestriol excretion, require investigation and may enable reduction of perinatal mortality and morbidity.

The Influence of Smoking on Intrauterine Fetal Growth and on Maternal Oestriol Excretion

Summary: Of 3,000 patients with singleton pregnancies, 237 (7.9%) smoked more than 20 cigarettes per day. Heavy smoking had a highly significant correlation with intrauterine growth retardation (P<0.001) and subnormal oestriol excretion (P<0.001), but these parameters of fetal welfare were not significantly influenced by light smoking when compared to non‐smokers. Birth weight was lower and the incidence of intrauterine growth retardation was increased in proportion to increasing total consumption of tar and nicotine during pregnancy. It was concluded that heavy smokers should be encouraged to reduce the number of cigarettes smoked to less than 5 per day.

Importance of abnormal glucose tolerance (hypoglycaemia and hyperglycaemia) in the aetiology of pre-eclampsia.

In a series of 794 patients who had glucose tolerance tests done before the onset of pre-eclampsia, both hypoglycaemia (less than 5th percentile) and hyperglycaemia (P less than 95th percentile) had a significant association with early-onset severe pre-eclampsia ( less than 0.05). In the total series of 794 patients, hypoglycaemia had a significant association with low oestriol excretion (p less than 0.01), fetal growth retardation (p less than 0-05), low Apgar score (p less than 0.05), and perinatal mortality (p less than 0.05). These data indicate that, in patients with pre-eclampsia, hypoglycaemia is directly related to the cause of perinatal death.

Parity and pre-eclampsia.

Summary: In a series of 26,209 patients, the incidence of pre‐eclampsia was 9.3%, being significantly higher in primiparae (14.1%) than multiparae (5.7%) (P<0.001). In patients with early‐onset pre‐eclampsia there were highly significant (P<0.001) increases in the incidences of proteinuria, severe hypertension, placental abruption, fetal growth retardation, neonatal asphyxia and perinatal mortality. There were no significant differences between the incidences of these complications in primiparae and multiparae. The incidence of subnormal oestriol excretion was increased before the emergence of early‐onset pre‐eclampsia with equal significance (P<0.001) in primiparae and multiparae. Eclampsia was more common in patients with late‐onset pre‐eclampsia, but not significantly so.

The Relationship Between Maternal Glucose Tolerance and Fetal Size at Birth

Summary: Two thousand consecutive patients have been studied to investigate the association between maternal glucose tolerance during pregnancy and fetal size at birth. It was shown that the incidences of small for dates (SFD) and low birth weight (LBW) babies were significantly increased when there was maternal hypoglycaemia (P<0.001), particularly when this occurred at the 3‐hour reading of the test. This finding has therapeutic implications. The incidences of large for dates (LFD) and high birth weight (HBW) babies were not related to the degree of maternal hyperglycaemia. Glucose is essential for fetal growth, but does not appear to be the cause of excessive fetal size.