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Urinary estriol excretion in pregnancy anemias
Urinary estriol excretion in pregnancy anemias N.
A.
BEISCHER,
F.R.A.C.S., LANCE
J.
Melbourne,
M.D., M.B.,
BROWN,
MARGERY
F.R.C.S.(EDIN.),
F.R.C.S.(EDIN.),
F.R.C.O.G.
HOLSMAN, B.
M.G.O.,
M.R.C.O.G.
TOWNSEND,
F.R.A.C.S., M.
M.B.,
B.S.,
M.Sc.(N.Z.), A.
SMITH,
M.R.C.O.G. PH.D.(EDIN.)
B.Sc.
Australia
Urinary estriol values below normal were found after 30 weeks’ gestation in 25 per cent of I33 patients with hemoglobin levels below 10 Gm. per 100 ml.; the Percentage of low estriol levels was the same whether the anemia was due to thalassemia (46 patients) or to other causes (87 patients). The significance of these low estriol values is discussed and illustrative case reports are presented. These findings indicate that anemia should be classified along with the other well-known conditions as having an important association with low estriol values.
A L T H o u G H chronic anemia has a serious influence on maternal mortality and morbidity, there is less certainty regarding its importance in terms of fetal survival, and any correlation may be seen only when anemia is severe and untreated.ll Llewellyn- Jones8 reported that the main effects of maternal anemia on the fetus were a high stillbirth rate and an increase in premature births; in his series of 2,250 patients with hemoglobin values below 6.5 Gm. per 100 ml. the stillbirth rate was 9.1 per cent compared with a rate of 1.5 per cent in “nonanemic” patients. Patients with thalassemia minor provide an ideal group in which to study the effects of maternal anemia on fetal well-being, for the
degree of anemia is often severe and varies little throughout pregnancy because treatment with blood transfusion is contraindicated and coexistent iron deficiency is unusual (Table I). A review of 196 patients with beta thalassemia disclosed unusually high incidences of placentas weighing above 900 grams and below 300 grams, and the stillbirth rate was twice the over-all hospital figure.2 In a previous study of urinary estriol excretion in 211 “normal” pregnancies,g an unexpected finding was that 4 of 13 patients showing estriol excretion below the fifth percentile had hemoglobin values below 10 Gm. per 100 ml., and, of these, 3 had thalassemia minor. These findings suggested that in thalassemia there was a predisposition to abnormal placental weight, low estriol excretion, and intrauterine fetal death. Therefore a prospective study was planned to investigate
From the Royal Women’s Hospital and Department of Obstetrics and Gynaecology, University of Melbourne.
819
820
Beischer
et
November Am. J. Ohst.
al.
Table I. Hemoglobin
and serum iron levels in 133 patients
-. Other
Thalassemia Normal estriol excretion No.
Lowest hemoglobin (Gm. %) 3.1 4.1 5.1 6.1 7.1 8.1 9.1
-
Normal ertriol excretion
Low estriol excretion
of patients
No.
of patients
No.
of patients
15, 1968 & Gynec.
- -_--.anemias Low estriol excretion No.
of patients
value
4.0 5.0 6.0 7.0 8.0 9.0 9.9
1 4 9 15 5
1
1
2 7 2
r 3 43 18
3 6 9 13 1 -
3 3 4 1 1
11 20 9 2 -
-
-
18 9 7
5 3 4
4 -
s 8 6
Serum iron (pg %) o4181121 161Above
Hemoglobin
40 80 120 160 200 200
A? (% ) 4.1 - 6.0
6.1 - 8.0 8.1 - 10.0 Above 10.0
Table II. Associated
complications
in 133 anemic
I Normal Condition
*Prolonged
pregnancy
Hypertension Pre-e&mpsia Renal tract Cholestatic
infection jaundice
Number
Porphyria Puerperal Antenatal Total
infection blood transfusion
number
“Prolonged
of patients pregnancy
4 5 1 3 5 -
Thalassemia
minor
estriol
Low
%
Number
1
11.7 -
3 i
14.7 2.9 8.8 14.7 -
34
estriol excretion in patients with and other pregnancy anemias.
-
4 -
patients Other
I estriol 1
Normal %
) Number
estriol 1
%
14 7 3
-
25.0 16.6 16.6 -
z
21.2 11.6 4.1 4.1 3.0
r 1
16.6 8.3
12 -
18.1 -
12
= 14 days or more beyond
: 3 1
66
anemias Low 1 Number 6 1 2 ” 1 5 -
estriol (
% 28.5 4.7 9.5 14.2 4.7 23.8 -
21
the due date of confinement.
thalassemia
fk+wW and me#wds At the Royal Women’s Hospital, Melbourne, approximately 30 per cent of the 7,500 patients delivered annually are of Greek or Italian birth and the incidences of ealassemia minor in women of these nation-
alities are 6.8 and 2.0 per cent, respectively.6 In this hospital 50 to 60 new cases of thalassemia are recognized each year, the criterion for diagnosis being a hemoglobin A, component above 6.0 per cent as measured by paper electrophoresis. Hemoglobin estimations are performed on all antenatal patients at the first visit and at 26 and 36 weeks, and
further hematologic
investigations are carried
Volume Number
102 6
Urinary
estriol excretion
821
Table III. Mode of delivery and other obstetric data in 133 patients Thalassemia Normal Number Type
of delivery
Country
Spontaneous vertex Forceps Breech Cesarean section Greece Italy Australia Primiparas Multiparas Ma!e Female
of birth
Parity Fetal
sex
Fetal distress in labor Perinatal wastage Average fetal birth weight (grams) Average placental weight (grams) Total number Datients ‘Intrauterine
Low
%
Numi ber
Other estriol
Normal
anemias
estriol
Low
9%
Number
&riot
%
Number
70.5
7
58.3
44
66.6
14
66.6
17.5 5.8 5.8
3
25.0 16.6
14 3 5
21.2 4.5 7.5
4 3
19.0
21 13
61.7 38.2
9 3
8
16 18 18 16 12 NIL 3,252
47.0 52.9 52.9 47.0 35.2
7 5 6 6 5
37.8 21.2 40.9 30.3 69.6 51.5 48.4 15.1
38.0 28.5 33.3 47.6 52.3 57.1 42.8 33.3
24
I
!
2
NIL 3,142
596
of
minor
estriol
34
75.0 25.0 58.3 41.6 50.0 50.0 41.6
25 14 27 20 46 34 32 10 1” 3,439
%
; 10 :: 9 7
14.2
NIL 3,315
558
597
574
12
66
21
death
due
to cord
prolapse.
out only in those found to have hemoglobin values below 10 Gm. per 100 ml. In the present seriesestriol excretion was studied in 133 antenatal patients, the majority of whom were delivered during the 12 months from April, 1966, to March, 1967. One patient had sickle cell thalassemia, 45 had thalassemia minor, and most of the remaining 87 had iron deficiency anemia. These patients were not consecutive because those with thalassemiaand more severe degreesof anemia were preferentially selected. No patient having antepartum vaginal bleeding was included. Urinary estriol excretion was measured by the method of Brown and associates.4This is a rapid method based on the Kober color reaction, and extractions are performed in a semiautomatic partition apparatus. A normal series involving 425 measurements on 2 11 women has been described elsewhere.*?’ All these patients were seen before 13 weeks to insure that menstrual dates correlated with the size of the ut~~s, and only those preg-
nanciesproceeding uneventfully and resulting in delivery of normal surviving infants were included. The lower limit of normal estriol excretion was taken as a line which joined 8 mg. per 24 hours at 30 weeks and 12 mg. at 40 weeks and which remained at 12 mg. thereafter. This was approximately the fifth percentile line for this group of pregnancies. Results
Urinary estriol excretion after 30 weeks’ gestation was below normal on one or more occasionsin 33 of the 133 (24.8 per cent) patients investigated; the incidences of subnormal estriol excretion were similar in the 46 patients with thalassemia (26.0 per. cent) and the 87 with anemia due to other causes (24.1 per cent). Tbalassemia minor. A total of 158 estriol estimations were performed after 30 weeks in 46 patients with thalassemia. Values below normal were obtained in 12 patients but in qnly 6 was this finding made on more than one occasion. The presence of associatedob-
822
November
Beischer et al.
Fig. 1. Placental and fetal weights from 46 patients with thalassemia. Percentile curves derived from 2,054 consecutive deliveries where gestational age was assessed as correct. Subnormal estriol excretion.
complications in some patients made it difficult to single out maternal anemia as the factor responsiblefor the abnormal estriol excretion (Table II). In 2 patients estriol excretion fell below the normal range only when the pregnancies had proceeded beyond
stetric
41 weeks. There was poor correlation between low estriol excretion and placental or feta1 birth weights (Fig. 1). In patients whose estriol excretion was within the normal range the average fetal and placental weights were higher than in those with low estriol excretion (Table III), but the differences were not
stati$icaIly significant (t = 0.90 and 0.88, respectively). In the group as a whole the incidence of abnormally large placentas was above norma1.2 Urinary estriol values were unrelated to the degree of maternal anemia (Fig. 2) or to the sex of the fetus (Table III). The method of delivery, race, parity,
and other obstetric data of the patients studied
are shown
15, 1968
Am. J. Obst. & Gynec.
in Table
III.
There
was
were -I- =
a high incidence of fetal distress in labor which was however unrelated to the level of urinary estriol excretion. Case reports. CASE 1. An Italian primigravida with sickle cell thalassemia and chronic renal disease had hemolytic crises necessitating blood transfusions at 24 and 32 weeks’ gestation (Fig. 3). Urinary estriol values were persistently below normal and a small living infant was delivered by cesarean section at 37 weeks. The low estriol values could have been due to the renal disease or to impairment of oxygenation of the fetus and placenta consequent upon the severe maternal anemia. CASE 2. A Greek multigravida with thalassemia minor had an uneventful pregnancy except for failure to gain weight after 31 weeks. Estriol values were always low (Fig. 4) and hypertension (150/90) developed at 40 weeks. A normal delivery occurred 32 hours after amniotomy and the ir&nt, although slow at birth, respor;Kted to resudrarien. The at&i excretion wis below normal for at least 5 weeks before delivery and therefore
IO00 900
+
300
1 + 5 I
I
3
,
I
,
I
1
6
7
8
3
IO
(&per
/Oomph
HEh4O~LOBhV
Fig. 2. The distribution of hemoglobin values lack of correlation between maternal hemoglobin excretion.
in
46 thalassemic patients is shown as is the and urinary estriol values. + = Low estriol
2624-
.l ? p: 6
14IZ-
W tot 3
8
s
6-
I
I
20
Fig. The
22
24
26
28 WEEKS
30 32 OF CE$TATlON
3. Sickle cell thalassemia (Case 1). Urinary dotted line indicates the lower limit of normal
I
I
I
9*
36
36
estriol and hemoglobin estriol excretion.
7
.W
values
are
shown
824
Beischer
November 15, I!%)68 Am. J. Obst. & Gynec.
et al.
higher than in those with low estriol excretion (Table III), but the differences were not statistically significant (t = 0.28 and 0.76, respectively). The degree of maternal anemia was unrelated to urinary estriol values (Fig. 6). The incidence of fetal distress in labor in patients with low estriol excretion was twice that of patients whose estriol excretion was within the normal range (Table III). Case report. CASE 3. An
32
34 WEEKS
36
36 OF
40
42
GESTATION
Fig. 4. Thalassemia minor (Case 2). Urinary estrio1 values were consistently below the normal range. Mild hypertension developed at 40 weeks.
would seem to be related to the patient’s anemia rather than to the mild hypertension which appeared at term. Other anemias. A total of 263 estriol estimations were performed after 30 weeks’ gestation in 87 patients. Values below normal were obtained in 21 patients, but in only 8 was this finding made on more than one occasion. Postterm pregnancy seemed to be an important associated condition which may have resulted in the subnormal estriol values found in some patients (Table II) ; indeed, there were 6 who had normal estriol excretion until the pregnancies proceeded beyond 41 weeks and at this time only 4 had hemoglobin values which had remained below 10 Gm. per cent. There was poor correlation between low estriol excretion and placental and fetal birth weights (Fig. 5). In patients in whom estriol excretion was within the normal range, the average fetal and placental weights were
Australian multigravida, whose 2 previous pregnancies were uneventful, presented at 27 weeks’ gestation with malnutrition and dehydration due to vomiting and diarrhea. Results of relevant investigations were: hemoglobin 6.4 Gm. per 100 ml., serum iron 147 pg per 100 ml., total serum proteins 3.9 Gm. per 100 ml. (albumin 2.1 Gm.), and prothrombin time 8 per cent. Bone marrow examination revealed a classical megaloblastic picture, and after administration of folic acid (15 mg. daily) the reticulocyte count rose from 0.3 to 19.1 per cent. Thereafter the hemoglobin, after falling to 4.7 Gm. per 100 ml., rose steadily and was paralleled by a similar increase in urinary estriol values which, during the period of severe anemia, were well below the normal range (Fig. 7). The vomiting and diarrhea ceased and further antenatal progress was uneventful until at term the patient’s weight became stationary, and estriol excretion again fell below the normal range and was 6.1 mg. per 24 hours when the patient was 11 days past term. Labor began spontaneously and resulted in a normal delivery of a living infant. The severe anemia and depression of serum protein formation were indicative of the profound state of malnutrition seen in this patient and either could have caused the subnormal estrio1 excretion recorded from 27 to 31 weeks. No satisfactory explanation can be offered for the progressive fall in estriol excretion after 38 weeks. Comment Urinary estriol excretion below normal at any time during the third trimester is associated with a perinatal mortality of approximately 30 per cent in patients with preeclampsia, hypertension, chronic renal disease, or a poor past obstetric history.s It is also true that fetal prognosis in the same
800 3 t- 700 3 I? g 600 ii 2 2 3
500 4cK) 300
I&
aim
2400
fioo
36io
fliw
B/RTH WE/GMT &) Fig. 5. Placental thalassemia. + =
and fetal Low estriol
too0
-
900
-
weights excretion.
from
87 patients
I
6. Distribution between maternal
anemia
due
to causes
other
than
0 l
4
Fig.
with
5 6 HEMOGLOBIN
I
7 8 (q. per IO0 ml.)
of hemoglobin values in 87 patients is shown hemoglobin and estriol excretion. + = Low urinary
I 9 as is the estriol.
1
IO poor
correlation
826
Beischer
November 15, 1968 Am. J. Obst. & Gynec.
et al.
WEEKS
OF
Fig. 7. Nutritional megaloblastic anemia (Case 3). as the anemia responded to folic acid adntiniitration birth did not appear to have “placental insuficiency.”
groups of patients is excellent when estriol excretion remains in the normal range.s Recent reports indicate that surviving infants have a 15 to 35 per cent risk of having developmental abnormalities or severe cerebral sequelae, such as convulsive disorders or mental retardation, when maternal estriol values have been below normal.12a I3 The present study indicates that subnormal estriol excretion occurs in approximately 25 per cent of patients with hemoglobin values below 10 Gm. per 100 ml., the incidence being similar in patients with thalassemia minor and those with anemia due to other causes. Although the incidence of fetal distress in labor was high, the only fetal death was due to cord prolapse in a patient with normal estriol excretion, and none of the 133 surviving infants have so far shown
GESTATiON Estriol values rose to within but fell after 38 weeks.
normal limits The infant at
evidence of neurological abnormalities, although there has not yet been time for a long-term follow-up. Hocking and Ibbotson” also found an increased incidence of fetal distress in patients with thalassemia, but their data unlike ours indicated that the distress was the result of mechanical causes. In our series estriol values did not, in general, correlate with the degree of anemia even in thalassemia, a condition in which hemoglobin levels remain fairly constant. However, in Case 3, in which anemia was profound, the estriol values increased progressively as the anemia responded to treatment, suggesting a cause-and-effect relationship, and also that correction of anemia n&g&t improve disordered placental function. When considering the poor correlation found between hemoglobin and estriol values, it is
Volume Number
102 6
well to remember that a similar relationship occurs in patients with hypertension and renal disease, for here too estriol values are not proportional to the severity of the disease. In these conditions estriol excretion is below normal in 29 per cent of pregnancies,g but it is only when estriols are low that the fetus is at risk. In the present series the absence of perinatal deaths when anemia was associated with low estriol values might suggest that the fetuses were not in jeopardy and that low estriol excretion is not an ominous finding when maternal anemia is the only obstetric abnormality present. However, in these patients the incidence of fetal distress in labor was high, and the cesarean section rate (Table III) was more than 3 times that in the over-all hospital population. We believe these findings indicate the need for caution before assuming that low estriol values are without significance in anemic patients. The placental weights seen in this series were also of interest in that the incidence of placentas weighing above 700 grams was approximately twice normal,* although there were examples of both abnormally small and abnormally large placentas associated with low estriol excretion (Figs. 2 and 6). The relationship between placental weight and the high stillbirth rate reported by Llewellyn-Jones* in severely anemic patients still awaits clarification, but our data would suggest that placental insufficiency can occur in such patients when the placenta is enlarged
Urinary
estriol
excretion
827
as well as when the classical syndrome of “hypoplacentosis”’ is present. The presence of associated obstetric complications, such as pre-eclampsia and prolonged pregnancy, which are also associated with low estriol excretion, increased the difficulty in deciding whether the low estriol values found in some patients were in fact related to anemia per se. We have encountered instances in which low estriol values preceded the onset of pre-eclampsia and hypertension, and this sequence is illustrated by Case 2. It is possible that in such patients maternal anemia influences placental formation and function which results in the subsequent development of complications that are accepted by the clinician as being associated with placental insufficiency and low estriol excretion. It is well to recall that in prolonged pregnancy and hypertension as well as in anemia the finding of low estriol excretion establishes a clinical association without providing an explanation of the operative mechanism. We are grateful to the Medical Staff of the Hospital for their cooperation in this study and to Misses M. L. Johnson and G. Haag, Department of Pathology, Royal Women’s Hospital, for preparation of the illustrations. Misses P. Goode, P. Fischer, and Y. Piatek provided skilled technical assistance. This study was supported by a grant from the National Health and Medical Research Council.
REFERENCES
1.
2. 3.
4.
5. 6.
Beischer, N. A., Brown, J. B., MacLeod, S. C., and Smith, M. A.: J. Obst. & Gynaec. Brit. Comm. 74: 51, 1967. Beischer, N. A., Holsman, M., and Kitchen, W. H.: AM. J. OBST. & GYNEC. In press. Brown, J. B., and Beischer, N. A.: Fifth World Congress of Gynaecology and Obstetrics, Sydney, 1967, Butterworth & Company, Ltd., p.75. Brown, J. B., MacLeod, S. C., Macnaughton, C., Smith, M. A., and Smyth, B.: J. Endocrinol. In press. Hocking, I. W., and Ibbotson, R. N.: M. J. Australia 2: 397, 1966. Ibbotson, R. N., and Crompton, B. A.: Brit. J. Haemat. 9: 523, 1963.
7. 8. 9.
10. 11. 12. 13.
Jeffcoate, T. N. A., and Scott, J, S.: AM. J. OBST. & GYNEC. 77: 475, 1959. Llewellyn-Jones, D.: Australia and New Zealand J. Obst. & Gynaec. 5: 191, 1965. MacLeod, S. C., Brown, J. B., Beischer, N. A., and Smith, M. A.: Australia and New Zealand J. Obst. & Gynaec. 7: 25, 1967. Smith, K., Greene, J. W., and Touchstone, J. C.: Aar. J. OBST. & GYNEC. 96: 901, 1966. Tasker, P. W. G.: M. J. Malaya 13: 3, 1958. Wallace, S. J., and Michie, E. A.: Lancet 2: 560, 1966. Yousem, H., Seitchik, J., and Solomon, D.: Obst. & Gynec. 28: 491, 1966.
A.
BEISCHER,
F.R.A.C.S., LANCE
J.
Melbourne,
M.D., M.B.,
BROWN,
MARGERY
F.R.C.S.(EDIN.),
F.R.C.S.(EDIN.),
F.R.C.O.G.
HOLSMAN, B.
M.G.O.,
M.R.C.O.G.
TOWNSEND,
F.R.A.C.S., M.
M.B.,
B.S.,
M.Sc.(N.Z.), A.
SMITH,
M.R.C.O.G. PH.D.(EDIN.)
B.Sc.
Australia
Urinary estriol values below normal were found after 30 weeks’ gestation in 25 per cent of I33 patients with hemoglobin levels below 10 Gm. per 100 ml.; the Percentage of low estriol levels was the same whether the anemia was due to thalassemia (46 patients) or to other causes (87 patients). The significance of these low estriol values is discussed and illustrative case reports are presented. These findings indicate that anemia should be classified along with the other well-known conditions as having an important association with low estriol values.
A L T H o u G H chronic anemia has a serious influence on maternal mortality and morbidity, there is less certainty regarding its importance in terms of fetal survival, and any correlation may be seen only when anemia is severe and untreated.ll Llewellyn- Jones8 reported that the main effects of maternal anemia on the fetus were a high stillbirth rate and an increase in premature births; in his series of 2,250 patients with hemoglobin values below 6.5 Gm. per 100 ml. the stillbirth rate was 9.1 per cent compared with a rate of 1.5 per cent in “nonanemic” patients. Patients with thalassemia minor provide an ideal group in which to study the effects of maternal anemia on fetal well-being, for the
degree of anemia is often severe and varies little throughout pregnancy because treatment with blood transfusion is contraindicated and coexistent iron deficiency is unusual (Table I). A review of 196 patients with beta thalassemia disclosed unusually high incidences of placentas weighing above 900 grams and below 300 grams, and the stillbirth rate was twice the over-all hospital figure.2 In a previous study of urinary estriol excretion in 211 “normal” pregnancies,g an unexpected finding was that 4 of 13 patients showing estriol excretion below the fifth percentile had hemoglobin values below 10 Gm. per 100 ml., and, of these, 3 had thalassemia minor. These findings suggested that in thalassemia there was a predisposition to abnormal placental weight, low estriol excretion, and intrauterine fetal death. Therefore a prospective study was planned to investigate
From the Royal Women’s Hospital and Department of Obstetrics and Gynaecology, University of Melbourne.
819
820
Beischer
et
November Am. J. Ohst.
al.
Table I. Hemoglobin
and serum iron levels in 133 patients
-. Other
Thalassemia Normal estriol excretion No.
Lowest hemoglobin (Gm. %) 3.1 4.1 5.1 6.1 7.1 8.1 9.1
-
Normal ertriol excretion
Low estriol excretion
of patients
No.
of patients
No.
of patients
15, 1968 & Gynec.
- -_--.anemias Low estriol excretion No.
of patients
value
4.0 5.0 6.0 7.0 8.0 9.0 9.9
1 4 9 15 5
1
1
2 7 2
r 3 43 18
3 6 9 13 1 -
3 3 4 1 1
11 20 9 2 -
-
-
18 9 7
5 3 4
4 -
s 8 6
Serum iron (pg %) o4181121 161Above
Hemoglobin
40 80 120 160 200 200
A? (% ) 4.1 - 6.0
6.1 - 8.0 8.1 - 10.0 Above 10.0
Table II. Associated
complications
in 133 anemic
I Normal Condition
*Prolonged
pregnancy
Hypertension Pre-e&mpsia Renal tract Cholestatic
infection jaundice
Number
Porphyria Puerperal Antenatal Total
infection blood transfusion
number
“Prolonged
of patients pregnancy
4 5 1 3 5 -
Thalassemia
minor
estriol
Low
%
Number
1
11.7 -
3 i
14.7 2.9 8.8 14.7 -
34
estriol excretion in patients with and other pregnancy anemias.
-
4 -
patients Other
I estriol 1
Normal %
) Number
estriol 1
%
14 7 3
-
25.0 16.6 16.6 -
z
21.2 11.6 4.1 4.1 3.0
r 1
16.6 8.3
12 -
18.1 -
12
= 14 days or more beyond
: 3 1
66
anemias Low 1 Number 6 1 2 ” 1 5 -
estriol (
% 28.5 4.7 9.5 14.2 4.7 23.8 -
21
the due date of confinement.
thalassemia
fk+wW and me#wds At the Royal Women’s Hospital, Melbourne, approximately 30 per cent of the 7,500 patients delivered annually are of Greek or Italian birth and the incidences of ealassemia minor in women of these nation-
alities are 6.8 and 2.0 per cent, respectively.6 In this hospital 50 to 60 new cases of thalassemia are recognized each year, the criterion for diagnosis being a hemoglobin A, component above 6.0 per cent as measured by paper electrophoresis. Hemoglobin estimations are performed on all antenatal patients at the first visit and at 26 and 36 weeks, and
further hematologic
investigations are carried
Volume Number
102 6
Urinary
estriol excretion
821
Table III. Mode of delivery and other obstetric data in 133 patients Thalassemia Normal Number Type
of delivery
Country
Spontaneous vertex Forceps Breech Cesarean section Greece Italy Australia Primiparas Multiparas Ma!e Female
of birth
Parity Fetal
sex
Fetal distress in labor Perinatal wastage Average fetal birth weight (grams) Average placental weight (grams) Total number Datients ‘Intrauterine
Low
%
Numi ber
Other estriol
Normal
anemias
estriol
Low
9%
Number
&riot
%
Number
70.5
7
58.3
44
66.6
14
66.6
17.5 5.8 5.8
3
25.0 16.6
14 3 5
21.2 4.5 7.5
4 3
19.0
21 13
61.7 38.2
9 3
8
16 18 18 16 12 NIL 3,252
47.0 52.9 52.9 47.0 35.2
7 5 6 6 5
37.8 21.2 40.9 30.3 69.6 51.5 48.4 15.1
38.0 28.5 33.3 47.6 52.3 57.1 42.8 33.3
24
I
!
2
NIL 3,142
596
of
minor
estriol
34
75.0 25.0 58.3 41.6 50.0 50.0 41.6
25 14 27 20 46 34 32 10 1” 3,439
%
; 10 :: 9 7
14.2
NIL 3,315
558
597
574
12
66
21
death
due
to cord
prolapse.
out only in those found to have hemoglobin values below 10 Gm. per 100 ml. In the present seriesestriol excretion was studied in 133 antenatal patients, the majority of whom were delivered during the 12 months from April, 1966, to March, 1967. One patient had sickle cell thalassemia, 45 had thalassemia minor, and most of the remaining 87 had iron deficiency anemia. These patients were not consecutive because those with thalassemiaand more severe degreesof anemia were preferentially selected. No patient having antepartum vaginal bleeding was included. Urinary estriol excretion was measured by the method of Brown and associates.4This is a rapid method based on the Kober color reaction, and extractions are performed in a semiautomatic partition apparatus. A normal series involving 425 measurements on 2 11 women has been described elsewhere.*?’ All these patients were seen before 13 weeks to insure that menstrual dates correlated with the size of the ut~~s, and only those preg-
nanciesproceeding uneventfully and resulting in delivery of normal surviving infants were included. The lower limit of normal estriol excretion was taken as a line which joined 8 mg. per 24 hours at 30 weeks and 12 mg. at 40 weeks and which remained at 12 mg. thereafter. This was approximately the fifth percentile line for this group of pregnancies. Results
Urinary estriol excretion after 30 weeks’ gestation was below normal on one or more occasionsin 33 of the 133 (24.8 per cent) patients investigated; the incidences of subnormal estriol excretion were similar in the 46 patients with thalassemia (26.0 per. cent) and the 87 with anemia due to other causes (24.1 per cent). Tbalassemia minor. A total of 158 estriol estimations were performed after 30 weeks in 46 patients with thalassemia. Values below normal were obtained in 12 patients but in qnly 6 was this finding made on more than one occasion. The presence of associatedob-
822
November
Beischer et al.
Fig. 1. Placental and fetal weights from 46 patients with thalassemia. Percentile curves derived from 2,054 consecutive deliveries where gestational age was assessed as correct. Subnormal estriol excretion.
complications in some patients made it difficult to single out maternal anemia as the factor responsiblefor the abnormal estriol excretion (Table II). In 2 patients estriol excretion fell below the normal range only when the pregnancies had proceeded beyond
stetric
41 weeks. There was poor correlation between low estriol excretion and placental or feta1 birth weights (Fig. 1). In patients whose estriol excretion was within the normal range the average fetal and placental weights were higher than in those with low estriol excretion (Table III), but the differences were not
stati$icaIly significant (t = 0.90 and 0.88, respectively). In the group as a whole the incidence of abnormally large placentas was above norma1.2 Urinary estriol values were unrelated to the degree of maternal anemia (Fig. 2) or to the sex of the fetus (Table III). The method of delivery, race, parity,
and other obstetric data of the patients studied
are shown
15, 1968
Am. J. Obst. & Gynec.
in Table
III.
There
was
were -I- =
a high incidence of fetal distress in labor which was however unrelated to the level of urinary estriol excretion. Case reports. CASE 1. An Italian primigravida with sickle cell thalassemia and chronic renal disease had hemolytic crises necessitating blood transfusions at 24 and 32 weeks’ gestation (Fig. 3). Urinary estriol values were persistently below normal and a small living infant was delivered by cesarean section at 37 weeks. The low estriol values could have been due to the renal disease or to impairment of oxygenation of the fetus and placenta consequent upon the severe maternal anemia. CASE 2. A Greek multigravida with thalassemia minor had an uneventful pregnancy except for failure to gain weight after 31 weeks. Estriol values were always low (Fig. 4) and hypertension (150/90) developed at 40 weeks. A normal delivery occurred 32 hours after amniotomy and the ir&nt, although slow at birth, respor;Kted to resudrarien. The at&i excretion wis below normal for at least 5 weeks before delivery and therefore
IO00 900
+
300
1 + 5 I
I
3
,
I
,
I
1
6
7
8
3
IO
(&per
/Oomph
HEh4O~LOBhV
Fig. 2. The distribution of hemoglobin values lack of correlation between maternal hemoglobin excretion.
in
46 thalassemic patients is shown as is the and urinary estriol values. + = Low estriol
2624-
.l ? p: 6
14IZ-
W tot 3
8
s
6-
I
I
20
Fig. The
22
24
26
28 WEEKS
30 32 OF CE$TATlON
3. Sickle cell thalassemia (Case 1). Urinary dotted line indicates the lower limit of normal
I
I
I
9*
36
36
estriol and hemoglobin estriol excretion.
7
.W
values
are
shown
824
Beischer
November 15, I!%)68 Am. J. Obst. & Gynec.
et al.
higher than in those with low estriol excretion (Table III), but the differences were not statistically significant (t = 0.28 and 0.76, respectively). The degree of maternal anemia was unrelated to urinary estriol values (Fig. 6). The incidence of fetal distress in labor in patients with low estriol excretion was twice that of patients whose estriol excretion was within the normal range (Table III). Case report. CASE 3. An
32
34 WEEKS
36
36 OF
40
42
GESTATION
Fig. 4. Thalassemia minor (Case 2). Urinary estrio1 values were consistently below the normal range. Mild hypertension developed at 40 weeks.
would seem to be related to the patient’s anemia rather than to the mild hypertension which appeared at term. Other anemias. A total of 263 estriol estimations were performed after 30 weeks’ gestation in 87 patients. Values below normal were obtained in 21 patients, but in only 8 was this finding made on more than one occasion. Postterm pregnancy seemed to be an important associated condition which may have resulted in the subnormal estriol values found in some patients (Table II) ; indeed, there were 6 who had normal estriol excretion until the pregnancies proceeded beyond 41 weeks and at this time only 4 had hemoglobin values which had remained below 10 Gm. per cent. There was poor correlation between low estriol excretion and placental and fetal birth weights (Fig. 5). In patients in whom estriol excretion was within the normal range, the average fetal and placental weights were
Australian multigravida, whose 2 previous pregnancies were uneventful, presented at 27 weeks’ gestation with malnutrition and dehydration due to vomiting and diarrhea. Results of relevant investigations were: hemoglobin 6.4 Gm. per 100 ml., serum iron 147 pg per 100 ml., total serum proteins 3.9 Gm. per 100 ml. (albumin 2.1 Gm.), and prothrombin time 8 per cent. Bone marrow examination revealed a classical megaloblastic picture, and after administration of folic acid (15 mg. daily) the reticulocyte count rose from 0.3 to 19.1 per cent. Thereafter the hemoglobin, after falling to 4.7 Gm. per 100 ml., rose steadily and was paralleled by a similar increase in urinary estriol values which, during the period of severe anemia, were well below the normal range (Fig. 7). The vomiting and diarrhea ceased and further antenatal progress was uneventful until at term the patient’s weight became stationary, and estriol excretion again fell below the normal range and was 6.1 mg. per 24 hours when the patient was 11 days past term. Labor began spontaneously and resulted in a normal delivery of a living infant. The severe anemia and depression of serum protein formation were indicative of the profound state of malnutrition seen in this patient and either could have caused the subnormal estrio1 excretion recorded from 27 to 31 weeks. No satisfactory explanation can be offered for the progressive fall in estriol excretion after 38 weeks. Comment Urinary estriol excretion below normal at any time during the third trimester is associated with a perinatal mortality of approximately 30 per cent in patients with preeclampsia, hypertension, chronic renal disease, or a poor past obstetric history.s It is also true that fetal prognosis in the same
800 3 t- 700 3 I? g 600 ii 2 2 3
500 4cK) 300
I&
aim
2400
fioo
36io
fliw
B/RTH WE/GMT &) Fig. 5. Placental thalassemia. + =
and fetal Low estriol
too0
-
900
-
weights excretion.
from
87 patients
I
6. Distribution between maternal
anemia
due
to causes
other
than
0 l
4
Fig.
with
5 6 HEMOGLOBIN
I
7 8 (q. per IO0 ml.)
of hemoglobin values in 87 patients is shown hemoglobin and estriol excretion. + = Low urinary
I 9 as is the estriol.
1
IO poor
correlation
826
Beischer
November 15, 1968 Am. J. Obst. & Gynec.
et al.
WEEKS
OF
Fig. 7. Nutritional megaloblastic anemia (Case 3). as the anemia responded to folic acid adntiniitration birth did not appear to have “placental insuficiency.”
groups of patients is excellent when estriol excretion remains in the normal range.s Recent reports indicate that surviving infants have a 15 to 35 per cent risk of having developmental abnormalities or severe cerebral sequelae, such as convulsive disorders or mental retardation, when maternal estriol values have been below normal.12a I3 The present study indicates that subnormal estriol excretion occurs in approximately 25 per cent of patients with hemoglobin values below 10 Gm. per 100 ml., the incidence being similar in patients with thalassemia minor and those with anemia due to other causes. Although the incidence of fetal distress in labor was high, the only fetal death was due to cord prolapse in a patient with normal estriol excretion, and none of the 133 surviving infants have so far shown
GESTATiON Estriol values rose to within but fell after 38 weeks.
normal limits The infant at
evidence of neurological abnormalities, although there has not yet been time for a long-term follow-up. Hocking and Ibbotson” also found an increased incidence of fetal distress in patients with thalassemia, but their data unlike ours indicated that the distress was the result of mechanical causes. In our series estriol values did not, in general, correlate with the degree of anemia even in thalassemia, a condition in which hemoglobin levels remain fairly constant. However, in Case 3, in which anemia was profound, the estriol values increased progressively as the anemia responded to treatment, suggesting a cause-and-effect relationship, and also that correction of anemia n&g&t improve disordered placental function. When considering the poor correlation found between hemoglobin and estriol values, it is
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102 6
well to remember that a similar relationship occurs in patients with hypertension and renal disease, for here too estriol values are not proportional to the severity of the disease. In these conditions estriol excretion is below normal in 29 per cent of pregnancies,g but it is only when estriols are low that the fetus is at risk. In the present series the absence of perinatal deaths when anemia was associated with low estriol values might suggest that the fetuses were not in jeopardy and that low estriol excretion is not an ominous finding when maternal anemia is the only obstetric abnormality present. However, in these patients the incidence of fetal distress in labor was high, and the cesarean section rate (Table III) was more than 3 times that in the over-all hospital population. We believe these findings indicate the need for caution before assuming that low estriol values are without significance in anemic patients. The placental weights seen in this series were also of interest in that the incidence of placentas weighing above 700 grams was approximately twice normal,* although there were examples of both abnormally small and abnormally large placentas associated with low estriol excretion (Figs. 2 and 6). The relationship between placental weight and the high stillbirth rate reported by Llewellyn-Jones* in severely anemic patients still awaits clarification, but our data would suggest that placental insufficiency can occur in such patients when the placenta is enlarged
Urinary
estriol
excretion
827
as well as when the classical syndrome of “hypoplacentosis”’ is present. The presence of associated obstetric complications, such as pre-eclampsia and prolonged pregnancy, which are also associated with low estriol excretion, increased the difficulty in deciding whether the low estriol values found in some patients were in fact related to anemia per se. We have encountered instances in which low estriol values preceded the onset of pre-eclampsia and hypertension, and this sequence is illustrated by Case 2. It is possible that in such patients maternal anemia influences placental formation and function which results in the subsequent development of complications that are accepted by the clinician as being associated with placental insufficiency and low estriol excretion. It is well to recall that in prolonged pregnancy and hypertension as well as in anemia the finding of low estriol excretion establishes a clinical association without providing an explanation of the operative mechanism. We are grateful to the Medical Staff of the Hospital for their cooperation in this study and to Misses M. L. Johnson and G. Haag, Department of Pathology, Royal Women’s Hospital, for preparation of the illustrations. Misses P. Goode, P. Fischer, and Y. Piatek provided skilled technical assistance. This study was supported by a grant from the National Health and Medical Research Council.
REFERENCES
1.
2. 3.
4.
5. 6.
Beischer, N. A., Brown, J. B., MacLeod, S. C., and Smith, M. A.: J. Obst. & Gynaec. Brit. Comm. 74: 51, 1967. Beischer, N. A., Holsman, M., and Kitchen, W. H.: AM. J. OBST. & GYNEC. In press. Brown, J. B., and Beischer, N. A.: Fifth World Congress of Gynaecology and Obstetrics, Sydney, 1967, Butterworth & Company, Ltd., p.75. Brown, J. B., MacLeod, S. C., Macnaughton, C., Smith, M. A., and Smyth, B.: J. Endocrinol. In press. Hocking, I. W., and Ibbotson, R. N.: M. J. Australia 2: 397, 1966. Ibbotson, R. N., and Crompton, B. A.: Brit. J. Haemat. 9: 523, 1963.
7. 8. 9.
10. 11. 12. 13.
Jeffcoate, T. N. A., and Scott, J, S.: AM. J. OBST. & GYNEC. 77: 475, 1959. Llewellyn-Jones, D.: Australia and New Zealand J. Obst. & Gynaec. 5: 191, 1965. MacLeod, S. C., Brown, J. B., Beischer, N. A., and Smith, M. A.: Australia and New Zealand J. Obst. & Gynaec. 7: 25, 1967. Smith, K., Greene, J. W., and Touchstone, J. C.: Aar. J. OBST. & GYNEC. 96: 901, 1966. Tasker, P. W. G.: M. J. Malaya 13: 3, 1958. Wallace, S. J., and Michie, E. A.: Lancet 2: 560, 1966. Yousem, H., Seitchik, J., and Solomon, D.: Obst. & Gynec. 28: 491, 1966.