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Application of plasma estriol estimations in the management of high-risk pregnancies
Application
of plasma estriol estimations
the management R. S.
S. K.
MATHUR, CHESTNUT,
B.S.
B.
LEAMING
H.
0.
WILLIAMSON, South
of high-risk pregnancies
PH.D.
A.
Charleston,
in
M.D.
Carolina
Serial plasma estriol levels were determined in 51 uncomplicated and 58 complicated pregnancies. Additionally, in 13 uncomplicated, 16 toxemic, and 4 diabetic pregnancies, urinary estriol levels were also collated with plasma estriol ualues. Highly significant correlation was observed between plasma and urinary estriol levels in both uncomplicated and complicated pregnancies. In 5 of 37 toxemic patients, unusually high plasma estriol levels were found, though no definite correlation could be established between estriol levels and the severity of toxemia. From the thirty-fourth week of gestation, plasma estriol levels in diabetic and pre-eclamptic patients were essentially the same as those found in uncomplicated pregnancies; however, the levels in hypertensive pregnant patients were significantly lower. Broad guidelines have been postulated to correlate plasma estriol levels with fetal status from the thirty-sixth week of gestation to term. Levels of less than 5 pg per 100 ml. of plasma in this period are not compatible with a living fetus; values of less than 10 pg per 100 ml. with a dropping estriol pattern are indicative of fetal distress.
1 T I s N o w well recognized that estimation of estriol in a 24 hour urine sample can provide useful information regarding fetal well-being, provided the reliability of both the method and the technician performing the assays has been established. Urinary estrio1 assays suffer from two major drawbacks : Often the collection is incomplete and, as a consequence of the time required for collection of each sample, a delay of 24 hours in performing the assay is inevitable. In highrisk pregnancies, such as those complicated by diabetes or severe toxemia, where time
From the Department Gynecology, Medical Carolina.
may be a critical factor, reliance on a single 24 hour urinary assay could be inadequate as well as misleading. A delay of at least another 24 hours is unavoidable if the assay needs to be repeated; hence, urinary estriol estimations are not of much help in those high-risk pregnancies where they are needed the most. Serial plasma estriol assays may obviate those difficulties. Results of a blood sample collected in the morning can be made available to the clinician the same afternoon. The present investigation was undertaken to assess reliability of serial plasma estriol determinations in the management of high-risk pregnancies to assist a clinician in deciding the most appropriate time to effect delivery, i.e., reducing the chances of intrauterine fetal death on one hand and prematurity on the other.
of Obstetrics and University of South
Presented at the Thirty-fifth Annual Meeting of the South Atlantic Association of Obstetricians and Gynecologistt Plot Springs, Virginia, February 4-7, 1973.
Mafdal Radioactive steroids, solvents, reagents, glassware, and spectrofluorometer were the same as described in a previous report.’
Reprint requests: H. 0. Williamson, M.D., Medical University of South Carolina, 80 Barre St., Charleston, South Carolina 29401.
210
Volume Number
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Plasma
estriol
in high-risk
pregnancies
211
Table I. Amount of estriol in pregnancy plasma obtained from uncomplicated and complicated pregnancies. All figures (mean + S.D.) are expressed as micrograms per 100 ml. of plasma. Numbers in parentheses indicate the total number of samples analyzed , Week of gestation
Uncomplicated
34 35 36 37 38 39 40
15.7? 18.32 18.82 17.52 21.82 26.42 27.6 2
Mean Median Range
“t”
(total)
8.8 6.2 9.6 6.4 9.1 10.0 9.9
21.6 t 9.7 (187) 19.8 6.2 - 52.5
-
Diabetic 14.7+ 17.55 19.0t 17.1 2 21.05 25.3 + 31.2 2
Pre-eclamptic 7.6 6.9 6.6 6.2 6.6 9.8 15.9
16.5 16.42 17.0 20.02 23.9 25.3 25.2
19.92 9.7 (92) 17.0 6.3 - 103.8 1.335 -
Patients included in this study were monitored by serial plasma estriol determinations in the third trimester of pregnancy. Blood was drawn for estriol assays either once a week or more frequently if necessitated by the severity of the complication. A total of 109 patients included in this study had completed their pregnancies. This group included 51 uncomplicated pregnancies, 19 preeclamptic patients, 18 hypertensive patients, and 21 diabetic patients. Cases of preeclampsia were classified as “mild” or “severe,” according to the criteria of Hellman and Pritchard.z Diabetic patients in this study included 13 who were insulin dependent and 8 with gestational diabetes controlled by diet. However, in view of the small number of patients followed, they were grouped simply as “diabetic.” Patients with pregnancies classified as “uncomplicated” did not have adverse clinical signs in the current pregnancy. However, some of these patients did have either missed abortions or stillbirths in their previous pregnancies. Method Plasma estriol levels were determined by a method described before.= Urinary estriols were measured with the use of an adaptation of the plasma estriol method which is specific and accurate even in the presence of glucose up to a concentration of 2 Gm. per 100 ml. Only 0.1 ml. of a 24 hour urine sample is
1 2 5 + 2
8.9 7.5 10.3 11.7 15.6 15.3 16.5
20.8% 13.1 (110) 19.2 6.9 - 77.4 0.858
Hypertensive 12.12 5.0 16.8f 5.5 18.4+ 5.3 17.3+ 8.4 17.42 8.3 22.8 + 11.5 23.7 + 17.8 17.6? 9.0 (81) 16.9 6.4 - 64.8 3.169
required to carry out the assay. The method provides reliable estimates if estriol levels are 1 mg. or more per 24 hour urine sample. Details of this method will be published later. Results Plasma estriol levels in uncomplicated and complicated pregnancies are given in Table I. It is noteworthy that from the thirty-fourth week to term plasma estriol levels in diabetic and pre-eclamptic patients were nut distinguishable from those in uncomplicated pregnancies, whereas the levels were significantly lower in patients with hypertensive vascular disease. Representative examples of the “estrio1 pattern” of patients in different groups are shown in Fig. 1. In each case, the patient went into spontaneous labor and was delivered of a viable infant. Correlation of estriol levels in plasma and urine in uncomplicated pregnancies and diabetic and toxemic patients is shown in Fig. 2, with representative examples from each group in Table II. Estriol levels of less than 5 pg per 100 ml. of plasma were observed in 9 of 10 pregnancies resulting in intrauterine fetal death; in the tenth case, the value was 6.9 pg per 100 ml The temporal relationship between sampling and the fetal death is given in Table III. Four of these patients were serially monitored, and the plasma estriol patterns are shown in Fig. 3. Plasma estriol patterns in 8 pregnancies in which labor
212
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75
et al.
1 .--a O-Q A.G. S.N. K.K. J.A. L.H.
*--a --
60
I 35. i g30a 52s. I B p 20-
IS-
IO -
s-
OA,
. 30
51
1
32
I
33
I
34 mrhl
I
1
I
.
1
t
35
36
37
36
39
40
OIstotion
Fig. 1. Representative examples of plasma estriol patterns in a patient with an uncomplicated pregnancy (S. N.), a diabetic patient (K. K.), a hypertensive patient (L. H.), and pre-eclamptic patients (J. A. and A. G.).
was induced based on total clinical evaluation including plasma estriol levels are shown in Fig. 4. In each case, a viable mature infant was delivered. Also shown in Fig. 4 are the 4 estriol zones proposed for evaluation of individual estriol patterns in relation to fetal well-being. Based on observations made in this study, a scheme to be used in conjunction with clinical findings for interpretation of plasma estriol patterns in assessing fetal well-being is presented in Table IV. Comment The purpose of this investigation was to assess reliability of serial plasma estriol determinations in predicting the status of the fetus, not only in uncomplicated pregnancies but also in high-risk pregnancies such as those complicated by pre-eclampsia, hypertension, and diabetes. This has been done by following each pregnancy on a regular basis-
usually once 3 week or more frequently if felt necessary----and correlating the individual estriol pattern with the outcome of the pregnancy. Additionally, levels of plasma estriol were also compared with urinary estriol to have a better understanding of plasma estriol levels in relation to fetal well-being. A comparison of plasma estriol levels showed that from the thirty-fourth week of gestation to term levels in diabetic and preeclampic patients were not distinguishable from those in uncomplicated pregnancies. However, levels in the hypertensive group were found to be significantly lower. The maxirnum plasma estriol value observed was 103.8 /Lg per 100 ml. (Patient N. G.) This 33-year-old woman. gravida 7, para 6, abortus 0, weighed 237vz pounds and had a blood pressure of 128/92 when examined at the thirty-eighth gestational week; she bvas found to be diabetic, and the diabetes was controlled by diet. Four of the 6 previous infants had weighed 10 pounds or more, with the maximum being 12 pounds, 5 ounces. The previous pregnancies were complicated by hypertensive cardiovascular disease ; however, in the last pregnancy, overt diabetes could not be diagnosed. The plasma estriol values increased from 76 to 103.8 hkg per 100 ml. within a 24 hour period. Corresponding urinary estriol values were 61 and 71 mg. per 24 hours. In an insulindependent diabetic patient (E. J.) with acute pyelonephritis, a maximum plasma estriol level of 42.4 ELg per 100 ml. was observed. The corresponding urinary estriol value was 46 mg. per 24 hours. These rather high values in both plasma and urine may be indicative of increased estriol synthesis by the fetoplacental unit. Additionally, high plasma estriol levels were observed in 4 pre-eclamptic patients (maximum value 77.4 pg per 100 ml.) and 1 patient whose pregnancy was complicated by hypertensive vascular disease (maximum
value
64.8
of
urinary
terminations tients
were
not
pg
performed.
per
100
estriol
in Factor
ml.).
De-
these
pa-
respon-
sible for unusually high plasma estriol levels in complicated pregnancies have not been fully
investigated.
Carrington
and
associates”
Volume Number
117 2
Plasma
estriol
uncompticotrd
60. Uncomplicalad A Diabetic 113) 0 Toxemic (41)
55
pregnancies
213
::~~~+“O’
(40)
SO-
A
DiabgtiCy.080~+13a r-078
45. 2
in high-risk
Toxemic
40.
y.o721+122
r ‘0 01
ti ,e 353 ‘C 30. t w 6 .g
25.
=
20-
0
5
IO
I
IS
20
Plarma
Extriol
25 (p91100
I
30
35
I
f
40
45
ml)
Fig. 2. Correlation between plasma and urinary estriol levels in uncomplicated pregnancy diabetic and toxemic patients. Numbers in parentheses represent the total number of samples analyzed. measured creatinine and estriol clearances in complicated pregnancies. Reduced estriol and creatinine clearances were observed in 28 of 44 pregnancies. However, a normal estriol clearance was associated with a low creatinine clearance in 15 of 44 patients. Additionally, in 13 of 43 pregnqncies, a reduced estriol clearance with a normal creatinine clearance was also noted. A reduced estriol clearance would hardly seem likely to cause such a dramatic increase in plasma estriol levels as those observed in some of our patients (Fig. 1, A. G.) . Taylor and colleague+ B found decreased estriol excretion in 6 patients with pyelonephritis; they attributed this to a reduced placental blood flow rather than a direct renal effect. Additionally, the proportions of “free” estriol to the conjugated form in toxemic pregnancies, were found to be identical to those observed in uncomplicated pregnancies.” Thus, unusually high plasma estriol levels in
complicated pregnancies may be a consequence of increased estriol biosynthesis and/ or altered estrogen metabolism. Further research is warranted to clarify this point. Representative examples of plasma estriol patterns in uncomplicated and complicated pregnancies are shown in Fig. 1. An occasional drop in plasma estriol levels has been observed in uncomplicated pregnancies. Similar observations were also made by Nachtigall and co-workers.7 In all such cases in our study, the drop in the estriol level was less than 50 per cent of the levels of the preceeding week. Diurnal variation in plasma estriol levels has been reported.* In one patient in our study, plasma .levels from the blood samples drawn tit: 8 A.*.., 12:30 P.M., 4 P.M., and 8 P.M. were-34.5, 19.7, 17.7, and 20.8 pg per 100 ml., respectively. Thus, one might expect to observe a decrease of up to 50 per cenr betuteenithe morning and afternoon “levels. An occas&onal
214
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Septrmbcx 15, l!J?3 Am. J. Obstet. Gynecol.
et al.
30
.-..a o--o D---CI I.-.
25
B.C. E.H. M.G N.E
a
31
32
33
34 Weeks
35 36 Gestotion
37
36
39
40
Fig. 3. Plasma estriol pattern observed in 4 pregnancies which resulted in intrauterine fetal deaths. B. C.: Diabetes mellitus for 5 years. E. H.: Diabetes mellitus for 9 years. M. G.: Stillbirth in previous pregnancy. N. E.: Chronic glomerulonephritis. *: Last blood sample drawn before fetal death. t: Last blood sample drawn after intrauterine fetal death.
Table II. Representative examples of serial plasma and urinary estriol determinations in patients with uncomplicated and complicated pregnancies. Plasma levels are expressedas micrograms per 100 ml., whereas urinary amounts are given in milligrams per 24 hrs. Uncomglicated No.
Plasma
1
2.2 2.6 3.9 ;:9”
2 3 4 5 6 7 8 9 Coeficient
(M.
K.)
Urine
Diabetic Plasma
1.6 2.9 7.2 9.3 12.1 19.6 20.4 27.5
11.2 12.2 15.3
(E.
J.)
Urine
14.6 18.8 21.8 24.2 42.4 26.0 27.8
22.6 29.5 37.3 38.2 46.0 28.4 41.4
Pre-eclamptic Plasma
(L.
C.)
Urine
12.4 18.0 16.6 4.8 17.8 28.4 29.4
Hypertensiue
(B. B.)
Plasma
12.0 18.6 21.2 13.1 17.7 31.0 41.2
Urine
7.6 8.2 8.9 10.4 11.6 20.8 20.6 25.5 34.9
15.5 10.5 18.2 18.4 23.1 32.9 15.7 41.3 40.1
of correlation
r
0.975
t
10.74
E. J.: Insulin-requiring cardiovascular disease.
0.817 3.17 diabetes mellitus.
L. C.:
Severe
drop observed in the plasma estriol level in uncomplicated pregnancies either may reflect a physiologic variation or may be a consequenceof diurnal variation. We insist that the blood samplesbe drawn at about 9 A.M. Excellent correlation has been observed (at the 99 per cent confidence level) between amounts of estriol in plasma and urine, not only in uncomplicated pregnancies, which has been shown before,3*9 but also in
0.899 4.62 pre-eclampsia,
history
0.844 4.16 of
sterility.
B.
B.:
Hypertensive
toxemic and diabetic pregnant patients as well (Fig. 2). Representative examples from each group are given in Table II. In 9 to 10 pregnancies which resulted in intrauterine fetal death, plasma estriol levels were lessthan 5 ,ug per 100 ml., whereas, in the tenth case, the value was 6,9 lug per 100 ml. (Table III). Four of these patients were serially monitored (Fig. 3) . In each case, fetal death was associated with either
Volume Number
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117 2
3s-
30-
25z 8 2 i
H M O-O D--U
pregnancies
215
6.8. B.C. G.S. J.G. L.J. M.G. MT. SF.
20-
f 5
15-
8 f 0.
‘O-
I
31
I
32
33
I
34 Woekr
I
35 36 Gestation
3-f
‘
39
39
40
Fig. 4. Plasma estriol pattern in 8 patients in whom pregnancy was terminated based on adverse clinical signs and/or dropping plasma estriol levels. B. B: Mild hypertension. B. C.: Insulin requiring diabetes for 7 years. Two previous stillbirths. G. S.: Pre-eclampsia, sterility patient for 12 years. J. B.: Gestational diabetes controlled by diet. L. I.: Severe pre-eclampsia. M. G.: Pre-eclampsia. M. T. Family history of diabetes. Previous stillbirth unexplained. S. F.: Stillbirth in previous pregnancy. A, B, C, and D: Proposed estriol zones (see text).
a dropping plasma estriol pattern or a failure of estriol levels to increase with progressing gestation. Patient M. G. had almost identical plasma estriol levels from the thirty-third (4.8 pg) to the thirty-sixth week (4.3 pg) when fetal death occurred. Patient B. C. did not report to the clinic after the thirty-third gestational week but was admitted when she was in the thirty-eighth week of gestation. A reduced fetal heart rate was observed, and the fetus died shortly thereafter. Plasma estrio1 on the day of admissionwas 6.9 pg per 100 ml. Patient E. H. was not examined at the thirty-sixth week. She returned at the thirty-seventh week when no fetal movement Ivas felt. The plasma estriol value was 1.1 /Lg per 100 ml. In Patient N. E., when examined at 35yz weeks, the fetus was considered too immature for delivery. It seems that a value of 5 ,lg per 100 ml. of plasma or lessfrom the thirty-sixth gestational week suggestsfetal death. Additionally, a value of lessthan 10 pg per 100 ml. of plasma with a dropping estriol pattern seemsindicative of fetal distress. Fig. 4 shows estriol patterns of 8 patients whose pregnancies were terminated because
of adverse clinical signs, including dropping estriol patterns. In each case, the pregnancy resulted in delivery of a mature viable infant. In Patient M. G., the fetal heart rate was 110. Patient B. B., who was mildly hypertensive, did not show any adverse clinical signs, yet the plasma estriol pattern showed a continuous drop from a value of 21.4 pg at the thirty-fifth week to 9.2 pg per 100 ml. at the thirty-eighth week. This represented a decrement of more than 50 per cent. The urinary estriol level at the thirtyeighth week was 10.8 mg. per 24 hours, which is indicative of fetal jeopardy as suggested by Greene and associates.1°Labor was induced in Patient G. S. at the thirty-ninth week based on more than a 50 per cent decrease in estriol levels. Desquamation of the fetal soleswas observed upon delivery. J. B., a gestational diabetic, was delivered by cesarean section. The estriol pattern was that of a continuous drop from the thirty-sixth week, i.e., from 27.7 to 10.9 pg at 39j/2 weeks-a cumulative drop of more than 60 per cent. Based on the unfavorable estriol pattern, she was delivered at 39f/2 weeks of a healthy infant weighing 8 pounds, 8 ounces.
216
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Table III. Levels of plasma estriol in pregnancies resulting in intrauterine fetai death. Estriol levels shown are for the week fetal death occurred
No. 1 2 3 4 : 7 8 9 10
Patient C. E. N. G. J. H. H. B. C. E.
B. H. E. M. R. S. R. C. R. G.
Weeks’ gestation
Estriol (/Q/l 00 ml.)
38 37 355 36 30 30 33 36 36 40
6.9 1.1 3.6 4.3 3.0 1.8 2.5 4.8 4.4 3.1
Temporal relationship of sampling* Before After After Before After After After Before Before After
E. H.: Diabetes mellitus, 2 previous miscarriages, did not keep appointment at thirty-sixth week. N. E.: Chronic glomerulonephritis. J. R.: Poorly I-egulated diabetes Ior 21 years. H. S.: Very small uterus. H. R., B. C., C. R., and E. G. were not followed serially. Only one blood sample from each was received. *Where the blood the fetal death, death
was drawn from the patients occurred within 24 hours.
before
Table IV. Guidelines for clinical management of dropping plasma estriol levels (micrograms per 100 ml. of plasma ) from the thirty-sixth week to term
A, >15
kg
B, lo-15
<50 >50, >65 <50 >50, >65
cg
C, >5-
pg
<65
<65 --
D. 5 se or less The proposed in conjunction patient.
scheme should with the total
A A A A, B A A A B, C
:: Equivocal No Equivocal Yes Yes Equivocal* Fetal death
be taken into consideration clinical assessment of each
*A value of less than 8 pg per 100 ml. of plasma Gth a dropping rstriol pattern would call for immediate termination of pregnancy (see text).
Proposed
scheme
Based on our limited experience, a clinical plan for utilization of estriol patterns in assessing fetal status has been devised. From the thirty-sixth week to term, plasma estriol levels are divided into 4 broad zones-A, B, C, and D-with dividing lines at 15, 10, and
pvr 100 ml. l~,~cls ;E’i#. 4, ‘l’abk I\’ Unlike previous suggestions for zones of winary cstriol in the tllird trimester.‘! 11-e suggest that the plasma zones havt> the same cutoff points, irrespective of the week of gestation. if the pregnancy has advanced to the thirty-sixth week or more. A drop in the estriol level of more than 50 per cent is considered significant, whereas a drop ,of more than 65 per cent is thought to be highly significant. Where a failure of plasma estriol to increase or a reduction in plasma estriol occurs with progressing gestation, utilization of the zone in which the last estriol value falls and the extent of the cumulative decrease from the previous maximum (Table assessment of IV) may provide a reliable fetal well-being. The clinician should consider an immediate re-evaluation of the patient and termination of pregnancy if necessary. At the thirty-sixth week, an estriol level of less than 10 pg per 100 ml. of plasma would call for close observation of the patient. However, if the pattern showed a small but definite increase with progressing gestation, no intervention would be required (Fig. 4, Patient M. T. j . In general, values in Zone A, if not preceded by a greater than 65 per cent drop, should be considered as an indication of normal fetoplacental a(‘tivity. Levels in Zones B and C should be interpreted in conjunction with the individual estriol pattern and the extent of the cumulative drop in the estriol level. Values of less than 10 pg per 100 ml. of plasma with a dropping estriol pattern should be regarded as indicative of fetal distress, whereas values of less than 8 pg per 100 ml. \\ould call for immediate termination of pregnant) if adverse clinical signs were noted. Levels in Zone D, i.e., less than 5 pg per 100 ml. of plasma, are either not compatible with a living fetus or indicative of imminent fetal death. Pregnancies complicated with diabetes need to be evaluated somewhat differently in view of our experience with serial plasma estriol determinations. Diabetic pregnancies, as a matter of practice, are not usually car5 pg
Volume Number
117 2
ried to term. Induction of labor is performed to reduce the incidence of intrauterine fetal deaths. In the latter part of this study, based on serial plasma estriol estimations, 3 diabetic pregnancies were carried to term. Two of these patients were insulin dependent, whereas the third was a gestational diabetic treated by diet. A fourth patient, J. B. (Fig. 4)) a gestational diabetic, was delivered at 39f/2 weeks, because of an unfavorable plasma estriol pattern. We propose that based on serial plasma estriol determinations diabetic pregnancies may be allowed to continue unless definite unfavorable clinical signs, including a dropping plasma estriol pattern, should dictate otherwise. However, obstetric delivery may still be complicated because of fetal gigantism if diabetic control has not been optimal.
Plasma
estriol
in high-risk
pregnancies
217
It is realized that the proposed scheme may require modifications as more experience is gained. These proposals should be regarded as the first step in the formulation of a more comprehensive scheme which would include the entire third trimester and may prove helpful to a clinician in the management of high-risk pregnancies. The scheme proposed has worked satisfactorily in our hands. We have not observed an intrauterine fetal death during the last gestational month in that group of patients in which serial plasma estrio1 estimations were used to determine the optimal time to effect delivery. The authors thank Miss L. 0. Moody for help in retrieving clinical information from records and Dr. C. B. Loadholt, Department of Biometry, for the statistical analysis.
REFERENCES
1. Mathur, R. S., Learning, A. B., and Williamson, H. 0.: AM. J. OBSTET. GYNECOL. 113: 1120, 1972. 2. Hellman, L. M., and Pritchard, J. A.: In Williams’ Obstetrics, ed. 14, New York, 1971, Appleton-Century-Crofts, Inc., pp. 686-687. 3. Carrington, E. R., Osterling, M. J., and Adams, F. M.: Aar. J. OBSTET. GYNECOL. 106: 1131, 1970. 4. Taylor, E. S., Hassner, A., Bruns, P. D., and Drose, V. E.: AM. J. OBSTET. GYNECOL. 85: 10, 1963. 5. Taylor, E. S., Bruns, P. D., and Drose, V. E.: Obstet. Gynecol. 25: 177, 1965.
6. Mathur, R. S., Learning, A. B., and Williamson, H. 0.: AM. J. OBSTET. GYNECOL. In press. 7. Nachtigall, L., Bassett, M., Hogsander, V., and Levitz, M.: AM. J. OBSTET. GYNECOL. 101: 638, 1968. 8. Selinger, M., and Levitz, M.: J. Clin. Endocrinol. 29: 995, 1969. 9. Roy, E. J., Harkness, R. A., and Kerr, M. G.: J. Obstet. Gynaecol. Br. Commonw. 70: 1034, 1963. 10. Greene, J. W., Touchstone, J. E., and Fields, H.: Am. J. Med. Sci. 244: 756, 1962. 11. Hausknecht, R. V.: Obstet. Gynecol. 30: 639, 1967.
Discussion DR. JOEL B. HUNEYCUTT (Official Guest). Rock Hill, South Carolina. Surveillance of the fetal health in 109 patients by plasma estriol estimations is reported. In 33 of these patients, additional urinary estriol determinations were made which showed close correlation with the plasma determinations in both the complicated and uncomplicated pregnancies. The generally rising estriol levels as pregnancy progressed and the low levels around the time of fetal death are clearly shown. Plasma estriol levels in the last 6 weeks of gestation were found to be essentially the same in uncomplicated pregnancies and diabetic and pre-eclamptic patients. The estriol levels in the hypertensive patients are said to be significantly lower, but the wide range of values
recorded in these 4 groups make the difference unimpressive. The rate of decline of estriol values before fetal death occurs needs to be known in evaluating and managing fetal jeopardy. This knowledge is especially needed in diabetic pregnancies where fetal death can occur suddenly without clinical warning even when the diabetes is well regulated. The proposed scheme of managing diabetic patients by allowing them to continue unless unfavorable clinical signs, including a dropping estriol pattern, should indicate otherwise may be useful as indicated by 0thers.l Such a proposal does not appear justified by the data of this study alone. Of the 21 diabetic patients studied, 3 had intrauterine deaths, 2 were delivered be-
218
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et
al.
cause of falling estriol levels, and 3 were allowed to continue to term with the assurance of fetal well-being by normal estriol patterns. Apparently, 13 patients were managed by early delivery without regard to the plasma estriol levels. and the neonatal results in these patients are not recorded. Beischer and Brown” studied urinar) estriol levels in 93 diabetic pregnancies. They do not recommend continuation of pregnancy beyond 38 weeks even with normal estriol excretion patterns unless there are unresolvable doubts about the maturity of the fetus. They had 8 neonatal deaths from respiratory distress syndrome and 4 fetal deaths. Results other than fetal death or life at the time of delivery require consideration when evaluating the reliability of any test for placental function and fetal status. Neonatal complications including prematurity and neonatal deaths are not tabulated or discussed in relation to estriol values in this study. The plasma estriol patterns are clearly demonstrated in those 8 patients in whom termination of pregnancy appeared indicated according to the proposed scheme of management. The result of obtaining all mature viable infants by this management is commendable but what the result would have been without intervention really remains uncertain. The ideal test for assessing fetal health has not been developed. Plasma estriol determinations may become our best laboratory aid in managing some high-risk pregnancies and may replace urinary estriol determinations in clinical application. Perhaps newer methods of management for fetal jeopardy other than the timing of delivery will be our inheritance from further biochemical research on fetoplacental function. REFERENCES
1. Heikkila,
J., and Luukkainen, T.: AM. J. OB110: 509, 1971. 2. Be&her, N. A., and Brown, J. B.: Obstet. Gynecol. Survey 27: 303, 1972. STET.
GYNECOL.
DR. LEO J. DUNN, Richmond, Virginia. It is a pleasure to have the opportunity to discuss the paper of Dr. Williamson and colleagues as the work of their laboratory is contributing significantly to our understanding of the value of plasma estriol in the management of high-risk pregnancies. Much of the material presented is in the form of an ongoing study which is still in its preliminary stages, and final assessment will have to await more time and more experience. The authors have shown that plasma estriol
hm r; an cxccllent correlation with urinary estriol and therefore is valid xs a method of following the high-risk pregnancy. It should be recognized that the corollary is also tlue-~--these findings also indicate that urinary estriol values are equally valid in following high-risk pregnancies. In the varieties of nledical complications of pregnancy reported in thiy study, the urinary excretion of estriol was not deceptive because of a problem such as poor renal c.xcretion. This has been a concern in the past OII the theoretical basis that some patients showing a drop in urinary estriol might reflect only poor renal excretion rather than a true change in fetal status. Therefore, on the basis of the data in this paper, one might conclude that there is no advantage in the use of plasma estriol over urinary estriol as far as accuracy and reliability of technique is concerned. Therefore, one must justify the use of a more costly and colnplicated trchnique which because of its chemical nature is a “bench” technique not easily automated. Many obstetric units at the present time rely upon the urinary estriol technique and therefore must answer the question as to hole necessary it would be at this point in time to convert to a plasma technique. The author indicates that one of the disadvantages of the urinary technique is the necessity to wait for 24 hours in order to obtain another specimen to evaluate a change in the estriol level. This would imply that the plasma technique is immediate as compared with a 24 hour delay for the urinary technique, as far as collection of specimens is concerned. However, this may not be entirely true when one considers the marked diurnal variation described in this paper. The author makes a point that 9 A.RI. was deliberately selected as the time of specimen collection because of a 50 per cent change in the estriol level with diurnal variation. Therefore, the finding of an abnormal estriol value on a specimen collected one day would require a wait until the following day at the same time in order to obtain a valid specimen for comparison. A laboratory currently restricted to the urinary estriol technique could overcome their shortcomings by prophylactically collecting a second 24 hour specimen that could either be utilized for repeat analysis or discarded, depending upon their findings on the present specimen. There is one distinct advantage, however, to the use of the plasma technique, namely, that it does not require the cooperation of the patient to the degree that urinary collection does. Considering the varied populations for whom we care in ob-
Volume Number
117 2
stetrics, this can be a distinct advantage at times. The analysis of the use of this technique for the problem obstetric patient is clouded by several variables which make it difficult to be certain of the validity of the conclusions. Since our concern with this laboratory technique is the evaluation of patients at great risk for intrauterine fetal loss, it weakens the analysis to lump cases of borderline medical complications with those of severe medical complications such as the inclusion of gestational diabetes with longstanding insulin-dependent diabetes. It further weakens one’s ability to assess the technique when a variable such as clinical judgment is superimposed upon the laboratory technique itself. The author indicates that the plasma estriol levels were used in the decision of management in conjunction with clinical findings. One wonders then what the outcome of pregnancy is when the estriol technique indicates that the fetus is in distress but clinical observations indicate no difficulty. Similarly, one wonders what the outcome of pregnancy is when the clinical evidence is that of jeopardy to the fetus but the estriol level indicates well-being. It will be necessary as this study progresses to separate these factors in order to determine if the results in the management of high-risk pregnancies are truly improved by supplementing or replacing clinical judgment with estriol determinations. To be of maximum value to the physician, the technique should be able to detect changes in the status of the fetus not discernible by traditional clinical methods. It should also have the capability of separating for the physician those clinical signs which are clearly associated with jeopardy to the fetus from those which are only rarely so. If the technique would only confirm our previous clinical assessment and statistical approach, it would still have value but this value would be limited.
Plasma
estriol
in high-risk
pregnancies
219
The authors’ Fig. 3, showing 4 cases of fetal death in patients who were followed by serial plasma estriol levels, is somewhat difficult to interpret. It would seem reasonable to me to disregard the diabetic patient who had an interval of 5 weeks between estriol determinations. More data might have shown a precipitate drop in the plasma estriol value, but the wide interval between determinations limits the value of this determination in my mind. It also suggests that the majority of patients, regardless of the severity of their condition, were followed at weekly intervals or less, but rarely more frequently. Their finding that fetal death occurred within 24 hours of a marked drop in plasma estriol implies that samples would need to be evaluated at much more frequent intervals than every 7 days to be of value for management. If this supposition is correct, we should be looking for a technique which is not only reliable and rapid but one which is as economical as well. And, finally, although I realize that the authors’ scheme of management with the use of zones of plasma estriol is in the preliminary phase of evaluation and based upon limited data, I would question its value at this time. The overlap between zones which occurs in many of these patients if the standard deviation is superimposed upon the serial curves causes uncertainty. Although I may be proved wrong by future studies, it would lead me to predict that this type of variation will frustrate the attempts to make hard-and-fast rules for the interpretation of dayto-day variation in estriol levels. I believe the author and his co-workers are to be congratulated on the quality and the volume of this important work. Our knowledge of the assessment of the intrauterine fetus is still in its early stages, and Dr. Williamson and his coworkers are among the pioneers.
of plasma estriol estimations
the management R. S.
S. K.
MATHUR, CHESTNUT,
B.S.
B.
LEAMING
H.
0.
WILLIAMSON, South
of high-risk pregnancies
PH.D.
A.
Charleston,
in
M.D.
Carolina
Serial plasma estriol levels were determined in 51 uncomplicated and 58 complicated pregnancies. Additionally, in 13 uncomplicated, 16 toxemic, and 4 diabetic pregnancies, urinary estriol levels were also collated with plasma estriol ualues. Highly significant correlation was observed between plasma and urinary estriol levels in both uncomplicated and complicated pregnancies. In 5 of 37 toxemic patients, unusually high plasma estriol levels were found, though no definite correlation could be established between estriol levels and the severity of toxemia. From the thirty-fourth week of gestation, plasma estriol levels in diabetic and pre-eclamptic patients were essentially the same as those found in uncomplicated pregnancies; however, the levels in hypertensive pregnant patients were significantly lower. Broad guidelines have been postulated to correlate plasma estriol levels with fetal status from the thirty-sixth week of gestation to term. Levels of less than 5 pg per 100 ml. of plasma in this period are not compatible with a living fetus; values of less than 10 pg per 100 ml. with a dropping estriol pattern are indicative of fetal distress.
1 T I s N o w well recognized that estimation of estriol in a 24 hour urine sample can provide useful information regarding fetal well-being, provided the reliability of both the method and the technician performing the assays has been established. Urinary estrio1 assays suffer from two major drawbacks : Often the collection is incomplete and, as a consequence of the time required for collection of each sample, a delay of 24 hours in performing the assay is inevitable. In highrisk pregnancies, such as those complicated by diabetes or severe toxemia, where time
From the Department Gynecology, Medical Carolina.
may be a critical factor, reliance on a single 24 hour urinary assay could be inadequate as well as misleading. A delay of at least another 24 hours is unavoidable if the assay needs to be repeated; hence, urinary estriol estimations are not of much help in those high-risk pregnancies where they are needed the most. Serial plasma estriol assays may obviate those difficulties. Results of a blood sample collected in the morning can be made available to the clinician the same afternoon. The present investigation was undertaken to assess reliability of serial plasma estriol determinations in the management of high-risk pregnancies to assist a clinician in deciding the most appropriate time to effect delivery, i.e., reducing the chances of intrauterine fetal death on one hand and prematurity on the other.
of Obstetrics and University of South
Presented at the Thirty-fifth Annual Meeting of the South Atlantic Association of Obstetricians and Gynecologistt Plot Springs, Virginia, February 4-7, 1973.
Mafdal Radioactive steroids, solvents, reagents, glassware, and spectrofluorometer were the same as described in a previous report.’
Reprint requests: H. 0. Williamson, M.D., Medical University of South Carolina, 80 Barre St., Charleston, South Carolina 29401.
210
Volume Number
117 2
Plasma
estriol
in high-risk
pregnancies
211
Table I. Amount of estriol in pregnancy plasma obtained from uncomplicated and complicated pregnancies. All figures (mean + S.D.) are expressed as micrograms per 100 ml. of plasma. Numbers in parentheses indicate the total number of samples analyzed , Week of gestation
Uncomplicated
34 35 36 37 38 39 40
15.7? 18.32 18.82 17.52 21.82 26.42 27.6 2
Mean Median Range
“t”
(total)
8.8 6.2 9.6 6.4 9.1 10.0 9.9
21.6 t 9.7 (187) 19.8 6.2 - 52.5
-
Diabetic 14.7+ 17.55 19.0t 17.1 2 21.05 25.3 + 31.2 2
Pre-eclamptic 7.6 6.9 6.6 6.2 6.6 9.8 15.9
16.5 16.42 17.0 20.02 23.9 25.3 25.2
19.92 9.7 (92) 17.0 6.3 - 103.8 1.335 -
Patients included in this study were monitored by serial plasma estriol determinations in the third trimester of pregnancy. Blood was drawn for estriol assays either once a week or more frequently if necessitated by the severity of the complication. A total of 109 patients included in this study had completed their pregnancies. This group included 51 uncomplicated pregnancies, 19 preeclamptic patients, 18 hypertensive patients, and 21 diabetic patients. Cases of preeclampsia were classified as “mild” or “severe,” according to the criteria of Hellman and Pritchard.z Diabetic patients in this study included 13 who were insulin dependent and 8 with gestational diabetes controlled by diet. However, in view of the small number of patients followed, they were grouped simply as “diabetic.” Patients with pregnancies classified as “uncomplicated” did not have adverse clinical signs in the current pregnancy. However, some of these patients did have either missed abortions or stillbirths in their previous pregnancies. Method Plasma estriol levels were determined by a method described before.= Urinary estriols were measured with the use of an adaptation of the plasma estriol method which is specific and accurate even in the presence of glucose up to a concentration of 2 Gm. per 100 ml. Only 0.1 ml. of a 24 hour urine sample is
1 2 5 + 2
8.9 7.5 10.3 11.7 15.6 15.3 16.5
20.8% 13.1 (110) 19.2 6.9 - 77.4 0.858
Hypertensive 12.12 5.0 16.8f 5.5 18.4+ 5.3 17.3+ 8.4 17.42 8.3 22.8 + 11.5 23.7 + 17.8 17.6? 9.0 (81) 16.9 6.4 - 64.8 3.169
required to carry out the assay. The method provides reliable estimates if estriol levels are 1 mg. or more per 24 hour urine sample. Details of this method will be published later. Results Plasma estriol levels in uncomplicated and complicated pregnancies are given in Table I. It is noteworthy that from the thirty-fourth week to term plasma estriol levels in diabetic and pre-eclamptic patients were nut distinguishable from those in uncomplicated pregnancies, whereas the levels were significantly lower in patients with hypertensive vascular disease. Representative examples of the “estrio1 pattern” of patients in different groups are shown in Fig. 1. In each case, the patient went into spontaneous labor and was delivered of a viable infant. Correlation of estriol levels in plasma and urine in uncomplicated pregnancies and diabetic and toxemic patients is shown in Fig. 2, with representative examples from each group in Table II. Estriol levels of less than 5 pg per 100 ml. of plasma were observed in 9 of 10 pregnancies resulting in intrauterine fetal death; in the tenth case, the value was 6.9 pg per 100 ml The temporal relationship between sampling and the fetal death is given in Table III. Four of these patients were serially monitored, and the plasma estriol patterns are shown in Fig. 3. Plasma estriol patterns in 8 pregnancies in which labor
212
Mathur
75
et al.
1 .--a O-Q A.G. S.N. K.K. J.A. L.H.
*--a --
60
I 35. i g30a 52s. I B p 20-
IS-
IO -
s-
OA,
. 30
51
1
32
I
33
I
34 mrhl
I
1
I
.
1
t
35
36
37
36
39
40
OIstotion
Fig. 1. Representative examples of plasma estriol patterns in a patient with an uncomplicated pregnancy (S. N.), a diabetic patient (K. K.), a hypertensive patient (L. H.), and pre-eclamptic patients (J. A. and A. G.).
was induced based on total clinical evaluation including plasma estriol levels are shown in Fig. 4. In each case, a viable mature infant was delivered. Also shown in Fig. 4 are the 4 estriol zones proposed for evaluation of individual estriol patterns in relation to fetal well-being. Based on observations made in this study, a scheme to be used in conjunction with clinical findings for interpretation of plasma estriol patterns in assessing fetal well-being is presented in Table IV. Comment The purpose of this investigation was to assess reliability of serial plasma estriol determinations in predicting the status of the fetus, not only in uncomplicated pregnancies but also in high-risk pregnancies such as those complicated by pre-eclampsia, hypertension, and diabetes. This has been done by following each pregnancy on a regular basis-
usually once 3 week or more frequently if felt necessary----and correlating the individual estriol pattern with the outcome of the pregnancy. Additionally, levels of plasma estriol were also compared with urinary estriol to have a better understanding of plasma estriol levels in relation to fetal well-being. A comparison of plasma estriol levels showed that from the thirty-fourth week of gestation to term levels in diabetic and preeclampic patients were not distinguishable from those in uncomplicated pregnancies. However, levels in the hypertensive group were found to be significantly lower. The maxirnum plasma estriol value observed was 103.8 /Lg per 100 ml. (Patient N. G.) This 33-year-old woman. gravida 7, para 6, abortus 0, weighed 237vz pounds and had a blood pressure of 128/92 when examined at the thirty-eighth gestational week; she bvas found to be diabetic, and the diabetes was controlled by diet. Four of the 6 previous infants had weighed 10 pounds or more, with the maximum being 12 pounds, 5 ounces. The previous pregnancies were complicated by hypertensive cardiovascular disease ; however, in the last pregnancy, overt diabetes could not be diagnosed. The plasma estriol values increased from 76 to 103.8 hkg per 100 ml. within a 24 hour period. Corresponding urinary estriol values were 61 and 71 mg. per 24 hours. In an insulindependent diabetic patient (E. J.) with acute pyelonephritis, a maximum plasma estriol level of 42.4 ELg per 100 ml. was observed. The corresponding urinary estriol value was 46 mg. per 24 hours. These rather high values in both plasma and urine may be indicative of increased estriol synthesis by the fetoplacental unit. Additionally, high plasma estriol levels were observed in 4 pre-eclamptic patients (maximum value 77.4 pg per 100 ml.) and 1 patient whose pregnancy was complicated by hypertensive vascular disease (maximum
value
64.8
of
urinary
terminations tients
were
not
pg
performed.
per
100
estriol
in Factor
ml.).
De-
these
pa-
respon-
sible for unusually high plasma estriol levels in complicated pregnancies have not been fully
investigated.
Carrington
and
associates”
Volume Number
117 2
Plasma
estriol
uncompticotrd
60. Uncomplicalad A Diabetic 113) 0 Toxemic (41)
55
pregnancies
213
::~~~+“O’
(40)
SO-
A
DiabgtiCy.080~+13a r-078
45. 2
in high-risk
Toxemic
40.
y.o721+122
r ‘0 01
ti ,e 353 ‘C 30. t w 6 .g
25.
=
20-
0
5
IO
I
IS
20
Plarma
Extriol
25 (p91100
I
30
35
I
f
40
45
ml)
Fig. 2. Correlation between plasma and urinary estriol levels in uncomplicated pregnancy diabetic and toxemic patients. Numbers in parentheses represent the total number of samples analyzed. measured creatinine and estriol clearances in complicated pregnancies. Reduced estriol and creatinine clearances were observed in 28 of 44 pregnancies. However, a normal estriol clearance was associated with a low creatinine clearance in 15 of 44 patients. Additionally, in 13 of 43 pregnqncies, a reduced estriol clearance with a normal creatinine clearance was also noted. A reduced estriol clearance would hardly seem likely to cause such a dramatic increase in plasma estriol levels as those observed in some of our patients (Fig. 1, A. G.) . Taylor and colleague+ B found decreased estriol excretion in 6 patients with pyelonephritis; they attributed this to a reduced placental blood flow rather than a direct renal effect. Additionally, the proportions of “free” estriol to the conjugated form in toxemic pregnancies, were found to be identical to those observed in uncomplicated pregnancies.” Thus, unusually high plasma estriol levels in
complicated pregnancies may be a consequence of increased estriol biosynthesis and/ or altered estrogen metabolism. Further research is warranted to clarify this point. Representative examples of plasma estriol patterns in uncomplicated and complicated pregnancies are shown in Fig. 1. An occasional drop in plasma estriol levels has been observed in uncomplicated pregnancies. Similar observations were also made by Nachtigall and co-workers.7 In all such cases in our study, the drop in the estriol level was less than 50 per cent of the levels of the preceeding week. Diurnal variation in plasma estriol levels has been reported.* In one patient in our study, plasma .levels from the blood samples drawn tit: 8 A.*.., 12:30 P.M., 4 P.M., and 8 P.M. were-34.5, 19.7, 17.7, and 20.8 pg per 100 ml., respectively. Thus, one might expect to observe a decrease of up to 50 per cenr betuteenithe morning and afternoon “levels. An occas&onal
214
Mathur
Septrmbcx 15, l!J?3 Am. J. Obstet. Gynecol.
et al.
30
.-..a o--o D---CI I.-.
25
B.C. E.H. M.G N.E
a
31
32
33
34 Weeks
35 36 Gestotion
37
36
39
40
Fig. 3. Plasma estriol pattern observed in 4 pregnancies which resulted in intrauterine fetal deaths. B. C.: Diabetes mellitus for 5 years. E. H.: Diabetes mellitus for 9 years. M. G.: Stillbirth in previous pregnancy. N. E.: Chronic glomerulonephritis. *: Last blood sample drawn before fetal death. t: Last blood sample drawn after intrauterine fetal death.
Table II. Representative examples of serial plasma and urinary estriol determinations in patients with uncomplicated and complicated pregnancies. Plasma levels are expressedas micrograms per 100 ml., whereas urinary amounts are given in milligrams per 24 hrs. Uncomglicated No.
Plasma
1
2.2 2.6 3.9 ;:9”
2 3 4 5 6 7 8 9 Coeficient
(M.
K.)
Urine
Diabetic Plasma
1.6 2.9 7.2 9.3 12.1 19.6 20.4 27.5
11.2 12.2 15.3
(E.
J.)
Urine
14.6 18.8 21.8 24.2 42.4 26.0 27.8
22.6 29.5 37.3 38.2 46.0 28.4 41.4
Pre-eclamptic Plasma
(L.
C.)
Urine
12.4 18.0 16.6 4.8 17.8 28.4 29.4
Hypertensiue
(B. B.)
Plasma
12.0 18.6 21.2 13.1 17.7 31.0 41.2
Urine
7.6 8.2 8.9 10.4 11.6 20.8 20.6 25.5 34.9
15.5 10.5 18.2 18.4 23.1 32.9 15.7 41.3 40.1
of correlation
r
0.975
t
10.74
E. J.: Insulin-requiring cardiovascular disease.
0.817 3.17 diabetes mellitus.
L. C.:
Severe
drop observed in the plasma estriol level in uncomplicated pregnancies either may reflect a physiologic variation or may be a consequenceof diurnal variation. We insist that the blood samplesbe drawn at about 9 A.M. Excellent correlation has been observed (at the 99 per cent confidence level) between amounts of estriol in plasma and urine, not only in uncomplicated pregnancies, which has been shown before,3*9 but also in
0.899 4.62 pre-eclampsia,
history
0.844 4.16 of
sterility.
B.
B.:
Hypertensive
toxemic and diabetic pregnant patients as well (Fig. 2). Representative examples from each group are given in Table II. In 9 to 10 pregnancies which resulted in intrauterine fetal death, plasma estriol levels were lessthan 5 ,ug per 100 ml., whereas, in the tenth case, the value was 6,9 lug per 100 ml. (Table III). Four of these patients were serially monitored (Fig. 3) . In each case, fetal death was associated with either
Volume Number
Plasma estriol in high-risk
117 2
3s-
30-
25z 8 2 i
H M O-O D--U
pregnancies
215
6.8. B.C. G.S. J.G. L.J. M.G. MT. SF.
20-
f 5
15-
8 f 0.
‘O-
I
31
I
32
33
I
34 Woekr
I
35 36 Gestation
3-f
‘
39
39
40
Fig. 4. Plasma estriol pattern in 8 patients in whom pregnancy was terminated based on adverse clinical signs and/or dropping plasma estriol levels. B. B: Mild hypertension. B. C.: Insulin requiring diabetes for 7 years. Two previous stillbirths. G. S.: Pre-eclampsia, sterility patient for 12 years. J. B.: Gestational diabetes controlled by diet. L. I.: Severe pre-eclampsia. M. G.: Pre-eclampsia. M. T. Family history of diabetes. Previous stillbirth unexplained. S. F.: Stillbirth in previous pregnancy. A, B, C, and D: Proposed estriol zones (see text).
a dropping plasma estriol pattern or a failure of estriol levels to increase with progressing gestation. Patient M. G. had almost identical plasma estriol levels from the thirty-third (4.8 pg) to the thirty-sixth week (4.3 pg) when fetal death occurred. Patient B. C. did not report to the clinic after the thirty-third gestational week but was admitted when she was in the thirty-eighth week of gestation. A reduced fetal heart rate was observed, and the fetus died shortly thereafter. Plasma estrio1 on the day of admissionwas 6.9 pg per 100 ml. Patient E. H. was not examined at the thirty-sixth week. She returned at the thirty-seventh week when no fetal movement Ivas felt. The plasma estriol value was 1.1 /Lg per 100 ml. In Patient N. E., when examined at 35yz weeks, the fetus was considered too immature for delivery. It seems that a value of 5 ,lg per 100 ml. of plasma or lessfrom the thirty-sixth gestational week suggestsfetal death. Additionally, a value of lessthan 10 pg per 100 ml. of plasma with a dropping estriol pattern seemsindicative of fetal distress. Fig. 4 shows estriol patterns of 8 patients whose pregnancies were terminated because
of adverse clinical signs, including dropping estriol patterns. In each case, the pregnancy resulted in delivery of a mature viable infant. In Patient M. G., the fetal heart rate was 110. Patient B. B., who was mildly hypertensive, did not show any adverse clinical signs, yet the plasma estriol pattern showed a continuous drop from a value of 21.4 pg at the thirty-fifth week to 9.2 pg per 100 ml. at the thirty-eighth week. This represented a decrement of more than 50 per cent. The urinary estriol level at the thirtyeighth week was 10.8 mg. per 24 hours, which is indicative of fetal jeopardy as suggested by Greene and associates.1°Labor was induced in Patient G. S. at the thirty-ninth week based on more than a 50 per cent decrease in estriol levels. Desquamation of the fetal soleswas observed upon delivery. J. B., a gestational diabetic, was delivered by cesarean section. The estriol pattern was that of a continuous drop from the thirty-sixth week, i.e., from 27.7 to 10.9 pg at 39j/2 weeks-a cumulative drop of more than 60 per cent. Based on the unfavorable estriol pattern, she was delivered at 39f/2 weeks of a healthy infant weighing 8 pounds, 8 ounces.
216
Mathur
et al.
Table III. Levels of plasma estriol in pregnancies resulting in intrauterine fetai death. Estriol levels shown are for the week fetal death occurred
No. 1 2 3 4 : 7 8 9 10
Patient C. E. N. G. J. H. H. B. C. E.
B. H. E. M. R. S. R. C. R. G.
Weeks’ gestation
Estriol (/Q/l 00 ml.)
38 37 355 36 30 30 33 36 36 40
6.9 1.1 3.6 4.3 3.0 1.8 2.5 4.8 4.4 3.1
Temporal relationship of sampling* Before After After Before After After After Before Before After
E. H.: Diabetes mellitus, 2 previous miscarriages, did not keep appointment at thirty-sixth week. N. E.: Chronic glomerulonephritis. J. R.: Poorly I-egulated diabetes Ior 21 years. H. S.: Very small uterus. H. R., B. C., C. R., and E. G. were not followed serially. Only one blood sample from each was received. *Where the blood the fetal death, death
was drawn from the patients occurred within 24 hours.
before
Table IV. Guidelines for clinical management of dropping plasma estriol levels (micrograms per 100 ml. of plasma ) from the thirty-sixth week to term
A, >15
kg
B, lo-15
<50 >50, >65 <50 >50, >65
cg
C, >5-
pg
<65
<65 --
D. 5 se or less The proposed in conjunction patient.
scheme should with the total
A A A A, B A A A B, C
:: Equivocal No Equivocal Yes Yes Equivocal* Fetal death
be taken into consideration clinical assessment of each
*A value of less than 8 pg per 100 ml. of plasma Gth a dropping rstriol pattern would call for immediate termination of pregnancy (see text).
Proposed
scheme
Based on our limited experience, a clinical plan for utilization of estriol patterns in assessing fetal status has been devised. From the thirty-sixth week to term, plasma estriol levels are divided into 4 broad zones-A, B, C, and D-with dividing lines at 15, 10, and
pvr 100 ml. l~,~cls ;E’i#. 4, ‘l’abk I\’ Unlike previous suggestions for zones of winary cstriol in the tllird trimester.‘! 11-e suggest that the plasma zones havt> the same cutoff points, irrespective of the week of gestation. if the pregnancy has advanced to the thirty-sixth week or more. A drop in the estriol level of more than 50 per cent is considered significant, whereas a drop ,of more than 65 per cent is thought to be highly significant. Where a failure of plasma estriol to increase or a reduction in plasma estriol occurs with progressing gestation, utilization of the zone in which the last estriol value falls and the extent of the cumulative decrease from the previous maximum (Table assessment of IV) may provide a reliable fetal well-being. The clinician should consider an immediate re-evaluation of the patient and termination of pregnancy if necessary. At the thirty-sixth week, an estriol level of less than 10 pg per 100 ml. of plasma would call for close observation of the patient. However, if the pattern showed a small but definite increase with progressing gestation, no intervention would be required (Fig. 4, Patient M. T. j . In general, values in Zone A, if not preceded by a greater than 65 per cent drop, should be considered as an indication of normal fetoplacental a(‘tivity. Levels in Zones B and C should be interpreted in conjunction with the individual estriol pattern and the extent of the cumulative drop in the estriol level. Values of less than 10 pg per 100 ml. of plasma with a dropping estriol pattern should be regarded as indicative of fetal distress, whereas values of less than 8 pg per 100 ml. \\ould call for immediate termination of pregnant) if adverse clinical signs were noted. Levels in Zone D, i.e., less than 5 pg per 100 ml. of plasma, are either not compatible with a living fetus or indicative of imminent fetal death. Pregnancies complicated with diabetes need to be evaluated somewhat differently in view of our experience with serial plasma estriol determinations. Diabetic pregnancies, as a matter of practice, are not usually car5 pg
Volume Number
117 2
ried to term. Induction of labor is performed to reduce the incidence of intrauterine fetal deaths. In the latter part of this study, based on serial plasma estriol estimations, 3 diabetic pregnancies were carried to term. Two of these patients were insulin dependent, whereas the third was a gestational diabetic treated by diet. A fourth patient, J. B. (Fig. 4)) a gestational diabetic, was delivered at 39f/2 weeks, because of an unfavorable plasma estriol pattern. We propose that based on serial plasma estriol determinations diabetic pregnancies may be allowed to continue unless definite unfavorable clinical signs, including a dropping plasma estriol pattern, should dictate otherwise. However, obstetric delivery may still be complicated because of fetal gigantism if diabetic control has not been optimal.
Plasma
estriol
in high-risk
pregnancies
217
It is realized that the proposed scheme may require modifications as more experience is gained. These proposals should be regarded as the first step in the formulation of a more comprehensive scheme which would include the entire third trimester and may prove helpful to a clinician in the management of high-risk pregnancies. The scheme proposed has worked satisfactorily in our hands. We have not observed an intrauterine fetal death during the last gestational month in that group of patients in which serial plasma estrio1 estimations were used to determine the optimal time to effect delivery. The authors thank Miss L. 0. Moody for help in retrieving clinical information from records and Dr. C. B. Loadholt, Department of Biometry, for the statistical analysis.
REFERENCES
1. Mathur, R. S., Learning, A. B., and Williamson, H. 0.: AM. J. OBSTET. GYNECOL. 113: 1120, 1972. 2. Hellman, L. M., and Pritchard, J. A.: In Williams’ Obstetrics, ed. 14, New York, 1971, Appleton-Century-Crofts, Inc., pp. 686-687. 3. Carrington, E. R., Osterling, M. J., and Adams, F. M.: Aar. J. OBSTET. GYNECOL. 106: 1131, 1970. 4. Taylor, E. S., Hassner, A., Bruns, P. D., and Drose, V. E.: AM. J. OBSTET. GYNECOL. 85: 10, 1963. 5. Taylor, E. S., Bruns, P. D., and Drose, V. E.: Obstet. Gynecol. 25: 177, 1965.
6. Mathur, R. S., Learning, A. B., and Williamson, H. 0.: AM. J. OBSTET. GYNECOL. In press. 7. Nachtigall, L., Bassett, M., Hogsander, V., and Levitz, M.: AM. J. OBSTET. GYNECOL. 101: 638, 1968. 8. Selinger, M., and Levitz, M.: J. Clin. Endocrinol. 29: 995, 1969. 9. Roy, E. J., Harkness, R. A., and Kerr, M. G.: J. Obstet. Gynaecol. Br. Commonw. 70: 1034, 1963. 10. Greene, J. W., Touchstone, J. E., and Fields, H.: Am. J. Med. Sci. 244: 756, 1962. 11. Hausknecht, R. V.: Obstet. Gynecol. 30: 639, 1967.
Discussion DR. JOEL B. HUNEYCUTT (Official Guest). Rock Hill, South Carolina. Surveillance of the fetal health in 109 patients by plasma estriol estimations is reported. In 33 of these patients, additional urinary estriol determinations were made which showed close correlation with the plasma determinations in both the complicated and uncomplicated pregnancies. The generally rising estriol levels as pregnancy progressed and the low levels around the time of fetal death are clearly shown. Plasma estriol levels in the last 6 weeks of gestation were found to be essentially the same in uncomplicated pregnancies and diabetic and pre-eclamptic patients. The estriol levels in the hypertensive patients are said to be significantly lower, but the wide range of values
recorded in these 4 groups make the difference unimpressive. The rate of decline of estriol values before fetal death occurs needs to be known in evaluating and managing fetal jeopardy. This knowledge is especially needed in diabetic pregnancies where fetal death can occur suddenly without clinical warning even when the diabetes is well regulated. The proposed scheme of managing diabetic patients by allowing them to continue unless unfavorable clinical signs, including a dropping estriol pattern, should indicate otherwise may be useful as indicated by 0thers.l Such a proposal does not appear justified by the data of this study alone. Of the 21 diabetic patients studied, 3 had intrauterine deaths, 2 were delivered be-
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cause of falling estriol levels, and 3 were allowed to continue to term with the assurance of fetal well-being by normal estriol patterns. Apparently, 13 patients were managed by early delivery without regard to the plasma estriol levels. and the neonatal results in these patients are not recorded. Beischer and Brown” studied urinar) estriol levels in 93 diabetic pregnancies. They do not recommend continuation of pregnancy beyond 38 weeks even with normal estriol excretion patterns unless there are unresolvable doubts about the maturity of the fetus. They had 8 neonatal deaths from respiratory distress syndrome and 4 fetal deaths. Results other than fetal death or life at the time of delivery require consideration when evaluating the reliability of any test for placental function and fetal status. Neonatal complications including prematurity and neonatal deaths are not tabulated or discussed in relation to estriol values in this study. The plasma estriol patterns are clearly demonstrated in those 8 patients in whom termination of pregnancy appeared indicated according to the proposed scheme of management. The result of obtaining all mature viable infants by this management is commendable but what the result would have been without intervention really remains uncertain. The ideal test for assessing fetal health has not been developed. Plasma estriol determinations may become our best laboratory aid in managing some high-risk pregnancies and may replace urinary estriol determinations in clinical application. Perhaps newer methods of management for fetal jeopardy other than the timing of delivery will be our inheritance from further biochemical research on fetoplacental function. REFERENCES
1. Heikkila,
J., and Luukkainen, T.: AM. J. OB110: 509, 1971. 2. Be&her, N. A., and Brown, J. B.: Obstet. Gynecol. Survey 27: 303, 1972. STET.
GYNECOL.
DR. LEO J. DUNN, Richmond, Virginia. It is a pleasure to have the opportunity to discuss the paper of Dr. Williamson and colleagues as the work of their laboratory is contributing significantly to our understanding of the value of plasma estriol in the management of high-risk pregnancies. Much of the material presented is in the form of an ongoing study which is still in its preliminary stages, and final assessment will have to await more time and more experience. The authors have shown that plasma estriol
hm r; an cxccllent correlation with urinary estriol and therefore is valid xs a method of following the high-risk pregnancy. It should be recognized that the corollary is also tlue-~--these findings also indicate that urinary estriol values are equally valid in following high-risk pregnancies. In the varieties of nledical complications of pregnancy reported in thiy study, the urinary excretion of estriol was not deceptive because of a problem such as poor renal c.xcretion. This has been a concern in the past OII the theoretical basis that some patients showing a drop in urinary estriol might reflect only poor renal excretion rather than a true change in fetal status. Therefore, on the basis of the data in this paper, one might conclude that there is no advantage in the use of plasma estriol over urinary estriol as far as accuracy and reliability of technique is concerned. Therefore, one must justify the use of a more costly and colnplicated trchnique which because of its chemical nature is a “bench” technique not easily automated. Many obstetric units at the present time rely upon the urinary estriol technique and therefore must answer the question as to hole necessary it would be at this point in time to convert to a plasma technique. The author indicates that one of the disadvantages of the urinary technique is the necessity to wait for 24 hours in order to obtain another specimen to evaluate a change in the estriol level. This would imply that the plasma technique is immediate as compared with a 24 hour delay for the urinary technique, as far as collection of specimens is concerned. However, this may not be entirely true when one considers the marked diurnal variation described in this paper. The author makes a point that 9 A.RI. was deliberately selected as the time of specimen collection because of a 50 per cent change in the estriol level with diurnal variation. Therefore, the finding of an abnormal estriol value on a specimen collected one day would require a wait until the following day at the same time in order to obtain a valid specimen for comparison. A laboratory currently restricted to the urinary estriol technique could overcome their shortcomings by prophylactically collecting a second 24 hour specimen that could either be utilized for repeat analysis or discarded, depending upon their findings on the present specimen. There is one distinct advantage, however, to the use of the plasma technique, namely, that it does not require the cooperation of the patient to the degree that urinary collection does. Considering the varied populations for whom we care in ob-
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stetrics, this can be a distinct advantage at times. The analysis of the use of this technique for the problem obstetric patient is clouded by several variables which make it difficult to be certain of the validity of the conclusions. Since our concern with this laboratory technique is the evaluation of patients at great risk for intrauterine fetal loss, it weakens the analysis to lump cases of borderline medical complications with those of severe medical complications such as the inclusion of gestational diabetes with longstanding insulin-dependent diabetes. It further weakens one’s ability to assess the technique when a variable such as clinical judgment is superimposed upon the laboratory technique itself. The author indicates that the plasma estriol levels were used in the decision of management in conjunction with clinical findings. One wonders then what the outcome of pregnancy is when the estriol technique indicates that the fetus is in distress but clinical observations indicate no difficulty. Similarly, one wonders what the outcome of pregnancy is when the clinical evidence is that of jeopardy to the fetus but the estriol level indicates well-being. It will be necessary as this study progresses to separate these factors in order to determine if the results in the management of high-risk pregnancies are truly improved by supplementing or replacing clinical judgment with estriol determinations. To be of maximum value to the physician, the technique should be able to detect changes in the status of the fetus not discernible by traditional clinical methods. It should also have the capability of separating for the physician those clinical signs which are clearly associated with jeopardy to the fetus from those which are only rarely so. If the technique would only confirm our previous clinical assessment and statistical approach, it would still have value but this value would be limited.
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The authors’ Fig. 3, showing 4 cases of fetal death in patients who were followed by serial plasma estriol levels, is somewhat difficult to interpret. It would seem reasonable to me to disregard the diabetic patient who had an interval of 5 weeks between estriol determinations. More data might have shown a precipitate drop in the plasma estriol value, but the wide interval between determinations limits the value of this determination in my mind. It also suggests that the majority of patients, regardless of the severity of their condition, were followed at weekly intervals or less, but rarely more frequently. Their finding that fetal death occurred within 24 hours of a marked drop in plasma estriol implies that samples would need to be evaluated at much more frequent intervals than every 7 days to be of value for management. If this supposition is correct, we should be looking for a technique which is not only reliable and rapid but one which is as economical as well. And, finally, although I realize that the authors’ scheme of management with the use of zones of plasma estriol is in the preliminary phase of evaluation and based upon limited data, I would question its value at this time. The overlap between zones which occurs in many of these patients if the standard deviation is superimposed upon the serial curves causes uncertainty. Although I may be proved wrong by future studies, it would lead me to predict that this type of variation will frustrate the attempts to make hard-and-fast rules for the interpretation of dayto-day variation in estriol levels. I believe the author and his co-workers are to be congratulated on the quality and the volume of this important work. Our knowledge of the assessment of the intrauterine fetus is still in its early stages, and Dr. Williamson and his coworkers are among the pioneers.