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Serial hormone assays in patients with uteroplacental insufficiency
Serial hormone assays in patients with uteroplacental insufficiency E. J.
T. A.
BELL,
H.
P.
D.
CHARLES,
Edinburgh
B.Sc.,
LORAINE, McEWAN,
and
PH.D. M.B., M.B.,
M.B., Glasgow,
PH.D.,
D.Sc.,
F.R.C.P.E.
M.R.C.O.G. M.R.C.O.G.*
Scotland
A detailed study has been made of serial urinary estrone, estradiol, estriol, pregnanediol, and chorionic gonadotropin levels during the latter half of pregnancy in 5 patients with previous unsuccessful pregnancies. The variation observed from day to day emphasize that serial studies were necessary in order to obtain reliable information. At the commencement of the investigation, estrogen and pregnanediol urinary levels were generally within the normal range, but the gonadotrojrin levels were abnormally low. The pregnanediol/estriol ratios in patients with uteroplacental insuficiency were compared with those reported for normal pregnancy. In the subjects studied the ratio tended to be high throughout, but prior to delivery a marked decrease was noted. It is considered that the changes resulted from differences in the relative contributions of fetus and placenta to the excretion of these metabolites in the maternal urine.
T H E 0 B S T E T R I C literature contains much information concerning the estimation of hormones and their metabolites in patients with placental insufficiency.l Previous studies in this field have, however, suffered from two major shortcomings; first, that isolated rather than serial determinations have usually been performed in individual women and second, that the investigations have generally been restricted to the estimation of a single hormone or hormone metabolite. The present communication describes hormone and steroid metabolite excretion patterns in 5 patients with placental insufficiency in previous pregnancies. Serial assays of estrone, estradiol, estriol, pregnanediol,
and human chorionic gonadotropin (HCG) in urine provide some assessment of hormonal interrelationships in this clinical condition. Furthermore, the ratios of preganediol to estriol throughout the third trimester were calculated and the figures compared with those found in normal pregnancy. The term placental insufficiency has traditionally been used to denote a syndrome characterized by a small baby and a small placenta in the presence or absence of recognizable maternal disease such as pre-eclampsia or chronic hypertension. In the present investigation the term uteroplacental insu@iciency has been used in preference to placental insufficiency since the abnormalities found in the previous pregnancies could have resulted from a defect in uterine as well as placental function.
From the Medical Research Council Clinical Endocrinology Research Unit, University of Edinburgh, and Department of Gynaecology and Pathology, Western Infirmary, Glasgow.
Materials
and
methods
Methods of assay. The subjects collected complete 24 hour urine samples throughout the period of investigation; assays were con-
*Present address: Department of Obstetrics and Gynecology, University of Pittsburgh, Magee-Womens Hospital, Pittsburgh, Pennsylvania 15213. 562
Volume Number
9i 4
ducted on 24,48, or 72 hour pools. Estrogens were determined by the method of Brown,’ pregnanediol by the technique of Klopper, Michie, and Brown3 and HCG by the method of Loraine.4 The results in the patients with uteroplacental insufficiency were compared with data previously reported in normal pregnancy by investigators who used the same or very similar assay methods to the techniques employed in the present study. Thus the curves used for comparison were, for estrogens, those of Brown’ and Coyle and Brown,6 for pregnanediol those of RUSsell and associates7 and Shearman,s and for HCG those of Loraine4 and Fairweather and Loraine.g Calculation of pregnanediol/estriol ratios. These were estimated by dividing the mean pregnanediol excretion over a period of one week by the corresponding figure for estriol; the ratios were calculated only from the twenty-seventh week until delivery. The normal subjects used for comparison were derived from data published by Klopper and Billewicz” and Shearmar? for pregnanediol, and by Klopper and Billewiczl” and Coyle and Brown’ for estriol. The curve for the ratios in normal pregnancy was calculated from the weighted means of the results reported by the above investigators. Case reports Patient 1. (Mrs. J. B., aged 27 years, para 1, gravida 0.) During this patient’s first pregnancy she was admitted to the hospital at 34 weeks on account of abruptio placentae and was delivered of a stillborn infant weighing 4 pounds, 11 ounces. In her second pregnancy during which the present study was conducted, she remained well until the thirty-seventh week of gestation when she was admitted to the hospital with abruptio placentae; the child was stillborn and weighed 6 pounds, 14 ounces. Patient 2. Mrs. P. B., aged 26 years, para 2, gravida 1). This subject’s first pregnancy in 1959 resulted in a spontaneous delivery of a full-term male infant weighing 6 pounds, 2 ounces. During the third trimester of her second pregnancy retardation of fetal growth was noted; she had a spontaneous delivery of a stillborn infant weighing 2 pounds, 13 ounces during the
Serial
hormone
assays
in placental
insufkiency
563
thirty-eighth week of gestation. In 1962 the patient had a spontaneous abortion at 12 weeks. In 1963 she was again pregnant and at this time the investigation shown in Fig. 2 was undertaken. At the twenty-fourth week of this pregnancy the uterine size was not compatible with the duration of amenorrhea, and at 31 weeks she was admitted to the hospital on account of antepartum hemorrhage; three further episodes of bleeding OCcurred, but in spite of this, the fetus continued to grow. Examination under anesthesia and induction of labor were performed at the thirtyseventh week. Incoordinate uterine action ensued, and as a result, a lower segment cesarean section was performed. She was delivered of a male infant weighing 5 pounds, 7 ounces, the placenta weighed 1 pound, 4 ounces. Patient 3. (Mrs. M. P., aged 26 years, para 1, gravida 0.) In her first pregnancy an intrauterine fetal death occurred at the fortieth week. During the second half of the present pregnancy, hypertension was present, and the size of the uterus was consistently smaller than the duration of amenorrhea would suggest. The patient went into labor spontaneously at the thirty-eighth week of pregnancy, and after a labor lasting 4 hours, was delivered of a female infant weighing 4 pounds, 15 ounces. The placenta weighed 1 pound, 3 ounces. Patient 4. (Mrs. E. F., aged 38 years, para 2, gravida 1.) This patient’s first pregnancy in 1959 was complicated by hypertension and terminated spontaneously at 32 weeks with a stillborn infant. The second pregnancy was also complicated by hypertension and resulted in a premature stillborn infant at 29 weeks’ gestation. The third pregnancy resulted in a spontaneous abortion at 12 weeks. The pregnancy shown in Fig. 4, except for hypertension, was clinically uneventful until the twenty-fourth week. Subsequently, uterine growth failed to correspond to the period of amenorrhea; eventually fetal movements ceased at the thirtieth week, and at 33 weeks she was delivered of a macerated fetus weighing 2 pounds, 1 ounce. Patient 5. (Mrs. E. H., aged 26 years, para 2, gravida 0.) This woman’s first pregnancy ended in a stillbirth at 30 weeks, the fetus weighing 2 pounds, 12 ounces. In the second pregnancy an antepartum hemorrhage occurred at the thirtieth week and this was found to be due to an abruptio placentae. The patient was delivered of a 3 pound, 8 ounce infant, which died after 8 hours. In the pregnancy shown in Fig. 5
564
Bell
et
February 15, 1967 Am. J. Obst. 81 Gynec.
al.
surgical induction of labor was performed at the thirty-eighth week, resulting in a spontaneous delivery of a living male infant, weighing 6 pounds, 8 ounces. The placenta weight was I pound, 7 ounces; macroscopic and microscopic examination of the placenta showed evidence of gross infarction. Two of the pregnancies in the 5 patients described above were complicated by hypertension. Results
Patient 1. (Mrs. J. B., Fig. 1.) Serial hormone assays were performed over a period of 44 days extending from the thirty-second week of pregnancy until 3 days after delivery which occurred on the forty-first day of the study. At the commencement of the investigation excretion values for estrogens and pregnanediol were within the normal range for the appropriate stage of pregnancy. However, no rise in the output of these steroids
Mrs.J.8.
Fig. 1. Hormone sufficiency.
AGE
27YEARS:
excretion
pattern
was noted during the remainder of the pregnancy and in the latter part of the study levels were below the appropriate normal The marked fluctuations in pregrange. nanediol excretion should be noted. In this case the HCG levels were consistently low throughout. Patient 2. (Mrs. P. B., Fig. 2.) Hormone assays were performed on a serial basis for 43 days commencing during the thirty-first week of pregnancy and continuing until 3 days before delivery by cesarean section. Pregnanediol levels remained relatively normal throughout although marked day-to-day fluctuations occurred. At the commencement of the investigation estrogen readings were within the normal range; however, the characteristic rise in estrogen values toward the end of pregnancy did not occur, and at the end of the study the readings were abnor-
PARA 1 +O
during
PLACENTAL
pregnancy
INSUFFICIENCY
in a patient
with
uteroplacental
in-
Volume Number
97 4
Serial
mally low. HCG levels were consistently low throughout. Patient 3. (Mrs. M. P., Fig. 3.) Serial hormone assays were commenced during the twenty-ninth week of pregnancy and continued for 70 days until the day of delivery. Apart from the low values noted prior to parturition, pregnanediol levels remained within the normal range. At the beginning of the study estrogen levels were normal; however, estrone and estradiol output showed no increase during the remainder of the pregnancy while the rise in estriol excretion was less pronounced than is customary, most of the readings being at the lower end of the normal range. HCG levels were slightly higher than in Patients 1 and 2 and for the
Mrs
PB’
AGE
26YEARS
PARA
hormone
assays
in
placental
insufficiency
565
greater part of the study were also at the lower end of the normal range. Patient 4. (Mrs. E. F., Fig. 4.) Serial hormone assays were conducted over a period of 81 days commencing during the twenty-third week of pregnancy and continuing until the time of delivery on day 81. Excretion values for estrone, estradiol, and estriol were within the normal range until week 24. Thereafter, readings started to fall progressively and by week 28 were only one third of the expected values. By the thirty-fourth week a further decrease had occurred, and at this time levels were only one tenth of normal. Pregnanediol readings were within the normal range during weeks 23, 24, and 25; however, by the twenty-sixth week they were decreasing, and
2+1
PLACENTAL
INSUFFICIENCY
I31 532 10 15 20 25 30 35 40 4s DA” OF lN”E 33 343536 37 WEE PRE
Fig. 2. Hormone sufficiency.
excretion
pattern
during
pregnancy
in
a patient
with
uteroplacental
in-
566
Bell et al.
February 15, 1967 Am. J. Obst. & Gynec.
from week 30 until the end of the pregnancy were all abnormally low. HCG levels throughout the study fluctuated markedly but the majority were within the normal range. Patient 5. (Mrs. E. H., Fig. 5.) In this subject hormone assays were started during the eighteenth week of pregnancy and continued for a total of 147 days; delivery occurred on day 143 of the investigation. Pregnanediol levels were within the normal range throughout, but showed marked fluctuations particularly toward the end of pregnancy. Estrogen readings showed a slow rise during pregnancy and generally remained at the lower end of the normal range; however, as in the case of pregnanediol, estriol figures fluctuated considerably during the last 5 weeks. HCG readings also varied markedly
Mrs
M.I? ; AGE
26 YEARS:
throughout the study but were generally somewhat low. Pregnanediol/estriol ratios. Ratios for the patients with uteroplacental insufficiency together with comparable data for normal subjects are given in Figs. 6 and 7. Fig. 6 shows ratios in Subjects 1, 2, 3, and 4, while in Fig. 7 corresponding data in Subject 5 are presented. It is apparent that in none of the patients with uteroplacental insufficiency reported herein was the pattern of the ratio similar to that in normally pregnant women. Another point to emerge is that, with the exception of Subject 2, the ratio in abnormal pregnancy was generally higher than in normal women. The precipitous fall in the ratio in Patients 1, 2, and 4 immediately prior to delivery should be noted.
PARA
1 +O
PLACENTAL
3.3
34
3s
INSUFFICIENCY
DAY OF INVESTfGATCN 29
Fig. 3. Hormone sufficiency.
30
excretion
31
pattern
32
during
pregnancy
in
16 WEEK OF%GN&
a patient
with
uteroplacental
in-
Vokme Number
97 4
Serial
Comment
Fig. 4. Hormone sufficiency.
E F AGE
excretion
38YEAFIS‘
pattern
PARA
during
assays
in placental
insufftciency
567
uteroplacental insufficiency while pregnanediol levels were either low or normal. An important feature of the present study was the marked day-to-day fluctuations in estrogen and pregnanediol output. Such fluctuations, which have also been noted by earlier workers in this field (see Loraine and Bell’), again emphasize the futility of placing any
The data reported herein confirm the results of previous investigators in which estimations of a single hormone or hormone metabolite have been performed. Thus urinary excretion values for estrogens and HCG were found to be at the lower end of or below the normal range in patients with
Mrs
hormone
WACENTAL
2+1
pregnancy
in
a patient
INSUFFICIENCY
with
uteroplacental
in-
568
Bell et al.
February 15, 1967 Am. J. Obst. & Gvnec.
Volume Number
97
Serial
4
50
45
4.0
3.5
E 5(u .g 3.0 St; ti$ !!h “, E2.5 E
2.0
1.5
1.0
I
I
27 20
I
I
29 30
I
I
I
31 32 33
I
,I
I
I
,
I
34 35 36 37 36 39 40 Week of Pregnancy
Fig. 6. PregnanedioVestriol ratios during the third trimester of pregnancy in normal women ( -) and in patients with uteroplacental insufficiency (Patient 1, x---x; Patient 2, O---O; Patient 3, l ---•; Patient 4, A-0-A).
7 57.06 56 O-
5 oa .* g p452% oe40e” “,?35E 3 o2 52 o1 510
, 27
( , ( 28 29 30
, , 31 P
I , 33 34
, , , , , , 35 36 37 38 39 40 Week of Pregnancy
Fig. 7. PregnanedioVestriol ratios during the third trimester of pregnancy in normal women ( -) and in Patient 5 (x -x) with uteroplacental insufficiency.
hormone
assays
in placental
insufkiency
569
reliance for purposes of patient management on isolated steroid estimations during pregnancy. In the 5 patients described in this paper estrogen excretion was generally normal during the earlier part of the study but failed to rise in the expected manner as pregnancy proceeded. Pregnanediol levels were also normal at the commencement of the investigation, but in the majority of the subjects rose to a relatively greater extent than the estrogens during the third trimester. HCG readings were below normal throughout the major part of the period of investigation in all the subjects studied. Measurements of urinary HCG appeared to be of little prognostic value as an index of placental function, a view in keeping with that previously expressed by Hughes and associate9’ who estimated levels of this hormone in the urine of patients with previous histories of threatened and habitual abortion. Pregnanediob’estriol ratios in patients with placental insufficiency were different from those found in normally pregnant women. In the former group the ratio tended to be higher while the pattern of values for the ratio throughout the gestation period was dissimilar in the two categories. Furthermore, in 3 subjects with uteroplacental insufficiency a marked fall in the ratio occurred immediately prior to delivery, a finding not noted in the normal women illustrated in Figs. 6 and 7. The high ratios in patients with uteroplacental insufficiency result from the presence of relatively low estriol levels in association with reasonably normal pregnanediol values. The exact significance of the alterations in ratio between the two groups of subjects remains to be established, but it is possible that the changes noted result from differences in the relative contributions of the fetus and placenta to the excretion of these steroids in maternal urine. Summary
Excretion patterns for estrogens, pregnanediol, and HCG have been studied in 5 patients with clinical evidence of uteroplacental insufficiency. In all subjects serial
570
February 15, 1967 Am. J. Obst. & Gym.
Bell et al.
rather than isolated determinations were made. At the commencement of the investigation estrogen and pregnanediol output was generally normal while HCG readings were abnormally low. As pregnancy proceeded estrogen excretion failed to rise in the normal manner while pregnanediol values were generally within
or just below the normal range. HCG levels remained low throughout. In patients with uteroplacental insufficiency the ratio pregnanediol/estriol tended to be higher than in normally pregnant women. In addition, the pattern of the ratio was dissimilar between the two groups during the third trimester of pregnancy.
REFERENCES
1. Loraine, 2. 3. 4. 5. 6. 7.
J. A., and Bell, E. T.: Hormone Assays and their Clinical Application, ed. 2, Edinburgh, 1966, E. & S. Livingstone, Ltd. Brown, J. B.: Biochem. J. 60: 185, 1955. Klopper, A., Michie, E. A., and Brown, J. B.: J. Endocrinol. 12: 209, 1955. Loraine, J. A.: J. Endocrinol. 6: 319, 1950. Brown, J. B.: Lancet 1: 704, 1956. Coyle, M. G., and Brown, J. B.: J. Obst. & Gynaec. Brit. Comm. 70: 225, 1963. Russell, C. S., Paine, C. G., Coyle, M. G.,
and Brit. 8.
Shearman, Emp.
9. 10. 11.
Dewhurst, Comm. 64: 66:
Fairweather,
C. J.: J. 649, 1957.
Obst.
&
Gynaec.
R. P.: J. Obst. & Gynaec. Brit. 1, 1959.
D. V. I., and Loraine,
J. A.:
Brit. M. J. 1: 66, 1962. Klopper, A., and Billewicz, W.: J. Obst. & Gynaec. Brit. Comm. 70: 1024, 1963. Hughes, H. E., Loraine, J. A., Bell, E. T., and Layton, R.: AM. J. OBST. & GYNEC. 90: 1297, 1964.
T. A.
BELL,
H.
P.
D.
CHARLES,
Edinburgh
B.Sc.,
LORAINE, McEWAN,
and
PH.D. M.B., M.B.,
M.B., Glasgow,
PH.D.,
D.Sc.,
F.R.C.P.E.
M.R.C.O.G. M.R.C.O.G.*
Scotland
A detailed study has been made of serial urinary estrone, estradiol, estriol, pregnanediol, and chorionic gonadotropin levels during the latter half of pregnancy in 5 patients with previous unsuccessful pregnancies. The variation observed from day to day emphasize that serial studies were necessary in order to obtain reliable information. At the commencement of the investigation, estrogen and pregnanediol urinary levels were generally within the normal range, but the gonadotrojrin levels were abnormally low. The pregnanediol/estriol ratios in patients with uteroplacental insuficiency were compared with those reported for normal pregnancy. In the subjects studied the ratio tended to be high throughout, but prior to delivery a marked decrease was noted. It is considered that the changes resulted from differences in the relative contributions of fetus and placenta to the excretion of these metabolites in the maternal urine.
T H E 0 B S T E T R I C literature contains much information concerning the estimation of hormones and their metabolites in patients with placental insufficiency.l Previous studies in this field have, however, suffered from two major shortcomings; first, that isolated rather than serial determinations have usually been performed in individual women and second, that the investigations have generally been restricted to the estimation of a single hormone or hormone metabolite. The present communication describes hormone and steroid metabolite excretion patterns in 5 patients with placental insufficiency in previous pregnancies. Serial assays of estrone, estradiol, estriol, pregnanediol,
and human chorionic gonadotropin (HCG) in urine provide some assessment of hormonal interrelationships in this clinical condition. Furthermore, the ratios of preganediol to estriol throughout the third trimester were calculated and the figures compared with those found in normal pregnancy. The term placental insufficiency has traditionally been used to denote a syndrome characterized by a small baby and a small placenta in the presence or absence of recognizable maternal disease such as pre-eclampsia or chronic hypertension. In the present investigation the term uteroplacental insu@iciency has been used in preference to placental insufficiency since the abnormalities found in the previous pregnancies could have resulted from a defect in uterine as well as placental function.
From the Medical Research Council Clinical Endocrinology Research Unit, University of Edinburgh, and Department of Gynaecology and Pathology, Western Infirmary, Glasgow.
Materials
and
methods
Methods of assay. The subjects collected complete 24 hour urine samples throughout the period of investigation; assays were con-
*Present address: Department of Obstetrics and Gynecology, University of Pittsburgh, Magee-Womens Hospital, Pittsburgh, Pennsylvania 15213. 562
Volume Number
9i 4
ducted on 24,48, or 72 hour pools. Estrogens were determined by the method of Brown,’ pregnanediol by the technique of Klopper, Michie, and Brown3 and HCG by the method of Loraine.4 The results in the patients with uteroplacental insufficiency were compared with data previously reported in normal pregnancy by investigators who used the same or very similar assay methods to the techniques employed in the present study. Thus the curves used for comparison were, for estrogens, those of Brown’ and Coyle and Brown,6 for pregnanediol those of RUSsell and associates7 and Shearman,s and for HCG those of Loraine4 and Fairweather and Loraine.g Calculation of pregnanediol/estriol ratios. These were estimated by dividing the mean pregnanediol excretion over a period of one week by the corresponding figure for estriol; the ratios were calculated only from the twenty-seventh week until delivery. The normal subjects used for comparison were derived from data published by Klopper and Billewicz” and Shearmar? for pregnanediol, and by Klopper and Billewiczl” and Coyle and Brown’ for estriol. The curve for the ratios in normal pregnancy was calculated from the weighted means of the results reported by the above investigators. Case reports Patient 1. (Mrs. J. B., aged 27 years, para 1, gravida 0.) During this patient’s first pregnancy she was admitted to the hospital at 34 weeks on account of abruptio placentae and was delivered of a stillborn infant weighing 4 pounds, 11 ounces. In her second pregnancy during which the present study was conducted, she remained well until the thirty-seventh week of gestation when she was admitted to the hospital with abruptio placentae; the child was stillborn and weighed 6 pounds, 14 ounces. Patient 2. Mrs. P. B., aged 26 years, para 2, gravida 1). This subject’s first pregnancy in 1959 resulted in a spontaneous delivery of a full-term male infant weighing 6 pounds, 2 ounces. During the third trimester of her second pregnancy retardation of fetal growth was noted; she had a spontaneous delivery of a stillborn infant weighing 2 pounds, 13 ounces during the
Serial
hormone
assays
in placental
insufkiency
563
thirty-eighth week of gestation. In 1962 the patient had a spontaneous abortion at 12 weeks. In 1963 she was again pregnant and at this time the investigation shown in Fig. 2 was undertaken. At the twenty-fourth week of this pregnancy the uterine size was not compatible with the duration of amenorrhea, and at 31 weeks she was admitted to the hospital on account of antepartum hemorrhage; three further episodes of bleeding OCcurred, but in spite of this, the fetus continued to grow. Examination under anesthesia and induction of labor were performed at the thirtyseventh week. Incoordinate uterine action ensued, and as a result, a lower segment cesarean section was performed. She was delivered of a male infant weighing 5 pounds, 7 ounces, the placenta weighed 1 pound, 4 ounces. Patient 3. (Mrs. M. P., aged 26 years, para 1, gravida 0.) In her first pregnancy an intrauterine fetal death occurred at the fortieth week. During the second half of the present pregnancy, hypertension was present, and the size of the uterus was consistently smaller than the duration of amenorrhea would suggest. The patient went into labor spontaneously at the thirty-eighth week of pregnancy, and after a labor lasting 4 hours, was delivered of a female infant weighing 4 pounds, 15 ounces. The placenta weighed 1 pound, 3 ounces. Patient 4. (Mrs. E. F., aged 38 years, para 2, gravida 1.) This patient’s first pregnancy in 1959 was complicated by hypertension and terminated spontaneously at 32 weeks with a stillborn infant. The second pregnancy was also complicated by hypertension and resulted in a premature stillborn infant at 29 weeks’ gestation. The third pregnancy resulted in a spontaneous abortion at 12 weeks. The pregnancy shown in Fig. 4, except for hypertension, was clinically uneventful until the twenty-fourth week. Subsequently, uterine growth failed to correspond to the period of amenorrhea; eventually fetal movements ceased at the thirtieth week, and at 33 weeks she was delivered of a macerated fetus weighing 2 pounds, 1 ounce. Patient 5. (Mrs. E. H., aged 26 years, para 2, gravida 0.) This woman’s first pregnancy ended in a stillbirth at 30 weeks, the fetus weighing 2 pounds, 12 ounces. In the second pregnancy an antepartum hemorrhage occurred at the thirtieth week and this was found to be due to an abruptio placentae. The patient was delivered of a 3 pound, 8 ounce infant, which died after 8 hours. In the pregnancy shown in Fig. 5
564
Bell
et
February 15, 1967 Am. J. Obst. 81 Gynec.
al.
surgical induction of labor was performed at the thirty-eighth week, resulting in a spontaneous delivery of a living male infant, weighing 6 pounds, 8 ounces. The placenta weight was I pound, 7 ounces; macroscopic and microscopic examination of the placenta showed evidence of gross infarction. Two of the pregnancies in the 5 patients described above were complicated by hypertension. Results
Patient 1. (Mrs. J. B., Fig. 1.) Serial hormone assays were performed over a period of 44 days extending from the thirty-second week of pregnancy until 3 days after delivery which occurred on the forty-first day of the study. At the commencement of the investigation excretion values for estrogens and pregnanediol were within the normal range for the appropriate stage of pregnancy. However, no rise in the output of these steroids
Mrs.J.8.
Fig. 1. Hormone sufficiency.
AGE
27YEARS:
excretion
pattern
was noted during the remainder of the pregnancy and in the latter part of the study levels were below the appropriate normal The marked fluctuations in pregrange. nanediol excretion should be noted. In this case the HCG levels were consistently low throughout. Patient 2. (Mrs. P. B., Fig. 2.) Hormone assays were performed on a serial basis for 43 days commencing during the thirty-first week of pregnancy and continuing until 3 days before delivery by cesarean section. Pregnanediol levels remained relatively normal throughout although marked day-to-day fluctuations occurred. At the commencement of the investigation estrogen readings were within the normal range; however, the characteristic rise in estrogen values toward the end of pregnancy did not occur, and at the end of the study the readings were abnor-
PARA 1 +O
during
PLACENTAL
pregnancy
INSUFFICIENCY
in a patient
with
uteroplacental
in-
Volume Number
97 4
Serial
mally low. HCG levels were consistently low throughout. Patient 3. (Mrs. M. P., Fig. 3.) Serial hormone assays were commenced during the twenty-ninth week of pregnancy and continued for 70 days until the day of delivery. Apart from the low values noted prior to parturition, pregnanediol levels remained within the normal range. At the beginning of the study estrogen levels were normal; however, estrone and estradiol output showed no increase during the remainder of the pregnancy while the rise in estriol excretion was less pronounced than is customary, most of the readings being at the lower end of the normal range. HCG levels were slightly higher than in Patients 1 and 2 and for the
Mrs
PB’
AGE
26YEARS
PARA
hormone
assays
in
placental
insufficiency
565
greater part of the study were also at the lower end of the normal range. Patient 4. (Mrs. E. F., Fig. 4.) Serial hormone assays were conducted over a period of 81 days commencing during the twenty-third week of pregnancy and continuing until the time of delivery on day 81. Excretion values for estrone, estradiol, and estriol were within the normal range until week 24. Thereafter, readings started to fall progressively and by week 28 were only one third of the expected values. By the thirty-fourth week a further decrease had occurred, and at this time levels were only one tenth of normal. Pregnanediol readings were within the normal range during weeks 23, 24, and 25; however, by the twenty-sixth week they were decreasing, and
2+1
PLACENTAL
INSUFFICIENCY
I31 532 10 15 20 25 30 35 40 4s DA” OF lN”E 33 343536 37 WEE PRE
Fig. 2. Hormone sufficiency.
excretion
pattern
during
pregnancy
in
a patient
with
uteroplacental
in-
566
Bell et al.
February 15, 1967 Am. J. Obst. & Gynec.
from week 30 until the end of the pregnancy were all abnormally low. HCG levels throughout the study fluctuated markedly but the majority were within the normal range. Patient 5. (Mrs. E. H., Fig. 5.) In this subject hormone assays were started during the eighteenth week of pregnancy and continued for a total of 147 days; delivery occurred on day 143 of the investigation. Pregnanediol levels were within the normal range throughout, but showed marked fluctuations particularly toward the end of pregnancy. Estrogen readings showed a slow rise during pregnancy and generally remained at the lower end of the normal range; however, as in the case of pregnanediol, estriol figures fluctuated considerably during the last 5 weeks. HCG readings also varied markedly
Mrs
M.I? ; AGE
26 YEARS:
throughout the study but were generally somewhat low. Pregnanediol/estriol ratios. Ratios for the patients with uteroplacental insufficiency together with comparable data for normal subjects are given in Figs. 6 and 7. Fig. 6 shows ratios in Subjects 1, 2, 3, and 4, while in Fig. 7 corresponding data in Subject 5 are presented. It is apparent that in none of the patients with uteroplacental insufficiency reported herein was the pattern of the ratio similar to that in normally pregnant women. Another point to emerge is that, with the exception of Subject 2, the ratio in abnormal pregnancy was generally higher than in normal women. The precipitous fall in the ratio in Patients 1, 2, and 4 immediately prior to delivery should be noted.
PARA
1 +O
PLACENTAL
3.3
34
3s
INSUFFICIENCY
DAY OF INVESTfGATCN 29
Fig. 3. Hormone sufficiency.
30
excretion
31
pattern
32
during
pregnancy
in
16 WEEK OF%GN&
a patient
with
uteroplacental
in-
Vokme Number
97 4
Serial
Comment
Fig. 4. Hormone sufficiency.
E F AGE
excretion
38YEAFIS‘
pattern
PARA
during
assays
in placental
insufftciency
567
uteroplacental insufficiency while pregnanediol levels were either low or normal. An important feature of the present study was the marked day-to-day fluctuations in estrogen and pregnanediol output. Such fluctuations, which have also been noted by earlier workers in this field (see Loraine and Bell’), again emphasize the futility of placing any
The data reported herein confirm the results of previous investigators in which estimations of a single hormone or hormone metabolite have been performed. Thus urinary excretion values for estrogens and HCG were found to be at the lower end of or below the normal range in patients with
Mrs
hormone
WACENTAL
2+1
pregnancy
in
a patient
INSUFFICIENCY
with
uteroplacental
in-
568
Bell et al.
February 15, 1967 Am. J. Obst. & Gvnec.
Volume Number
97
Serial
4
50
45
4.0
3.5
E 5(u .g 3.0 St; ti$ !!h “, E2.5 E
2.0
1.5
1.0
I
I
27 20
I
I
29 30
I
I
I
31 32 33
I
,I
I
I
,
I
34 35 36 37 36 39 40 Week of Pregnancy
Fig. 6. PregnanedioVestriol ratios during the third trimester of pregnancy in normal women ( -) and in patients with uteroplacental insufficiency (Patient 1, x---x; Patient 2, O---O; Patient 3, l ---•; Patient 4, A-0-A).
7 57.06 56 O-
5 oa .* g p452% oe40e” “,?35E 3 o2 52 o1 510
, 27
( , ( 28 29 30
, , 31 P
I , 33 34
, , , , , , 35 36 37 38 39 40 Week of Pregnancy
Fig. 7. PregnanedioVestriol ratios during the third trimester of pregnancy in normal women ( -) and in Patient 5 (x -x) with uteroplacental insufficiency.
hormone
assays
in placental
insufkiency
569
reliance for purposes of patient management on isolated steroid estimations during pregnancy. In the 5 patients described in this paper estrogen excretion was generally normal during the earlier part of the study but failed to rise in the expected manner as pregnancy proceeded. Pregnanediol levels were also normal at the commencement of the investigation, but in the majority of the subjects rose to a relatively greater extent than the estrogens during the third trimester. HCG readings were below normal throughout the major part of the period of investigation in all the subjects studied. Measurements of urinary HCG appeared to be of little prognostic value as an index of placental function, a view in keeping with that previously expressed by Hughes and associate9’ who estimated levels of this hormone in the urine of patients with previous histories of threatened and habitual abortion. Pregnanediob’estriol ratios in patients with placental insufficiency were different from those found in normally pregnant women. In the former group the ratio tended to be higher while the pattern of values for the ratio throughout the gestation period was dissimilar in the two categories. Furthermore, in 3 subjects with uteroplacental insufficiency a marked fall in the ratio occurred immediately prior to delivery, a finding not noted in the normal women illustrated in Figs. 6 and 7. The high ratios in patients with uteroplacental insufficiency result from the presence of relatively low estriol levels in association with reasonably normal pregnanediol values. The exact significance of the alterations in ratio between the two groups of subjects remains to be established, but it is possible that the changes noted result from differences in the relative contributions of the fetus and placenta to the excretion of these steroids in maternal urine. Summary
Excretion patterns for estrogens, pregnanediol, and HCG have been studied in 5 patients with clinical evidence of uteroplacental insufficiency. In all subjects serial
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Bell et al.
rather than isolated determinations were made. At the commencement of the investigation estrogen and pregnanediol output was generally normal while HCG readings were abnormally low. As pregnancy proceeded estrogen excretion failed to rise in the normal manner while pregnanediol values were generally within
or just below the normal range. HCG levels remained low throughout. In patients with uteroplacental insufficiency the ratio pregnanediol/estriol tended to be higher than in normally pregnant women. In addition, the pattern of the ratio was dissimilar between the two groups during the third trimester of pregnancy.
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