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The effect of rest and intravenous infusion of hypertonic dextrose on subnormal estriol excretion in pregnancy
The effect of rest and intravenous infusion of hypertonic dextrose on subnormal estriol excretion in pregnancy NORMAN
A.
BEISCHER,
M.D.,
F.R.A.C.S.,
(EDIN.),
EDWARD
F.
Melbourne,
F.R.C.S.
F.R.C.O.G.
O’SULLIVAN,
Victoria,
M.G.O.,
M.B.B.S.,
M.R.A.C.P.
Australia
The effects of rest in bed and intravenous infusion of hypertonic dextrose were evaluated in a consecutive series of 42 patients with persistently low estriol excretion. Estriol excretion rose above the lower limit of normal in 10 of 30 patients treated by rest in bed in the lateral position.Estriol excretion increased in 6 of 12 patients treated by hypertonic dextrose infusion, the rate of improvement being greater than in those who responded favorably to rest in bed alone. Neither method resuJted in improvement of estriol excretion when the patient had pre-eclampsia. Hypertonic dextrose infusion appeared to improve fetal nutrition and well-being even when the fetus was malformed and clinically growth retarded.
MEASUREMENT
of urinary estriol excretion of all pregnant patients allows detection of the fetus at risk of intrauterine death in both complicated and uncomplicated pregnancies.‘l 2 Many fetal deaths, although predictable by estriol assay, are inevitable because the fetus is not mature enough to survive if born alive by immediate delivery. The urgent need in obstetrics today is a method for improvement of fetoplacental function when there is no maternal contraindication, such as severe hypertension or preeclampsia, to continuation of the pregnancy. Recent reports have established that disordered fetoplacental function, as indicated From Mercy Department Gynaecology,
by subnormal urinary estriol excretion, can sometimes be improved by correction of maternal anemia,3 successful intrauterine blood transfusion when the fetus has severe erythroblastosis,4-6 intermittent abdominal decompression,7and administration of dietary supplements to undernourished pregnant women.8 Most obstetricians empirically believe that adequate rest and nutrition of the pregnant patient are of importance in determining fetal quality and survival. It is our purpose in this report to evaluate the effects of these measuresin 42 consecutive patients with persistently low urinary estriol excretion.
Maternity Hospital, and the of Obstetrics and University of Melbourne.
F;;;ived
for publication
Accepted 1972.
for
publication
Patients and methods During the 11 months from March, 1971, to January, 1972, urinary estriol assayswere performed on 1,014 consecutive patients who were delivered at the Mercy Maternity Hospital, Melbourne. This seriesincluded emergency admissionsas well as private and clinic patients. In this hospital, all patients have
February 23, March
13,
Reprint re uests: Dr. N. A. Be&her, Degt. 06. P Gyn., University of Melbourne, Mercy Maternit Hospital, Melbourne, Victoria, Austra Fta.
771
772
Be&her
July 15,
and O’Sullivan
Am, J. Obstet.
1972 Gynecol.
Table I. Fetal results in 1,014 consecutive pregnancies according to urinary estriol excretion
Stillbirths Estriol
excretion
Normal (911 patients) Subnormal (103 patients)
No.
4 14
1
Neonatal %
No.
0.4 13.5
estriol assaysperformed as a routine at 30 and 36 weeks’ gestation. The test was also carried out at other times when indicated by complications such as hypertension and preeclampsia, or when low estriol excretion had been detected. Urinary estriol excretion was measuredby the rapid method of Brown and associates.QThe lower limit of normal was defined as a line joining 8 mg. per 24 hours at 30 weeks’ gestation and 12 mg. at 40 weeks and thereafter.lO The study group consisted of 42 patients with persistently low estriol excretion in whom the period of gestation did not exceed 38 weeks. They were all admitted to the hospital for rest in the lateral position, and folic acid, 5 mg. per day, was prescribed in addition to the usual ward diet. All patients had urinary estriol assaysperformed at least three times per week until delivery. X-ray of the fetus was performed in all patients to exclude anencephaly and other skeletal defects. The first 30 patients were treated conservatively when there was no maternal indication for termination of pregnancy and allowed to come into spontaneous labor if estriol excretion rose above the lower limit of normal. When estriol excretion failed to improve, delivery was effected by amniotomy or cesarean section but, in the absence of maternal complications, not until the pregnancy had reached a maturity of at least 36 weeks. Twelve consecutive patients were treated with intravenous hypertonic dextrose infusion when estriol excretion remained subnormal after seven days of rest in the hospital. At the onset of the project, an empirical regimen of 2 L. of 25 per cent dextrose in water and 2 L. of 20 per cent fructose in water was infused into a central vein over a period of 48 hours. It was considered that
9 9
deaths (
%
0.9 8.7
Fetal weight below tenth percentile
Major malformations No.
14 9
/
%
1.5 8.7
No.
86 43
1
%
9.4 41.7
with such a regimen there would be little or no change in the acid-base status of the mother and that a 10 to 30 mg. per 100 ml. rise in fasting blood glucose would be achieved in most patients. Subsequently, the report of Pearson and Shuttleworthll was noted in which it was stated that a 500 ml. infusion of 20 per cent fructose, given to women in labor over a period of 30 minutes, resulted in deleterious changes in the acid-base status of the fetus. As a result of this report, our regimen was altered to an infusion of 4 L. of 25 per cent dextrose in water given over a period of 48 hours. Estriol collections were continued throughout the infusion period. It was noteworthy that, as a result of the infusion of hypertonic dextrose solutions, no patient developed clinical evidence of thrombophlebitis. Results
and
comment
Subnormal estriol excretion was recorded on one or more occasionsin 103 of the 1,014 patients (11.3 per cent) and was associated with a significant increase in the incidences of stillbirths, neonatal deaths, major fetal malformations, and intrauterine growth retardation (Table I). For the purpose of perspective, the fetal results according to the patterns of low estriol excretion are shown in Table II. In the study group of 42 patients with persistently low estriol values, there were 11 fetal deaths, 19 infants with birth weights lessthan the tenth percentile according to the period of gestation at delivery, and 4 fetuseswith major congenital abnormalities. Effect of bed rest. Favorable response. Estriol excretion improved and rose above the lower limit of normal in 10 of the 30 patients treated by
Volume Number
113 6
Subnormal
Table II. Fetal results according
to patterns
of low estriol
estriol excretion
excretion
in pregnancy
773
in 103 patients --__-.-._
Birth weight
I-
< tenth No. of patients
excretion
Estriol
One low value, then all normal One low value within a normal run Normal run with last value low Fluctuating above and below lower limits of normal Single low value
Stillbirths
Neonatal deaths
percentile
Cesarean section
18
-
-
4
2
6
-
-
3
1
9
1
-
5
2
12
-
2
5
5
1 Diaphragmatic
16
8
1
7
4
1 1 1 1
Congenital
malformations
hernia
Encephalocele Sacrococcygeal teratoma Idiopathic hydrops fetalis Hydrocephaly and me-
ningomyelocele Persistently
low
Treated by rest (Figs. 1
30
5
3
15
13
12
-
3
4
6
14 13.5
9 8.7
43 41.7
33 32.0
dextrose
infusion
and 2) Treated by rest and hypertonic dextrose infusion (Figs. 3 and 4) Totals Total
103 100
%
Table III. The effect of rest in bed and intravenous excretion
according
to prenatal
1 1 1 1
9 a.7
on persistently
Rest
Pre-eclamptic toxemia Hypertension Clinical placental insufficiency Abruptio placentae Cardiac disease Rhesus immunization Cortisone therapy for eczema Renal disease None
7 3
(5)
2
(1) (1)
1 : 1 4
Totals Figures
in the lateral
Estriol excretion remained low
complication
(1)
20 (8) in parentheses
denote
the number
low estriol
complications Rest
Prenatal
Anencephaly Absent septum pellucidum Potter’s syndrome Meningomyelocele
of fetal
plus
position
Estsiol excretion became normal
hypertonic infusion
Estriol excretion remained low
dextrose
Estriol excretion became normal
1 2 1 -
1 -
1 5
r 1
(1)
1 2
10
6
(7.)
6
2
(1) i. I
(1)
(1)
deaths.
rest in bed in the lateral position (Fig. 1). In this group, all infants survived, none had congenital anomalies, and five weighed less than the tenth percentile according to dates for infants born in this community.l* Rest did not result in improvement of estriol excretion when the patient had pre-eclamptic toxemia. Estriol excretion improved in 7 of 13 pregnancies where there was no maternal
complication or only clinical evidence of placental insufficiency (Table III). In Case 1 (Fig. 1) , the patient had an intrauterine death in her only previous pregIn the present pregnancy, she was nancy. admitted to the hospital at 33 weeks when estriol values were found to be subnormal. Estriol excretion improved from a minimal value of 5 mg. per 24 hours at 34 weeks to
774
July 15, 1972
Beischer and O’Sullivan
Am,J. Obstet. Cynecol.
30
32
34 WEEKS
36 OF
36
40
GESTATION
Fig. 1. Estriol excretion in 10 of 30 patients with persistently low values who responded favorablv to bed rest in the lateral Dosition. l = Infant survived. The heavy line denotes the lower l&it of normal estriol excretion. reach 14.5 mg. at 37 weeks.Labor then began spontaneously, and a normal delivery resulted in a surviving infant, who weighed 2,080 grams at birth. This patient had no prenatal complication and illustrated the possible value of bed rest even when the infant was severely growth retarded. In Case 2 (Fig. 1) , the patient had an episode of moderate abruptio placentae at 31 weeks, after which estriol excretion was 6.5 mg. per 24 hours. Estriol excretion remained low for three weeks but then entered and remained within the normal range. Repeat cesarean delivery at 39.5 weeks resulted in a healthy but growth-retarded infant, who weighed 2,400 grams at birth. The placenta weighed 320 grams, and one half of its surface was separated by an old blood clot. We have previously reported that low estriol excretion following abruptio placentae has a natural tendency to improve in some patients.13fI4 Unfavorable response. In the group of 20 patients in whom low estriol excretion persisted in spite of rest in bed (Fig. 2)) there were 8 fetal deaths, 2 fetuseswith major malformations, and 10 with growth retardation. There was a high incidence of pre-eclampsia
in this group, and fetal death occurred in 5 of 7 pregnancies associated with this complication (Table III). These findings provide further evidence that there is no place for conservative management when a patient has severe pre-eclampsia, especially when estriol excretion is subnormal. In Case 3 (Fig. 2)) the patient clinically had a normal pregnancy, but estriol values ranged between 5.6 and 4.3 mg. per 24 hours. Normal delivery occurred at 38 weeks after a spontaneous onset of labor. The infant weighed 2,560 grams and was in poor condition at birth. This child has survived but has cerebral malformations in the area of the hypothalamus. He has been shown to have an absent septum pellucidurn, optic atrophy, diabetes insipidus, and myxedema. In Case 4 (Fig. 2), the fetus was anencephalic, and, as expected, estriol excretion remained persistently low. Effect of hypertonic dextrose infusion. Favorable response. Estriol excretion improved and rose above the lower limits of normal in 6 of the 12 patients treated by intravenous infusion of dextrose (Fig. 3). Comparison with Fig. 1 illustrated that the rate of improvement was greater than in the
Volume Number
113 6
Subnormal
30
32
34 WEEKS
36 OF
estriol excretion
in pregnancy
38
775
40
GESTATION
Fig. 2. Estriol excretion in 20 of 30 patients with persistently low values who failed to respond to rest in bed. t = Stillbirth; X = neonatal death; l = infant survived.
30
32
36
34 WEEKS
OF
36
40
GESTATION
Fig. 3. Estriol excretion in 6 of 12 patients with persistentIy low values in spite of bed rest who responded favorably to intravenous dextrose infusion. Arrows denote times of administration of dextrose infusions. X = Neonatal death; l = infant survived. group of patients who responded favorably to rest in bed alone. Furthermore, these patients received dextrose infusion only after estriol excretion had failed to increase significantly with rest in the lateral position. We interpret these results as indicative of a substantial beneficial effect of intravenous dex-
trose infusion in these patients. We were surprised that a single infusion for 48 hours was sufficient to maintain normal es&o1 excretion until delivery, especially as 5 of the 6 patients were allowed to go home after three normal estriol values had been recorded. In this group, only one infant was growth
776
Be&her
July 15, 1972 Am. J. Obstet. Gynecol.
and O’Sullivan
1 30
32
36
34 WEEKS
OF
38
40
GESTATION
Fig. 4. Estriol excretion in 6 of 12 patients with persistently low values in spite of bed rest who also failed to respond favorably to intravenous dextrose infusion. Arrows denote timesof administration of dextrose infusions. X = Neonatal death; l = infant survived.
retarded at birth. There were two infants with major malformations; one of these malformations was the cause of the only fetal death in the group (Case 5, Fig. 3). It was noteworthy that intravenous dextrose infusion did not result in improvement of estriol excretion when the patient had pre-eclampsia. Estriol excretion improved in 4 of the 6 pregnancies where there was no maternal complication or only clinical evidence of placental insufficiency (Table III). In 2 of the 3 patients who showed an immediate and dramatic rise in estriol output after intravenous dextrose infusion, the fetuseswere malformed. In Case 5 (Fig. 3), the patient was an infertile, elderly primipara with multiple fibromyomas. Clinically, the fetus appeared small for dates, and she was admitted to the hospital at 33 weeks becauseestriol excretion was 5.9 mg. per 24 hours. Estriol values remained low with rest in the lateral position but rose from 7.2 to 17.6 mg. per 24 hours within 4 days of the intravenous dextrose infusion. Cesarean section was performed at 35.1 weekswhen the patient came into spontaneous labor. The fetus weighed 2,000 grams at birth and, although well nourished, was in
poor condition and died after 2.5 hours. At autopsy, the infant was shown to have pulmonary hypoplasia, renal agenesis,and malformations of the bony pelvis, legs, rectum, and external genitals. In Case 6 (Fig. 3)) the patient had recurrent urinary infections, and the fetus was clinically small for dates. In spite of rest in the hospital, estriol excretion fluctuated above and below the lower limit of normal and then became persistently low. After intravenous dextrose infusion, estriol excretion rose steadily from 6.4 mg. to reach 21.7 mg. per 24 hours at 38.2 weeks’ gestation, when spontaneous labor began. Forceps delivery resulted in a living female infant who weighed 2,580 grams at birth. The infant had a meningomyelocele which was corrected by immediate operation. This child has thrived and has no muscular or sensory impairment of the sphincters or lower limbs. These casesillustrate the over-all finding in this study that there is a high incidence of major congenital fetal abnormalities when maternal estriol excretion is persistently low (Table II). However, these caseshave made us even more enthusiastic about the probable value of intravenous dextrose infusion when
Volume 113 Number 6
Subnormal estriol excretion in pregnancy
estriol excretion is subnormal. It is well established that fetal growth retardation has a significant positive correlation with both fetal malformations and low maternal urinary excretion of estriol.15-1’ It would appear from this experience that intravenous dextrose infusion can promote an improvement of fetal nutrition and well-being, even when the fetus is malformed and clinically growth retarded. Unfavorable response. In the group of 6 patients in whom low estriol excretion persisted in spite of rest and intravenous dextrose infusion (Fig. 4)) there were two neonatal deaths, and three infants had birth weights less than the tenth percentile. There was no fetal malformation in this group. In the two patients with pre-eclampsia, the maternal condition seemed to deteriorate further after dextrose infusion. In Case 7 (Fig. 4)) cesarean section was performed at 32.3 weeks when the patient developed severe oliguria. The infant was born alive and died after 24 hours due to hyaline membrane disease and pulmonary hemorrhage. The infant was not small for dates and weighed 1,870 grams at autopsy. In Case 8 (Fig. 4)) there was no maternal complication, and cesarean section was performed at 36 weeks when estriol excretion fell to 3.3 mg. per 24 hours. The infant was growth retarded, weighed 1,840 grams at birth, and died due to the respiratory distress syndrome. In 4 of the 6 patients in this group, there was a short-lived but disconcerting fall in estriol excretion during the intravenous infusion. These patients all received 2 L. of fructose and 2 L. of dextrose, and it is possible that the depression of estriol excretion may have been due to a harmful effect of the fructose.ll The only patient who received two intravenous infusions showed a tempo-
777
rat-y fall of estriol output on the first occasion when she was given fructose and dextrose, but not on the second occasion when she was given dextrose alone (Fig. 4) . The physiologic explanation of the beneficial effect of bed rest and intravenous hypertonic dextrose infusion when maternal estriol excretion is subnormal is, at this stage, a matter for conjecture. Rest in the lateral position may improve placental blood flow and promote the transport of oxygen and nutriments to the fetus. This was also the explanation postulated by MacRae and colleagues7 to account for the significant rise in estriol output that occurred when patients with low estriol excretion and small-for-dates fetuses had intermittent abdominal decompression in pregnancy. It would be easy to believe that hypertonic dextrose could have a more direct favorable influence than bed rest in patients who have unusually low blood sugar levels. All patients at the Mercy Maternity Hospital have three hour glucose tolerance tests performed as a routine at 32 weeks’ gestation. Our preliminary data suggest that women with apparently normal pregnancies who have low and whose fetuses are estriol excretion, growth retarded, have unusually low fasting blood sugar levels and flat glucose tolerance tests. The correlation between low urinary estriol excretion and abnormally low glucose tolerance curves in pregnancy will be the subject of a further report. We wish to thank the Medical and Nursing Staffs of the hospital for their cooperation in this study and Mr. J. M. Schramp for preparation of the illustrations. We also thank Miss Frances McBride for skilled technical assistance.
REFERENCES
1. Beischer, 2. 3.
N. A., Bhargava,
V. L., Brown,
J. B., and Smith, M. A.: J. Obstet. Gynaecol. Br. Commonw. 75: 1024, 1968. Beischer, N. A., and Brown, J. B.: Obstet. Gynecol. Survey 1972. In press. Beischer, N. A., Townsend, L., Holsman, M., Brown, J. B., and Smith, M. A.: AM. J. OBSTET.GYNECOL. 102: 819,1968.
4.
5. 6. 7.
Bjerre, Doran,
S., Gold, C. C., Wilson, R., and T. A.: A111. J. OBSTET. GYNECOL. 102: 275, 1968. Dickey, R. P., Besch, P. K,, and Ullery, J. C.: AM. J. OBSTET. GYNECOL. 102: 222, 1968. Michie, E. A., and Robertson, J. G.: J. Obstet. Gynaecol. Br. Commonw. 78: 34, 1971. MacRae, D. J., Mohamedally, S. M., and
778
Beischer and O’Sullivan
Willmot, M. P.: J. Obstet. Gynaecol. Br. Commonw.78: 636, 1971. 8. Iyengar, L.: AM. J. OBSTET. GYNECOL. 102: 834, 1968. 9. Brown, J. B., MacLeod, S. C., MacNaughtan, C., Smith, M. A., and Smyth, B.: J. Endocrinol. 42: 5, 1968. 10. MacLeod, S. C., Brown, J. B., Be&her, N. A., and Smith, M. A.: Aust. N. Z. J. Obstet. Gynaecol. 7: 25, 1967. 11. Pearson, J. F., and Shuttleworth, R.: AM. J. OBSTET. GYNECOL. 111: 259, 1971. 12. Kitchen, W. H.: Aust. Paediatr. J. 4: 29, 1968.
July 15, 1972 Am. J. Obstet. Gynecol.
13. Beischer, N. A., Brown, J. B., MacLeod,
S. C.,
and Smith, M. A.: J. Obstet. Gynaecol. Br. Commonw. 74: 51, 1967. 14. Be&her, N. A., Reid, S., Brown, J. B., and Macafee, C. A. J.: Aust. N. Z. J. Obstet. Gynaecol. 10: 191, 1970. 15. Galbraith, R. S., Low, J. A., and Boston, R. W.: AM. J. OBSTET. GYNECOL. 106: 352, 1970. 16. Lugo, G., and Cassady, G.: AM. J. OBSTET. GYNECOL. 109: 615, 1971. 17. Reid, S., Beischer, N. A., Brown, J. B., and Smith, M. A.: Aust. N. Z. J. Obstet. Gynaecol. 8: 189, 1968.
A.
BEISCHER,
M.D.,
F.R.A.C.S.,
(EDIN.),
EDWARD
F.
Melbourne,
F.R.C.S.
F.R.C.O.G.
O’SULLIVAN,
Victoria,
M.G.O.,
M.B.B.S.,
M.R.A.C.P.
Australia
The effects of rest in bed and intravenous infusion of hypertonic dextrose were evaluated in a consecutive series of 42 patients with persistently low estriol excretion. Estriol excretion rose above the lower limit of normal in 10 of 30 patients treated by rest in bed in the lateral position.Estriol excretion increased in 6 of 12 patients treated by hypertonic dextrose infusion, the rate of improvement being greater than in those who responded favorably to rest in bed alone. Neither method resuJted in improvement of estriol excretion when the patient had pre-eclampsia. Hypertonic dextrose infusion appeared to improve fetal nutrition and well-being even when the fetus was malformed and clinically growth retarded.
MEASUREMENT
of urinary estriol excretion of all pregnant patients allows detection of the fetus at risk of intrauterine death in both complicated and uncomplicated pregnancies.‘l 2 Many fetal deaths, although predictable by estriol assay, are inevitable because the fetus is not mature enough to survive if born alive by immediate delivery. The urgent need in obstetrics today is a method for improvement of fetoplacental function when there is no maternal contraindication, such as severe hypertension or preeclampsia, to continuation of the pregnancy. Recent reports have established that disordered fetoplacental function, as indicated From Mercy Department Gynaecology,
by subnormal urinary estriol excretion, can sometimes be improved by correction of maternal anemia,3 successful intrauterine blood transfusion when the fetus has severe erythroblastosis,4-6 intermittent abdominal decompression,7and administration of dietary supplements to undernourished pregnant women.8 Most obstetricians empirically believe that adequate rest and nutrition of the pregnant patient are of importance in determining fetal quality and survival. It is our purpose in this report to evaluate the effects of these measuresin 42 consecutive patients with persistently low urinary estriol excretion.
Maternity Hospital, and the of Obstetrics and University of Melbourne.
F;;;ived
for publication
Accepted 1972.
for
publication
Patients and methods During the 11 months from March, 1971, to January, 1972, urinary estriol assayswere performed on 1,014 consecutive patients who were delivered at the Mercy Maternity Hospital, Melbourne. This seriesincluded emergency admissionsas well as private and clinic patients. In this hospital, all patients have
February 23, March
13,
Reprint re uests: Dr. N. A. Be&her, Degt. 06. P Gyn., University of Melbourne, Mercy Maternit Hospital, Melbourne, Victoria, Austra Fta.
771
772
Be&her
July 15,
and O’Sullivan
Am, J. Obstet.
1972 Gynecol.
Table I. Fetal results in 1,014 consecutive pregnancies according to urinary estriol excretion
Stillbirths Estriol
excretion
Normal (911 patients) Subnormal (103 patients)
No.
4 14
1
Neonatal %
No.
0.4 13.5
estriol assaysperformed as a routine at 30 and 36 weeks’ gestation. The test was also carried out at other times when indicated by complications such as hypertension and preeclampsia, or when low estriol excretion had been detected. Urinary estriol excretion was measuredby the rapid method of Brown and associates.QThe lower limit of normal was defined as a line joining 8 mg. per 24 hours at 30 weeks’ gestation and 12 mg. at 40 weeks and thereafter.lO The study group consisted of 42 patients with persistently low estriol excretion in whom the period of gestation did not exceed 38 weeks. They were all admitted to the hospital for rest in the lateral position, and folic acid, 5 mg. per day, was prescribed in addition to the usual ward diet. All patients had urinary estriol assaysperformed at least three times per week until delivery. X-ray of the fetus was performed in all patients to exclude anencephaly and other skeletal defects. The first 30 patients were treated conservatively when there was no maternal indication for termination of pregnancy and allowed to come into spontaneous labor if estriol excretion rose above the lower limit of normal. When estriol excretion failed to improve, delivery was effected by amniotomy or cesarean section but, in the absence of maternal complications, not until the pregnancy had reached a maturity of at least 36 weeks. Twelve consecutive patients were treated with intravenous hypertonic dextrose infusion when estriol excretion remained subnormal after seven days of rest in the hospital. At the onset of the project, an empirical regimen of 2 L. of 25 per cent dextrose in water and 2 L. of 20 per cent fructose in water was infused into a central vein over a period of 48 hours. It was considered that
9 9
deaths (
%
0.9 8.7
Fetal weight below tenth percentile
Major malformations No.
14 9
/
%
1.5 8.7
No.
86 43
1
%
9.4 41.7
with such a regimen there would be little or no change in the acid-base status of the mother and that a 10 to 30 mg. per 100 ml. rise in fasting blood glucose would be achieved in most patients. Subsequently, the report of Pearson and Shuttleworthll was noted in which it was stated that a 500 ml. infusion of 20 per cent fructose, given to women in labor over a period of 30 minutes, resulted in deleterious changes in the acid-base status of the fetus. As a result of this report, our regimen was altered to an infusion of 4 L. of 25 per cent dextrose in water given over a period of 48 hours. Estriol collections were continued throughout the infusion period. It was noteworthy that, as a result of the infusion of hypertonic dextrose solutions, no patient developed clinical evidence of thrombophlebitis. Results
and
comment
Subnormal estriol excretion was recorded on one or more occasionsin 103 of the 1,014 patients (11.3 per cent) and was associated with a significant increase in the incidences of stillbirths, neonatal deaths, major fetal malformations, and intrauterine growth retardation (Table I). For the purpose of perspective, the fetal results according to the patterns of low estriol excretion are shown in Table II. In the study group of 42 patients with persistently low estriol values, there were 11 fetal deaths, 19 infants with birth weights lessthan the tenth percentile according to the period of gestation at delivery, and 4 fetuseswith major congenital abnormalities. Effect of bed rest. Favorable response. Estriol excretion improved and rose above the lower limit of normal in 10 of the 30 patients treated by
Volume Number
113 6
Subnormal
Table II. Fetal results according
to patterns
of low estriol
estriol excretion
excretion
in pregnancy
773
in 103 patients --__-.-._
Birth weight
I-
< tenth No. of patients
excretion
Estriol
One low value, then all normal One low value within a normal run Normal run with last value low Fluctuating above and below lower limits of normal Single low value
Stillbirths
Neonatal deaths
percentile
Cesarean section
18
-
-
4
2
6
-
-
3
1
9
1
-
5
2
12
-
2
5
5
1 Diaphragmatic
16
8
1
7
4
1 1 1 1
Congenital
malformations
hernia
Encephalocele Sacrococcygeal teratoma Idiopathic hydrops fetalis Hydrocephaly and me-
ningomyelocele Persistently
low
Treated by rest (Figs. 1
30
5
3
15
13
12
-
3
4
6
14 13.5
9 8.7
43 41.7
33 32.0
dextrose
infusion
and 2) Treated by rest and hypertonic dextrose infusion (Figs. 3 and 4) Totals Total
103 100
%
Table III. The effect of rest in bed and intravenous excretion
according
to prenatal
1 1 1 1
9 a.7
on persistently
Rest
Pre-eclamptic toxemia Hypertension Clinical placental insufficiency Abruptio placentae Cardiac disease Rhesus immunization Cortisone therapy for eczema Renal disease None
7 3
(5)
2
(1) (1)
1 : 1 4
Totals Figures
in the lateral
Estriol excretion remained low
complication
(1)
20 (8) in parentheses
denote
the number
low estriol
complications Rest
Prenatal
Anencephaly Absent septum pellucidum Potter’s syndrome Meningomyelocele
of fetal
plus
position
Estsiol excretion became normal
hypertonic infusion
Estriol excretion remained low
dextrose
Estriol excretion became normal
1 2 1 -
1 -
1 5
r 1
(1)
1 2
10
6
(7.)
6
2
(1) i. I
(1)
(1)
deaths.
rest in bed in the lateral position (Fig. 1). In this group, all infants survived, none had congenital anomalies, and five weighed less than the tenth percentile according to dates for infants born in this community.l* Rest did not result in improvement of estriol excretion when the patient had pre-eclamptic toxemia. Estriol excretion improved in 7 of 13 pregnancies where there was no maternal
complication or only clinical evidence of placental insufficiency (Table III). In Case 1 (Fig. 1) , the patient had an intrauterine death in her only previous pregIn the present pregnancy, she was nancy. admitted to the hospital at 33 weeks when estriol values were found to be subnormal. Estriol excretion improved from a minimal value of 5 mg. per 24 hours at 34 weeks to
774
July 15, 1972
Beischer and O’Sullivan
Am,J. Obstet. Cynecol.
30
32
34 WEEKS
36 OF
36
40
GESTATION
Fig. 1. Estriol excretion in 10 of 30 patients with persistently low values who responded favorablv to bed rest in the lateral Dosition. l = Infant survived. The heavy line denotes the lower l&it of normal estriol excretion. reach 14.5 mg. at 37 weeks.Labor then began spontaneously, and a normal delivery resulted in a surviving infant, who weighed 2,080 grams at birth. This patient had no prenatal complication and illustrated the possible value of bed rest even when the infant was severely growth retarded. In Case 2 (Fig. 1) , the patient had an episode of moderate abruptio placentae at 31 weeks, after which estriol excretion was 6.5 mg. per 24 hours. Estriol excretion remained low for three weeks but then entered and remained within the normal range. Repeat cesarean delivery at 39.5 weeks resulted in a healthy but growth-retarded infant, who weighed 2,400 grams at birth. The placenta weighed 320 grams, and one half of its surface was separated by an old blood clot. We have previously reported that low estriol excretion following abruptio placentae has a natural tendency to improve in some patients.13fI4 Unfavorable response. In the group of 20 patients in whom low estriol excretion persisted in spite of rest in bed (Fig. 2)) there were 8 fetal deaths, 2 fetuseswith major malformations, and 10 with growth retardation. There was a high incidence of pre-eclampsia
in this group, and fetal death occurred in 5 of 7 pregnancies associated with this complication (Table III). These findings provide further evidence that there is no place for conservative management when a patient has severe pre-eclampsia, especially when estriol excretion is subnormal. In Case 3 (Fig. 2)) the patient clinically had a normal pregnancy, but estriol values ranged between 5.6 and 4.3 mg. per 24 hours. Normal delivery occurred at 38 weeks after a spontaneous onset of labor. The infant weighed 2,560 grams and was in poor condition at birth. This child has survived but has cerebral malformations in the area of the hypothalamus. He has been shown to have an absent septum pellucidurn, optic atrophy, diabetes insipidus, and myxedema. In Case 4 (Fig. 2), the fetus was anencephalic, and, as expected, estriol excretion remained persistently low. Effect of hypertonic dextrose infusion. Favorable response. Estriol excretion improved and rose above the lower limits of normal in 6 of the 12 patients treated by intravenous infusion of dextrose (Fig. 3). Comparison with Fig. 1 illustrated that the rate of improvement was greater than in the
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Fig. 2. Estriol excretion in 20 of 30 patients with persistently low values who failed to respond to rest in bed. t = Stillbirth; X = neonatal death; l = infant survived.
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Fig. 3. Estriol excretion in 6 of 12 patients with persistentIy low values in spite of bed rest who responded favorably to intravenous dextrose infusion. Arrows denote times of administration of dextrose infusions. X = Neonatal death; l = infant survived. group of patients who responded favorably to rest in bed alone. Furthermore, these patients received dextrose infusion only after estriol excretion had failed to increase significantly with rest in the lateral position. We interpret these results as indicative of a substantial beneficial effect of intravenous dex-
trose infusion in these patients. We were surprised that a single infusion for 48 hours was sufficient to maintain normal es&o1 excretion until delivery, especially as 5 of the 6 patients were allowed to go home after three normal estriol values had been recorded. In this group, only one infant was growth
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Fig. 4. Estriol excretion in 6 of 12 patients with persistently low values in spite of bed rest who also failed to respond favorably to intravenous dextrose infusion. Arrows denote timesof administration of dextrose infusions. X = Neonatal death; l = infant survived.
retarded at birth. There were two infants with major malformations; one of these malformations was the cause of the only fetal death in the group (Case 5, Fig. 3). It was noteworthy that intravenous dextrose infusion did not result in improvement of estriol excretion when the patient had pre-eclampsia. Estriol excretion improved in 4 of the 6 pregnancies where there was no maternal complication or only clinical evidence of placental insufficiency (Table III). In 2 of the 3 patients who showed an immediate and dramatic rise in estriol output after intravenous dextrose infusion, the fetuseswere malformed. In Case 5 (Fig. 3), the patient was an infertile, elderly primipara with multiple fibromyomas. Clinically, the fetus appeared small for dates, and she was admitted to the hospital at 33 weeks becauseestriol excretion was 5.9 mg. per 24 hours. Estriol values remained low with rest in the lateral position but rose from 7.2 to 17.6 mg. per 24 hours within 4 days of the intravenous dextrose infusion. Cesarean section was performed at 35.1 weekswhen the patient came into spontaneous labor. The fetus weighed 2,000 grams at birth and, although well nourished, was in
poor condition and died after 2.5 hours. At autopsy, the infant was shown to have pulmonary hypoplasia, renal agenesis,and malformations of the bony pelvis, legs, rectum, and external genitals. In Case 6 (Fig. 3)) the patient had recurrent urinary infections, and the fetus was clinically small for dates. In spite of rest in the hospital, estriol excretion fluctuated above and below the lower limit of normal and then became persistently low. After intravenous dextrose infusion, estriol excretion rose steadily from 6.4 mg. to reach 21.7 mg. per 24 hours at 38.2 weeks’ gestation, when spontaneous labor began. Forceps delivery resulted in a living female infant who weighed 2,580 grams at birth. The infant had a meningomyelocele which was corrected by immediate operation. This child has thrived and has no muscular or sensory impairment of the sphincters or lower limbs. These casesillustrate the over-all finding in this study that there is a high incidence of major congenital fetal abnormalities when maternal estriol excretion is persistently low (Table II). However, these caseshave made us even more enthusiastic about the probable value of intravenous dextrose infusion when
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estriol excretion is subnormal. It is well established that fetal growth retardation has a significant positive correlation with both fetal malformations and low maternal urinary excretion of estriol.15-1’ It would appear from this experience that intravenous dextrose infusion can promote an improvement of fetal nutrition and well-being, even when the fetus is malformed and clinically growth retarded. Unfavorable response. In the group of 6 patients in whom low estriol excretion persisted in spite of rest and intravenous dextrose infusion (Fig. 4)) there were two neonatal deaths, and three infants had birth weights less than the tenth percentile. There was no fetal malformation in this group. In the two patients with pre-eclampsia, the maternal condition seemed to deteriorate further after dextrose infusion. In Case 7 (Fig. 4)) cesarean section was performed at 32.3 weeks when the patient developed severe oliguria. The infant was born alive and died after 24 hours due to hyaline membrane disease and pulmonary hemorrhage. The infant was not small for dates and weighed 1,870 grams at autopsy. In Case 8 (Fig. 4)) there was no maternal complication, and cesarean section was performed at 36 weeks when estriol excretion fell to 3.3 mg. per 24 hours. The infant was growth retarded, weighed 1,840 grams at birth, and died due to the respiratory distress syndrome. In 4 of the 6 patients in this group, there was a short-lived but disconcerting fall in estriol excretion during the intravenous infusion. These patients all received 2 L. of fructose and 2 L. of dextrose, and it is possible that the depression of estriol excretion may have been due to a harmful effect of the fructose.ll The only patient who received two intravenous infusions showed a tempo-
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rat-y fall of estriol output on the first occasion when she was given fructose and dextrose, but not on the second occasion when she was given dextrose alone (Fig. 4) . The physiologic explanation of the beneficial effect of bed rest and intravenous hypertonic dextrose infusion when maternal estriol excretion is subnormal is, at this stage, a matter for conjecture. Rest in the lateral position may improve placental blood flow and promote the transport of oxygen and nutriments to the fetus. This was also the explanation postulated by MacRae and colleagues7 to account for the significant rise in estriol output that occurred when patients with low estriol excretion and small-for-dates fetuses had intermittent abdominal decompression in pregnancy. It would be easy to believe that hypertonic dextrose could have a more direct favorable influence than bed rest in patients who have unusually low blood sugar levels. All patients at the Mercy Maternity Hospital have three hour glucose tolerance tests performed as a routine at 32 weeks’ gestation. Our preliminary data suggest that women with apparently normal pregnancies who have low and whose fetuses are estriol excretion, growth retarded, have unusually low fasting blood sugar levels and flat glucose tolerance tests. The correlation between low urinary estriol excretion and abnormally low glucose tolerance curves in pregnancy will be the subject of a further report. We wish to thank the Medical and Nursing Staffs of the hospital for their cooperation in this study and Mr. J. M. Schramp for preparation of the illustrations. We also thank Miss Frances McBride for skilled technical assistance.
REFERENCES
1. Beischer, 2. 3.
N. A., Bhargava,
V. L., Brown,
J. B., and Smith, M. A.: J. Obstet. Gynaecol. Br. Commonw. 75: 1024, 1968. Beischer, N. A., and Brown, J. B.: Obstet. Gynecol. Survey 1972. In press. Beischer, N. A., Townsend, L., Holsman, M., Brown, J. B., and Smith, M. A.: AM. J. OBSTET.GYNECOL. 102: 819,1968.
4.
5. 6. 7.
Bjerre, Doran,
S., Gold, C. C., Wilson, R., and T. A.: A111. J. OBSTET. GYNECOL. 102: 275, 1968. Dickey, R. P., Besch, P. K,, and Ullery, J. C.: AM. J. OBSTET. GYNECOL. 102: 222, 1968. Michie, E. A., and Robertson, J. G.: J. Obstet. Gynaecol. Br. Commonw. 78: 34, 1971. MacRae, D. J., Mohamedally, S. M., and
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Willmot, M. P.: J. Obstet. Gynaecol. Br. Commonw.78: 636, 1971. 8. Iyengar, L.: AM. J. OBSTET. GYNECOL. 102: 834, 1968. 9. Brown, J. B., MacLeod, S. C., MacNaughtan, C., Smith, M. A., and Smyth, B.: J. Endocrinol. 42: 5, 1968. 10. MacLeod, S. C., Brown, J. B., Be&her, N. A., and Smith, M. A.: Aust. N. Z. J. Obstet. Gynaecol. 7: 25, 1967. 11. Pearson, J. F., and Shuttleworth, R.: AM. J. OBSTET. GYNECOL. 111: 259, 1971. 12. Kitchen, W. H.: Aust. Paediatr. J. 4: 29, 1968.
July 15, 1972 Am. J. Obstet. Gynecol.
13. Beischer, N. A., Brown, J. B., MacLeod,
S. C.,
and Smith, M. A.: J. Obstet. Gynaecol. Br. Commonw. 74: 51, 1967. 14. Be&her, N. A., Reid, S., Brown, J. B., and Macafee, C. A. J.: Aust. N. Z. J. Obstet. Gynaecol. 10: 191, 1970. 15. Galbraith, R. S., Low, J. A., and Boston, R. W.: AM. J. OBSTET. GYNECOL. 106: 352, 1970. 16. Lugo, G., and Cassady, G.: AM. J. OBSTET. GYNECOL. 109: 615, 1971. 17. Reid, S., Beischer, N. A., Brown, J. B., and Smith, M. A.: Aust. N. Z. J. Obstet. Gynaecol. 8: 189, 1968.