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Fetal growth and placental function assessed by urinary estriol excretion before the onset of pre-eclampsia
Fetal growth and placental function assessed by urinary estriol excretion before the onset of pre-eclampsia PETER
A.
LONG,
DAVID
A.
ABELL,
NORMAN Melbourne,
A.
M.B., M.B.,
BEISCHER,
Victoria,
B.S.,
M.R.C.O.G.
B.S.,
M.G.O.,
M.D.,
M.G.O.,
M.R.C.O.G.,
F.C.O.G.(S.A.)
F.R.C.S.(EDIN.),
F.R.A.C.S.,
F.R.C.O.G.
Australia
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 < 0.001). As assessed by the incidences of low estriol excretion, fetal growth retardation, and perinatal wastage, pm-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 < 0.001). Although further deterioration of placental function occurred after the onset of clinical signs (41.3%; p < O.Ol), fetal growth and prognosis were already determined. (AM. J. OBSTET.
GYNECOL.
135344,
1979.)
RECENTLY WE REPORTED thatmaternalhypoglycemia has a significant relationship with both fetal growth retardation and early-onset pre-eclampsia.’ This suggested that a cause of pre-eclampsia may be reduced maternal supply of nutrients to the fetus, a conclusion consistent with the clinical observation that fetal growth retardation often precedes the appearance of the signs of pre-eclampsia. Studies of placental clearance of dehydroepiandrosterone sulfate,* and assays of serum heat-stable alkaline phosphatase3 and plasma estriol level? have also shown, to a varying extent, that placental function may be abnormal before pre-eclampsia becomes clinically apparent. This study was designed to evaluate fetoplacental function by measurement of urinary estriol excretion, both before and after the onset of the clinical signs of pre-eclampsia, and to relate this to the time of onset of pre-eclampsia and fetal outcome (fetal growth retardation and perinatal death). This investigation was possiFrom the Mercy Maternity Obstetrics and Gynaecology, Received for Publication Accepted
November
Hospital and Department University of Melbourne.
June 20, 1978.
23, 1978.
Reprint requests: Professor Norman A. B&her, Department of Obstetrics and Gynaecology, Mercy Maternity Hospital, Clarendon Street, East Melbourne, Victoria, Australia, 3002.
344
of
ble because it is our practice to measure estriol tion in late pregnancy as a screening test. Matwisl
excre-
and methods
At the Mercy Maternity Hospital, Melbourne, many patients have urinary estriol excretion measured as a routine screening test between 30 and 36 weeks’ gestation. The test is also widely used to monitor fetal well being in patients with pre-eclampsia who are treated conservatively. During the period from March, 197 1, until January, 1975, 12,924 patients were delivered at this hospital and pre-eclampsia was diagnosed in 1,316 (10.2%). Pre-eclampsia was diagnosed when at least two of the signs, hypertension 140/90 mm Hg or above, generalized edema, and proteinuria not due to urinary infection or contamination, were present after week 20 of gestation. The high incidence of pre-eclampsia in this series was due to inclusion of patients who acquired these signs during labor. The spectrum of severity of the disease was wide and patients were grouped according to whether the diagnosis was made before or after the beginning of week 37 of gestation, and according to the presence or absence of proteinuria. From these 1,316 patients with pre-eclampsia 919 were selected for this study, those excluded being patients with multiple pregnancy, and patients in whom estriol excretion was not measured at any time during 0002-9378/79/190344+04$00.40/0
@ 1979 The C. V. Mosby Co
Urinary
pregnancy. The test was unavoidably omitted in unbooked patients who were admitted to hospital in labor or with severe disease requiring immediate delivery, and in booked patients who contracted severe preeclampsia before the routine screening test was performed. The test was more often omitted in private patients because of administrative reasons. Crinary rstriol excretion was measured according to the method of Brown and colleagues’ and was regarded as low when one or more values were obtained below a line joining 8 mg/24 hours (27.8 pmo1/24 hours) at 30 weeks’ and 12 mgi24 hours (4 1.6 pmol/24 hours) at 40 weeks’ gestation. Infants were diagnosed as small for dates (fetal growth retardation) when birth weight was below the tenth percentile according to gestational age for infants born in this community.’ Perinatal deaths included stillbirths and neonatal deaths occurring within 28 days of birth. Statistical analysis of the data was performed by testing of binomial distribution.
Results Severity of pre-eclampsia and fetal outcome according to time of onset. The group of patients with earlyonset pre-eclampsia had significantly higher incidences of proteinuria, fetal growth retardation, and perinatal death than the late-onset group (p < 0.001) (Table I). Fetal growth retardation was a complication in 43 of the 249 patients with early-onset pre-eclampsia. The signs of pre-eclampsia were present for no more than I week in 12 of the 43 pregnancies. Thus, the high incidence of fetal growth retardation in early-onset pre-eclampsia was not necessarily a consequence of protracted clinical disease. Estriol excretion before the onset of pre-eclampsia. As shown in Table II, the incidence of subnormal estrio1 excretion was 25.4% in patients destined to develop early-onset pre-eclampsia. This incidence was signilicantly higher than that in the total hospital population (13.7%‘: p < 0.001). By contrast, the incidence of subnormal estriol excretion in patients destined to develop late-onset pre-eclampsia was 10.3%, which was significantly less than that in the total hospital population (p < 0.05). There was a significant association between the level of estriol excretion before the emergence of preeclampsia and fetal outcome (Table III). When estriol excretion was normal the incidence of fetal growth retardation was 5.4% and the perinatal death rate was 0.5%. whereas when estriol excretion was subnormal the incidences were 16.8 and 5.3%, respectively (p < 0.001).
estriol
excretion
before
onset
of pre-eclampsia
345
Table I. Incidence of proteinuria, fetal growth retardation, and perinatal death according to time of onset of pre-eclampsia
Less than 31 weeks’
249
61.3
17.3
6.8
670
40.1***
tj.:<***
0.4***
_
__
-
-
919
45.8
9.2
2.2
gestation More than 37 weeks’
gestation Total series
***p < 0.001 = Significance of difference between the two pre-eclampsia groups. Statistically significant correlations between estriol excretion and fetal outcome were also present when the patients were divided into early- and late-onset groups (Table III). However, low estriol excretion carried a more sinister prognosis with regard to fetal outcome in the early-onset group. In this group the incidences of fetal growth retardation and perinatal death were 6.5 and 3.3%. respectively, when estriol excretion was normal, whereas when estriol excretion was subnormal the corresponding incidences were 22.6 (p < 0.05) and 12.9% (p < O.OOl), respectively. Estriol excretion after the onset of pre-eclampsia. After the appearance of the clinical signs of preeclampsia in the early-onset group the incidence of subnormal estriol excretion rose significantly from 25.4 to 41.3% (p < 0.01) (Table II). After the diagnosis of late-onset pre-eclampsia the incidence of subnormal estrio1 excretion rose from 10.3 to 15.7%. It can be concluded that the appearance of the clinical signs of preeclampsia is associated with deterioration of placental function mainly in patients with early-onset disease. In patients with early-onset pre-eclampsia both fetal growth retardation and perinatal death were found to have a highly significant correlation with low estriol excretion (Table III). In this group as a vvhole the incidence of fetal growth retardation was 17.3% and the perinatal death rate was 6.8% (Table I). When estriol excretion was normal after the onset of pre-eclampsia the incidences of these complications were 8.0 and 0.8%, respectively, whereas when estriol excretion was subnormal the corresponding incidences were 35.2 and 14.8%, respectively (p < 0.001) (Table III). Too few patients had estriol excretion measured after the signs of pre-eclampsia appeared in the lateonset group to permit adequate analysis of results. In the total series of 919 patients, among those patients tested after the onset of pre-eclampsia, estriol excretion
346
Long, Abell, and Beischer
Table
II. Incidence
of low estriol excretion
before
and after onset of pre-eclampsia Before
Time of onset
of p-e-eckzmpsia
Less than 37 weeks’ More than 37 weeks’ Total series
gestation gestation
No. of patients
No. of patients screened
249 670 919
122 622 744
*p < 0.05; ***p < 0.001; N.S. = Not excretion (13.7% in 5,000 patients’).
significant.
Table
to estriol excretion
III.
Fetal outcome
according
onset
Before
Significance
Low estriol excretion ( %)
of difference
onset of /we-eckzmpsia
More than 37 weeks’ gestation: Normal estriol excretion Low estriol excretion
5.2,, 14.1
1.6
Total series: Normal estriol excretion Low estriol excretion
5.4 *** 16.8
0.5 *** 5.3
**p < 0.01;
***p
< 0.001
= Significance
No. of patients screened
41.3*** 15.7 N.S. 30.6
213 153 366 with
hospital
Low rstriol excretion ( % )
incidence
of low
estriol
After
3.3 *** 12.9
of difference
onset of p-e-eclumpsia
Per&at51 death rate (%)
6.5, 22.6
*p < 0.05;
compared
onset of pre-eclampsia
before and after onset of pre-eclampsia
Less than 37 weeks’ gestation: Normal estriol excretion Low es&o1 excretion
estriol
After
25.4*** 10.3* 12.8
Small-fordates infants (76)
Time of onset of pre-eclampsia
of pre-eclampsia
between
8.0 *** 35.2
0.8 *** 14.8
9.3 8.3
8.3
8.7 *** 29.5 groups
of patients
0.4 *** 13.4 with
normal
and
subnormal
excretion.
was low in 33 of the 55 pregnancies (60%) complicated by fetal growth retardation and in 15 of the 16 (93%) complicated by perinatal death.
Comment This study showed that in patients with pre-eclampsia, low estriol excretion had a highly significant association with fetal jeopardy (growth retardation and perinatal death), both before and after the onset of the clinical signs of the disease (Table III). When assessed in terms of the incidences of low estriol excretion, fetal growth retardation, and perinatal death rate, preeclampsia of late onset (73% of cases) was shown to be a benign disease in comparison with pre-eclampsia of early onset (27% of cases). Whether or nbt the incidence of fetal growth retardation is increased in pre-edampsia is a matter of continuing debate in the literature. Indeed, in this series its over-all incidence (9.2%) was not significantly higher than that of the hospital population (8.6%). This study has shown that the distribution of fetal growth retardation was sharply polarized between pre-eclampsia of
REFERENCES 1. Long, P. A., Abell, D. A., and Beischer, N. A.: Importance of abnormal glucose tolerance (hypoglycaemia and hyper-
early and late onset, there being a large and significant increase in its incidence among patients with earlyonset disease. In comparison with the total obstetric population, patients destined to develop early-onset pre-eclampsia had a significantly increased incidence of low estriol excretion (p < 0.001) (Table II). In this group there was further deterioration of placental function after the onset of the clinical signs of the disease, the incidence of subnormal estriol excretion increasing from 25.4 to 41.3% (p < 0.01) (Table II). These data indicate tha; fetal growth and prognosis are already determined, presumably due to impaired placental function, before the onset of the clinical signs of preeclampsia, when the disease occurs before 37 weeks’ gest+ion. We are grateful to our colleagues on the medical and nursing staff of the hospital for their co-operation in this study, to Miss Michelle Willis for skilled technical assistance, and to Mrs. Janet Walstab for the statistical analyses.
glycaemia) in the aetiology of pre-eclampsia, Lancet 1:923, 1977.. 2. Cant, N. F., Madden, J. D., Siiteri, P. K., and MacDonald,
Volume Number
13.5 3
P. C.: The metabolic clearance rate of dehydroepiandrosterone sulfate. III. The effect of thiazide diuretics in normal and future pre-eclamptic pregnancies, AM. J. OBSTET. GYNECOL. 123: 159, 1975. 3. Merrett, J. D., and Hunter, R. J.: Serum heat stable alkaline phosphatase levels in normal and abnormal pregnancies, J. Obstet. Gynaecol. Br. Commonw. 80:957, 1973. 4. Masson. G. M.: Plasma oestriol in pre-eclampsia, J: Obstet. Gynaecol. Br. Commonw. 80:206, 1973. 5. Brown, J. B., MarLeod. S. C.. Macnaughtan, C., Smith, M.
Urinary
estriol
excretion
before
onset
of pre-eclampsia
347
A., and Smyth, B.: A rapid method for estimating oestrogens in urine,using a semi-automaticextractnr. ,J. Endocrinol. 42:5, 1968. 6. Kitchen, W. H.: The relationship between birth weight and gestational age in an Australian hospital pc~pulation. Auat. Paediatr. J. 429, 1968. 7. Abell, D. A., and Beischer, N. A.: The effc.cts of hjpoglycaemia and hyperglycaemia on pregnancy ourcome, Aust. N. %. J. Obstet. Gynaecol. 16:75, 1976.
A.
LONG,
DAVID
A.
ABELL,
NORMAN Melbourne,
A.
M.B., M.B.,
BEISCHER,
Victoria,
B.S.,
M.R.C.O.G.
B.S.,
M.G.O.,
M.D.,
M.G.O.,
M.R.C.O.G.,
F.C.O.G.(S.A.)
F.R.C.S.(EDIN.),
F.R.A.C.S.,
F.R.C.O.G.
Australia
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 < 0.001). As assessed by the incidences of low estriol excretion, fetal growth retardation, and perinatal wastage, pm-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 < 0.001). Although further deterioration of placental function occurred after the onset of clinical signs (41.3%; p < O.Ol), fetal growth and prognosis were already determined. (AM. J. OBSTET.
GYNECOL.
135344,
1979.)
RECENTLY WE REPORTED thatmaternalhypoglycemia has a significant relationship with both fetal growth retardation and early-onset pre-eclampsia.’ This suggested that a cause of pre-eclampsia may be reduced maternal supply of nutrients to the fetus, a conclusion consistent with the clinical observation that fetal growth retardation often precedes the appearance of the signs of pre-eclampsia. Studies of placental clearance of dehydroepiandrosterone sulfate,* and assays of serum heat-stable alkaline phosphatase3 and plasma estriol level? have also shown, to a varying extent, that placental function may be abnormal before pre-eclampsia becomes clinically apparent. This study was designed to evaluate fetoplacental function by measurement of urinary estriol excretion, both before and after the onset of the clinical signs of pre-eclampsia, and to relate this to the time of onset of pre-eclampsia and fetal outcome (fetal growth retardation and perinatal death). This investigation was possiFrom the Mercy Maternity Obstetrics and Gynaecology, Received for Publication Accepted
November
Hospital and Department University of Melbourne.
June 20, 1978.
23, 1978.
Reprint requests: Professor Norman A. B&her, Department of Obstetrics and Gynaecology, Mercy Maternity Hospital, Clarendon Street, East Melbourne, Victoria, Australia, 3002.
344
of
ble because it is our practice to measure estriol tion in late pregnancy as a screening test. Matwisl
excre-
and methods
At the Mercy Maternity Hospital, Melbourne, many patients have urinary estriol excretion measured as a routine screening test between 30 and 36 weeks’ gestation. The test is also widely used to monitor fetal well being in patients with pre-eclampsia who are treated conservatively. During the period from March, 197 1, until January, 1975, 12,924 patients were delivered at this hospital and pre-eclampsia was diagnosed in 1,316 (10.2%). Pre-eclampsia was diagnosed when at least two of the signs, hypertension 140/90 mm Hg or above, generalized edema, and proteinuria not due to urinary infection or contamination, were present after week 20 of gestation. The high incidence of pre-eclampsia in this series was due to inclusion of patients who acquired these signs during labor. The spectrum of severity of the disease was wide and patients were grouped according to whether the diagnosis was made before or after the beginning of week 37 of gestation, and according to the presence or absence of proteinuria. From these 1,316 patients with pre-eclampsia 919 were selected for this study, those excluded being patients with multiple pregnancy, and patients in whom estriol excretion was not measured at any time during 0002-9378/79/190344+04$00.40/0
@ 1979 The C. V. Mosby Co
Urinary
pregnancy. The test was unavoidably omitted in unbooked patients who were admitted to hospital in labor or with severe disease requiring immediate delivery, and in booked patients who contracted severe preeclampsia before the routine screening test was performed. The test was more often omitted in private patients because of administrative reasons. Crinary rstriol excretion was measured according to the method of Brown and colleagues’ and was regarded as low when one or more values were obtained below a line joining 8 mg/24 hours (27.8 pmo1/24 hours) at 30 weeks’ and 12 mgi24 hours (4 1.6 pmol/24 hours) at 40 weeks’ gestation. Infants were diagnosed as small for dates (fetal growth retardation) when birth weight was below the tenth percentile according to gestational age for infants born in this community.’ Perinatal deaths included stillbirths and neonatal deaths occurring within 28 days of birth. Statistical analysis of the data was performed by testing of binomial distribution.
Results Severity of pre-eclampsia and fetal outcome according to time of onset. The group of patients with earlyonset pre-eclampsia had significantly higher incidences of proteinuria, fetal growth retardation, and perinatal death than the late-onset group (p < 0.001) (Table I). Fetal growth retardation was a complication in 43 of the 249 patients with early-onset pre-eclampsia. The signs of pre-eclampsia were present for no more than I week in 12 of the 43 pregnancies. Thus, the high incidence of fetal growth retardation in early-onset pre-eclampsia was not necessarily a consequence of protracted clinical disease. Estriol excretion before the onset of pre-eclampsia. As shown in Table II, the incidence of subnormal estrio1 excretion was 25.4% in patients destined to develop early-onset pre-eclampsia. This incidence was signilicantly higher than that in the total hospital population (13.7%‘: p < 0.001). By contrast, the incidence of subnormal estriol excretion in patients destined to develop late-onset pre-eclampsia was 10.3%, which was significantly less than that in the total hospital population (p < 0.05). There was a significant association between the level of estriol excretion before the emergence of preeclampsia and fetal outcome (Table III). When estriol excretion was normal the incidence of fetal growth retardation was 5.4% and the perinatal death rate was 0.5%. whereas when estriol excretion was subnormal the incidences were 16.8 and 5.3%, respectively (p < 0.001).
estriol
excretion
before
onset
of pre-eclampsia
345
Table I. Incidence of proteinuria, fetal growth retardation, and perinatal death according to time of onset of pre-eclampsia
Less than 31 weeks’
249
61.3
17.3
6.8
670
40.1***
tj.:<***
0.4***
_
__
-
-
919
45.8
9.2
2.2
gestation More than 37 weeks’
gestation Total series
***p < 0.001 = Significance of difference between the two pre-eclampsia groups. Statistically significant correlations between estriol excretion and fetal outcome were also present when the patients were divided into early- and late-onset groups (Table III). However, low estriol excretion carried a more sinister prognosis with regard to fetal outcome in the early-onset group. In this group the incidences of fetal growth retardation and perinatal death were 6.5 and 3.3%. respectively, when estriol excretion was normal, whereas when estriol excretion was subnormal the corresponding incidences were 22.6 (p < 0.05) and 12.9% (p < O.OOl), respectively. Estriol excretion after the onset of pre-eclampsia. After the appearance of the clinical signs of preeclampsia in the early-onset group the incidence of subnormal estriol excretion rose significantly from 25.4 to 41.3% (p < 0.01) (Table II). After the diagnosis of late-onset pre-eclampsia the incidence of subnormal estrio1 excretion rose from 10.3 to 15.7%. It can be concluded that the appearance of the clinical signs of preeclampsia is associated with deterioration of placental function mainly in patients with early-onset disease. In patients with early-onset pre-eclampsia both fetal growth retardation and perinatal death were found to have a highly significant correlation with low estriol excretion (Table III). In this group as a vvhole the incidence of fetal growth retardation was 17.3% and the perinatal death rate was 6.8% (Table I). When estriol excretion was normal after the onset of pre-eclampsia the incidences of these complications were 8.0 and 0.8%, respectively, whereas when estriol excretion was subnormal the corresponding incidences were 35.2 and 14.8%, respectively (p < 0.001) (Table III). Too few patients had estriol excretion measured after the signs of pre-eclampsia appeared in the lateonset group to permit adequate analysis of results. In the total series of 919 patients, among those patients tested after the onset of pre-eclampsia, estriol excretion
346
Long, Abell, and Beischer
Table
II. Incidence
of low estriol excretion
before
and after onset of pre-eclampsia Before
Time of onset
of p-e-eckzmpsia
Less than 37 weeks’ More than 37 weeks’ Total series
gestation gestation
No. of patients
No. of patients screened
249 670 919
122 622 744
*p < 0.05; ***p < 0.001; N.S. = Not excretion (13.7% in 5,000 patients’).
significant.
Table
to estriol excretion
III.
Fetal outcome
according
onset
Before
Significance
Low estriol excretion ( %)
of difference
onset of /we-eckzmpsia
More than 37 weeks’ gestation: Normal estriol excretion Low estriol excretion
5.2,, 14.1
1.6
Total series: Normal estriol excretion Low estriol excretion
5.4 *** 16.8
0.5 *** 5.3
**p < 0.01;
***p
< 0.001
= Significance
No. of patients screened
41.3*** 15.7 N.S. 30.6
213 153 366 with
hospital
Low rstriol excretion ( % )
incidence
of low
estriol
After
3.3 *** 12.9
of difference
onset of p-e-eclumpsia
Per&at51 death rate (%)
6.5, 22.6
*p < 0.05;
compared
onset of pre-eclampsia
before and after onset of pre-eclampsia
Less than 37 weeks’ gestation: Normal estriol excretion Low es&o1 excretion
estriol
After
25.4*** 10.3* 12.8
Small-fordates infants (76)
Time of onset of pre-eclampsia
of pre-eclampsia
between
8.0 *** 35.2
0.8 *** 14.8
9.3 8.3
8.3
8.7 *** 29.5 groups
of patients
0.4 *** 13.4 with
normal
and
subnormal
excretion.
was low in 33 of the 55 pregnancies (60%) complicated by fetal growth retardation and in 15 of the 16 (93%) complicated by perinatal death.
Comment This study showed that in patients with pre-eclampsia, low estriol excretion had a highly significant association with fetal jeopardy (growth retardation and perinatal death), both before and after the onset of the clinical signs of the disease (Table III). When assessed in terms of the incidences of low estriol excretion, fetal growth retardation, and perinatal death rate, preeclampsia of late onset (73% of cases) was shown to be a benign disease in comparison with pre-eclampsia of early onset (27% of cases). Whether or nbt the incidence of fetal growth retardation is increased in pre-edampsia is a matter of continuing debate in the literature. Indeed, in this series its over-all incidence (9.2%) was not significantly higher than that of the hospital population (8.6%). This study has shown that the distribution of fetal growth retardation was sharply polarized between pre-eclampsia of
REFERENCES 1. Long, P. A., Abell, D. A., and Beischer, N. A.: Importance of abnormal glucose tolerance (hypoglycaemia and hyper-
early and late onset, there being a large and significant increase in its incidence among patients with earlyonset disease. In comparison with the total obstetric population, patients destined to develop early-onset pre-eclampsia had a significantly increased incidence of low estriol excretion (p < 0.001) (Table II). In this group there was further deterioration of placental function after the onset of the clinical signs of the disease, the incidence of subnormal estriol excretion increasing from 25.4 to 41.3% (p < 0.01) (Table II). These data indicate tha; fetal growth and prognosis are already determined, presumably due to impaired placental function, before the onset of the clinical signs of preeclampsia, when the disease occurs before 37 weeks’ gest+ion. We are grateful to our colleagues on the medical and nursing staff of the hospital for their co-operation in this study, to Miss Michelle Willis for skilled technical assistance, and to Mrs. Janet Walstab for the statistical analyses.
glycaemia) in the aetiology of pre-eclampsia, Lancet 1:923, 1977.. 2. Cant, N. F., Madden, J. D., Siiteri, P. K., and MacDonald,
Volume Number
13.5 3
P. C.: The metabolic clearance rate of dehydroepiandrosterone sulfate. III. The effect of thiazide diuretics in normal and future pre-eclamptic pregnancies, AM. J. OBSTET. GYNECOL. 123: 159, 1975. 3. Merrett, J. D., and Hunter, R. J.: Serum heat stable alkaline phosphatase levels in normal and abnormal pregnancies, J. Obstet. Gynaecol. Br. Commonw. 80:957, 1973. 4. Masson. G. M.: Plasma oestriol in pre-eclampsia, J: Obstet. Gynaecol. Br. Commonw. 80:206, 1973. 5. Brown, J. B., MarLeod. S. C.. Macnaughtan, C., Smith, M.
Urinary
estriol
excretion
before
onset
of pre-eclampsia
347
A., and Smyth, B.: A rapid method for estimating oestrogens in urine,using a semi-automaticextractnr. ,J. Endocrinol. 42:5, 1968. 6. Kitchen, W. H.: The relationship between birth weight and gestational age in an Australian hospital pc~pulation. Auat. Paediatr. J. 429, 1968. 7. Abell, D. A., and Beischer, N. A.: The effc.cts of hjpoglycaemia and hyperglycaemia on pregnancy ourcome, Aust. N. %. J. Obstet. Gynaecol. 16:75, 1976.