High-risk obstetrics

FETUS, PLACENTA, AND NEWBORN

High-risk obstetrics Ill. Cytohormonal evaluations and their practical utility in managing high-risk patients

RICHARD H. AUBRY, M.D. ROBERT E. L. NESBITT,

JR.,

M.D.

Svracuse, New York A control series of 20 normal obstetric patients and 133 high-risk patients, exhibiting diabetes, chronic hypertension, and/ or a history of repeated premature births were evaluated with serial determinations of estriol, pregnanediol, and quantitative chorionic gonadotropin excretion as well as vaginal hormonocytology as measured by the karyopyknotic index. The cytohormonal profile of these vulnerable patients who experienced normal outcome of pregnancy, in addition to those who e:cperienced fetal death, premature labor, or gave birth to an underweight infant, was presented and the predictive reliability for each assessment singly and in combination was determined. Estriol was the most sensitive reflector of fetal status in states of both chronic and acute stress and the predictive reliability of tests in combination was not significantly greater than that of estriol alone. The finding of depressed estriol excretion among complicated pregnancies eventuating in apparently normal perinatal outcome suggests that subtle degrees of fetal jeopardy may occur which escape notice in the usual clinical evaluations. Our experience indicates that it is unlikely that fetal mortality can be drematically reduced by the use of cytohormonal tests; however, by detecting patients who can be safely allowed to continue in pregnancy without early obstetric interference, some of the well-known hazards associated with prematurity may be avoided.

T H E c A R E o F the "high-risk" obstetric patier.,ts must be especially structured to meet their varied and complex needs. This includes bringing to the patient all of the most advanced components of comprehensive medical care. One such feature would be the ready availability of simple, yet reliable,

means of monitoring fetal status. To fulfill such an important need, a host of tests has been advocated. Among the most promising of these for large-scale practical utility have been those tests which involve some assessment of the endocrinologic status of the maternal-fetal unit. As part of the establishment of a highrisk facility in our community, special arrangements were made to carefully document the endocrinologic status of each of the problem patients referred to our facility. This was done with 2 objectives in mind. First,

From the Department of Obstetrics and Gynecology, State University of New York, Upstate Medical Center. This investigation was supported in part by a grant from Ayerst and Eaton Laboratories.

48

High-risk obstetrics 49

Volume 107 Number l

such a policy would provide us with information which might be of practical use in making rational clinical judgments and decisions about therapy which hopefully would not only improve perinatal salvage but also minimize sublethal fetal damage. The second goal was to obtain objective and quantitative cytohormonal data which might give some insights into the basic nature of the fetalplacental unit and its function in relation to perinatal outcome. The means that we chose to assess fetal status were a battery of 4 tests-urinary estriol, pregnanediol, and quantitative chorionic gonadotropin excretion, as well as vaginal hormonocytology as determined by the karyopyknotic index. Estriol excretion has been reported by many investigators 1 - 20 to be a sensitive reflector of both fetal welfare as well as fetal weight. Both pregnanedioF· 12 • 15 21 2 • " " and quantitative chorionic gonadotropin z6 - 33 excretion have been found to be reasonably good indices of placental function and over-all pregnancy status. Vaginal hormone cytology, representing the patient's own endogenous bioassay of the endocrine environment, might be expected to be an indirect reflection of the integrity of the entire maternal-placental-fetal complex. Indeed, some investigators have found alterations in the vaginal smear in association with perinatal problems. 34 -3 7

Material and methods Clinical aspects. 1. Control group. During 1964, 20 normal pregnant patients registering before the sixteenth week of pregnancy were followed throughout their pregnancy with serial 24 hour urine collections and midlateral vaginal wall :;mears. These were done biweekly to 28 to 30 weeks of gestation, and weekly therea.fter until delivery. Incomplete urine collecdons were excluded by random checks of creatinine excretion. Patients with symptomatic vaginitis were excluded. These control data are presented in detail elsewhere. 38 The range of normal for the controls consists of the mean ± 1 Standard Deviation. 2. Study group . From July, 1964, through

June, 1967, over 220 high-risk obstetric patients were studied in basically the same manner as the control group with serial 24 hour urine determinations and vaginal smears throughout their pregnancies. Data pertaining to 133 of these patients are presented here. Obstetric complications represented in this series include diabetes ( 38 patients) , chronic hypertension (52 patients), and repeated premature births ( 43 patients) . The diabetic patients are classified according to White's criteria. 39 Chronic hypertensives are those patients found to have documented hypertension ( 140/90 or greater) either prior to the pregnancy or prior to the twentyfourth week of the pregnancy under study. Patients who had repeatedly been delivered of premature infants are those who had been delivered of 2 or more low birth weight infants ( > 500 but < 2,500 grams) in the past. During this study period, in order to get an objective analysis of the ultimate potential clinical use of the assays, it was decided not to terminate any patient's pregnancy solely on the basis of the cytohormonal values. There were only 2 exceptions to this policy and these will be commented on later. Laboratory. Each 24 hour urine collection was quantitatively assayed for estriol, pregnanediol and chorionic gonadotropin. The estriol determination was by Brown's method.40 Pregnanediol was determined by the method of Klopper. 41 Quantitative chorionic gonadotropin (HCG) was assayed by the rat ovarian hyperemia method of Klempner as modified by Behnken, Lloyd, and Hughes.'12 The vaginal smear was read after staining according to the Papanicolaou technique and the results expressed as percentage of karyopyknotic cells per 300 cells counted or karyopyknotic index (KPI).

Results Normal control group. These data are presentee! elsewhere38 and therefore will not be presented here. The range of normal is quite comparable with that found by other investigators for estriol," pregnanediol, 43 HCG, 31 and KPI. 35

May 1, 1970

50 Aubry and Nesbitt

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Amer.

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ESTRIOL EXCRETION

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Obstet. Gynec.

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GESTATION

Fig. 1. Diabetes mellitus. Normal outcome.

High-risk groups with normal outcome of pregnancy. Diabetes mellitus. The mean cytohormonal values for 29 pregnant diabetic women who had a normal outcome of pregnancy ( > 2,500 grams, > 36 weeks) are compared with the normal control group in Fig. 1. It can be seen that mean estriol (I.A.) and HCG (I. C.) excretion as well as KPI values ( I.D.) are essentially within the normal nondiabetic range. Mean pregnanediol excretion (Fig. 1, B) is. in the upper range of the normal nondiabetic excretion pattern. The reason for this is obscure. The pregnanediol method used is not altered by the presence of glucose or acetone in the urine. The mean placental weight among the diabetic group was greater than the nondiabetic controls (682 grams vs. 610 grams, P < 0.05) and may be at least partly responsible. The mean fetal weight was somewhat greater in the diabetic group (3,510 vs. 3,332 grams), but was not of statistical significance. Fig. 1, A also demonstrates the estriol excretion in

each of the classes of diabetic patients. The differences by class of diabetic were not statistically significant because of the small numbers of patients but it is worthy of note that the group with advanced disease had the lowest average estriol excretion during the greater part of pregnancy. This finding may be a reflection of the fact that 2 out of the 4 Class C diabetic patients had chronic hypertension, a process which of itself is often associated with lowered estriol excretion. No similar trends existed in pregnanediol, HCG, or KPI when the data were similarly divided according to diabetic class. Likewise, no significant difference existed in the average fetal or placental weight in the several classes. Chronic hypertension. The mean cytohormonal values for pregnant chronic hypertensives who experienced a normal outcome of pregnancy are compared with the range for the control group in Fig. 2. No significant deviation from the normal range is seen for the total group. However, when the patients are divided into severe (BP > 180/

High-risk obstetrics 51

Volume 107 Number I

40

ESTRIOL EXCRETION

35

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HUMAN CHORIONIC GONADOTROPIN EXCRETION

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GESTATION

Fiig. 2. Chronic hypertension. Normal outcome.

110) versus mild (BP 140 to 180/90 to 110) hypertension, it can be seen that among the severe hypertensives mean estriol excretion is significantly lower, especially beyond the twenty-sixth week of pregnancy (Fig. 2, A). This may be due to the fact that a lower mean fetal weight was observed in the severe hypertensive group than in the mild group 0.05). No in(2,727 vs. 3,236 grams, P fants in either group, however, had recognizable dysmaturity. A similar trend to lower pregnanediol excretion (Fig. 2, B) occurred in the severe hypertensive group but this was not so striking as for estriol excretion. No similar trends occurred in HCG excretion (Fig. 2.. C) or in KPI values (Fig. 2, D) in this group of patients. None of the hypertensive patients studied developed superimposed pre-eclampsia. Repeated premature births. The mean cytohormonal values in patients with a history of repeated premature infants who had experienced a normal outcome of pregnancy (> 2,500 grams, > 36 weeks), are com-

<

pared with the normal controls in Fig. 3. It is apparent that estriol excretion is depressed to the low normal range and that this depression is demonstrable as early as the twentyfourth week of pregnancy (Fig. 3, A). The lowering of estriol excretion may be related to the fact that the mean birth weight was somewhat less in these patients as compared to that of the control group (2,877 vs. 3,332 grams, P < 0.05). However, no recognizable dysmaturity occurred in either group. Pregnanediol (Fig. 3, B) and HCG excreteion (Fig. 3, C) as well as KPI values (Fig. 3, D) did not show a significant alteration from the control range. Three patients in this general grouping who had experienced prior premature births exhibited noteworthy cytohormonal patterns in association with classical clinical findings of incompetent cervix. Each one developed midpregnancy cervical dilatation (3 to 4 em.) and effacement without appreciable uterine contractions or bleeding, and was subjected to a circlage procedure. The cytohormonal

52 Aubry and Nesbitt

May I, 19i( Amer. J. Ohstet. Gynrc

40

ESTRIOL EXCRETION

35

HUMAN CHORIONIC GONADOTROPIN EXCRETION

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GESTATION

Fig. 3. Repeated premature births. Normal outcome.

40

ESTRIOL EXCRETION

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40

High·risk obstetrics 53

Volume 107 Number I

count for the discrepancy in numbers of patients in each assay group. ESTRIOL EXCRETION. The estriol excretion patterns in the 17 pregnancies resulting in fetal death (Fig. 5, A) appear to fall into two categories. The first and largest category ( 13 of 17) revealed excretion values consistently below the normal range beyond 24 to 26 weeks. It is noteworthy that this group consisted of chronic hypertensive patients (7), hypertensive diabetic patients (4), those with a history of repeated premature births ( 1), and diabetic patients without hypertension ( 1) . Of the 7 chronic hypertensives, 4 had superimposed pre-eclampsia also. The fact that values obtained in the days and weeks before fetal death were not greatly reduced from preceding values is important to observe in this group, indicating that a terminal dramatic fall in level occurs only just prior to death of the fetus. The second category consists of 4 diabetic patients who had relatively normal values

patterns! course, and outcome of the pregnancies are depicted in Fig. 4. Estriol excretion was generally lower than the range for the normal control group, especially in Subjects Band C (Fig. 4, A). Pregnanediol (Fig. 4, B) showed a similar trend but somewhat less striking. HCG excretion (Fig. 4, C) was uniformly within the normal range. Only subject C had a disturbance of KPI and this was most striking early in the pregnancy (Fig. 4, D). It is noteworthy also that only Subject C's infant demonstrated obvious dysmaturity, although Subject B's infant had a lower birth weight than would be expected for the length of gestation. Pregnancy complications. Fetal death in utero. The cytohormonal values for those subjects who experienced fetal death were compared with the range for the control group and are depicted in Fig. 5. Data of some patients with fetal death who were being followed with estriols alone are added to the study group data and ac-

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54

~~ubry

May 1, 1970

and Nesbitt

Amer.

until just prior to fetal death. None of these patients were hypertensive. Two of the fetal deaths were nonpreventable (Cases 1 and 4) and one of these was unrelated to the diabetes. The other 2 (Cases 2 and 3) occurred at 32 and 34 weeks. PREGNANEDIOL The patterns of pregnanediol excretion among patients whose pregnancies terminated in fatal death was compared with the normal control range and depicted in Fig. 5, B. The trend to lower levels prior to fetal death exists but much less consistently than in estriol. Three subjects (all with chronic hypertension) had values below the normal range just prior to fetal death. Three hypertensive diabetic patients had values within the normal range as did the remaining 3 diabetics (Cases 2, 3, and 4). It must be remembered that the diabetic patients with normal outcome of pregnancy had a mean excretion of pregnanediol in the upper range of the normal control group. This consideration would place Cases 2 and 3 in the lower range for diabetics.

40~1

.

HUMAN CHORIONIC GONADOTROPIN EXCRETION

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Obstot. Gynec.

CHORIONIC GONADOTIWPIN. As may be seen in Fig. 5, C, with but a single exception, all cases of fetal death in utero showed HCG excretions within the normal range both prior to and at the time of fetal death. KPI. Five of the 8 subjects in whom KPI values were determined prior to fetal death showed no change from the normal control range (Fig. 5, D). However, 3 subjects (2 with hypertension with superimposed preeclampsia, 1 with hypertension and diabetes) showed elevations. Of these, 2 were striking and both occurred in patients with superimposed pre-eclampsia. The subject with the most persistent elevation of KPI (chronic hypertension with superimposed pre-eclampsia) was in the midst of premature labor when the fetal death occurred and represents the only intrapartal fetal death in the entire series. Premature labor. The cytohormonal profile for those 12 patients under study who experienced spontaneous onset of premature labor ( 20 to 36 weeks) is presented in Fig.

ESTRIOL EXCRETION

35-['

J.

GESTATION

40

High-risk obstetrics 55

Volume 107 Number 1

normal control range. No pattern of prelabor decreases was noted. One of the 2 infants which were smaller than expected for gestational age consistently had values in the normal range. CHORIONIC GONADOTROPIN. Only 2 patients had HCG values outside of the normal control range (Fig. 6, C). These were single values and occurred early in the pregnancy. No trend indicative of prelabor increases could be detected. KPI. A very wide scatter of KPI values occurred in this group of patients (Fig. 6, D) . Almost half of the values fell above the normal control range. An informative mean could not be plotted. Seven of the 12 subjects (3 with chronic hypertension, 4 with repeated premature infants) had values above the normal range at some time during the pregnancy. One of the 2 patients with infants smaller than expected for gestational dates had values for KPI consistently in the normal range. Among those patients with elevated KPI, there appeared to be a difference in the trend for the KPI

6. Eight of the patients had a history of repeated low birth weight infants and the remaining 4 had chronic hypertension as their only problem. ESTRIOL EXCRETION. Despite a scattering of values, it can be seen that the mean estriol excretion lies at the lower limits of the normal control range, especially beyond 20 weeks' gestation (Fig. 6, A). Indeed, approximately half of the values are below the normal control range. No sharp decreases were noted prior to the onset of premature labor. A partial explanation for the lowered value!i in this group may be found in the observation that 2 of the 12 infants were smaller than expected for gestational age, although no obvious dysmaturity was present. Both of these patients had values which frequently fell well below the control range. PREGNANEDIOL EXCRETION. A wider range of va:.ues was found for pregnanediol excretion than for estriol in these same subjects. The mean excretion was closer to the mean for the normal controls (Fig. 6, B). However, one third of the values fell below the

40

ESTRIOL EXCRETION

35

i

HUMAN CHORIONIC GONADOTROPIN EXCRETION

• Repeated Premature o Chronic Hypertensive -Mean

30

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Fig. 7. Complications associated with low birth weight infants (

> 36 weeks' gestation).

56 Aubry and Nesbitt

between those patients in the repeated premature infant group and the chronic hypertension group. The patients with previous repeated premature infants tended to have high values early in pregnancy which decreased toward and sometimes into the normal range later in pregnancy. The patients with chronic hypertension tended to maintain elevated values until the onset of labor and in one subject there was a further marked. prelabor increase. No such trend to prelabor increases in KPI was noted, however, in the remainder of patients of either group. In the total group, 4 neonatal deaths occurred, and the cytohormonal patterns in this group exhibited no special characteristics as distinguished from those in which survival occurred. Low birth weight infants (LOBI) at term. The cytohormonal profile in 11 subjects who were delivered of living low birth weight ininfants at term ( > 36 weeks) is depicted in Fig. 7. Five of the patients had a history of repeated prematures in the past and 6 subjects were chronic hypertensive. All but one infant showed some recognizable stigma of dysmaturity other than the birth weight, but all survived. Two successful inductions were carried out (37 and 39 weeks) because of falling estriol values. Both had chronic hypertension and both infants survived. ESTRIOL. The pattern of estriol excretion reveals strikingly depressed levels in these subjects (Fig. 7, A). Almost all of the values fall below the mean of the control group. The mean estriol excretion becomes increasingly depressed and falls below the control range beyond 24 weeks. No characteristic difference in estriol excretion patterns between the patients with chronic hypertension or repeated prematurity was noted. The mean birth weight in this group was significantly :less than the normal control group (2,210 vs. 3,332 grams, P < 0.01). PREGNANEDIOL. The pattern of pregnanediol excretion in this group reveals a tendency to lower values but to a less striking extent than estriol (Fig. 7, B). The spread of the values is greater but the mean excretion

May I, 1970 Amer.

J.

Obstet. Gynec.

shows the same tendency to fall into the lower control range beyond 28 weeks. Roughly two thirds of the values fall below the mean for the control group and about one-third fall below the lower limits of the normal range. CHORIONIC GONADOTROPIN. The pattern of chorionic gonadotropin excretion reveals that only an exceptional value falls outside of the normal control range (Fig. 7, C). Two subjects had a total of 5 values above the normal range. KPI. The KPI values in this group of patients showed little tendency to be abnormal and with rare exception fell within the normal range (Fig. 7, D). Only one patient had a value greater than 10 per cent beyond the twentieth week of pregnancy. Relationship of final estriol or pregnanediol excretion of newborn weight. There were 55 patients in whom both estriol and pregnanediol excretion values were obtained within 7 days prior to delivery of a living infant. Those final values were plotted against the corresponding newborn weight for these subjects and the mean for certain ranges of hormone excretion of the study group is compared to the over-all trend for the normal control group. The general correlation of estriol excretion to newborn fetal weight is fairly good, especially in the lower birth weight range (Fig. 8). This relationship holds equally as well for hypertensive, diabetic, and the repeated premature infant groups. It is of interest that the trend of the relationship of estriol excretion with birth weight for this problem group is almost exactly the same as for the correlation for the normal control group. Indeed, even in the low birth weight range the correlation maintains the same slope as in the normal birth weight range. Those infants with a low birth weight at term also seem to fit the linear relationship except for 3 patients exhibiting chronic hypertension who had smaller infants than would be expected based on the estriol excretion. Eleven out of 12 patients with estriol excretions of less than I 0 mg. per 24 hours were delivered of infants weighing less

Volume 107 Number I

High-risk obstetrics 57

x Hypertensive-13 t8l Hypertensive- LOBI at Term- 4 oDiabetic -16 cDiabetic LOBI at Term-1 ~Repeated Premature-IS IZ:iRepeated Premature-LOBI at Term-6 -Mean 1----1 Norma I Control

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6

8

10

12

14

18

16

20

22

24

26

28

30

32

FINAL ESTRIOL EXCRETION (mg./24hrs.)

Fig. 8. Newborn weight versus estriol excretion.

x Hypertensive-13 181Hypertensive-LOBI at Term-4 oDiabetic-16 cDiabetic LOBI at Term- I ~Repeated Premature-IS ill Repeated Premature-LOBI at Term-6

5000

--Mean 1-----1 Norma I Control

0

X

-:

4000

0



""~0

E Cl

•

I:I:

~0

3000

IJJ

3:

z

cA

X

(!)

ill"'181 ill

2000

Of"" A

0::

0

~

m 3: IJJ z I 000

0

i:li D

ill

0

0

0

ill

X

2500

X 0

0

ox_.....-i

~L!II

~

X X

o

4

8 12 16 20

28

36

44

52

60

68

76

84

FINAL PREGNANEDIOL EXCRETION (mg /24hrs.)

Fig. 9. Newborn weight versus pregnanediol excretion.

92

58 Aubry and

May 1, 1970

N~~sbitt

Amer.

J. Obstet. Gynec.

Tabk I. Cytohormonal values in patients with abnormal outcome beyond 20 weeks' gestation

Estriol

Fetal death Diabetes Chronic hypertensive diabetes Total fetal deaths Low birth weight infants Premature labor Total Percentage

Karyopyknotic index 10%

Estriol and pregnanediol

Estriol and karyopyknotic index

(mg./24 hr.)

Pregnanediol 20 (mg./24 hr.)

6/8*

0/3

1/3

0/3

0/3

0/3

4/4 10/12 10/11 8/10 28/33 85

3/3 3/6 5/11 5/10 13/27

0/2 1/5 2/11 0/10 3/26 12

111 1/4 0/11 4/10 5/25 20

3/3 3/6 5/11 5/10 13/27 48

1/1 1/4 0/11 4/10 5/25 20


1'roblem category

Chorionic ganadotropin 20,000 (R.U./24 hr.)

<

48

>

>

*No. of patients with abnormal values/total No. of patients with the problem.

than ~~,500 grams, and 41 out of 48 patients with more than 10 mg. per 24 hours were delivered of infants weighing in excess of 2,500 grams. However, only 11 out of 18 patients who were delivered of infants less than ~~,500 grams had an estriol excretion of less than 10 mg. per 24 hours. There is also a general correlation between pregnanediol excretion and newborn birth weight but not as close as for estriol and the spread of values is much greater (Fig. 9). The above noted predictive value of estriol excretion is not nearly as consistent for pregnanediol excretion. Attempts at correlating either estriol or pregnanediol excretion with placental weights revealed poor or no correlation. Sensitivity and predictive value of cytohonnonal data. In order to make use of cytohormonal data to help make clinical decisions or clarify the prognostic status of the pregnancy, we must establish the sensitivity with which each test will reflect an impending pregnancy complication. We also must know to what extent abnormal cytohormonal data may sporadically appear in a high-risk pregnancy which eventuates in a normal outcome, i.e., defined as a living newborn infant, birth weight of 2,500 grams or more and gestational age of 36 weeks. Thus, an analysis of our combined cytohormonal data was made to estimate what predictive value can

be placed on abnormal values occurring in single tests or in combination before perinatal outcome is known. Since the most pressing prognostic and therapeutic problems occur from 30 weeks of pregnancy to term, we have analyzed our data on all our study patients whose pregnancies reached the thirtieth week of pregnancy and beyond. The comparable sensitivity of all four cytohormonal parameters are presented in Table I. Relatively arbitrary lower or upper limits were established for each type of test. In the over-all results, it may be seen that estriol was a far more sensitive reflector of impending problems than any of the other tests. This sensitivity varied somewhat according to the problem. Estriol was more consistently abnormal prior to fetal death, for example, than it was prior to premature labor. It is also important to note how poorly pregnanediol served as a sensitive reflector of impending fetal death in the diabetic patient. Chorionic gonadotropin excretion was of relatively little value. The KPI was not especially sensitive either except in fetal death or premature labor occurring in chronic hypertensives. Various combinations of tests did not improve on the sensitivity of estriol alone. The sensitivity of the KPI would be somewhat greater if determinations prior to the thirtieth gestational week were included, especially among patients who experienced premature labor.

High-risk obstetrics 59

Volume 107 Number 1

Table II. Occurrence of abnormal cytohormonal values in patients with normal outcome of pregnancy Chorionic ganadotropin PregnanediEstriol 20,000 ol 20 10 mg./ mg./24 hr. R.U./24 hr. No. of pa24hr. No. of Pa· No. with tients with tients with abnormal abnormal abnormal value value value (> 1}* (> 1) (> 1)

<

< Total No. of patients Diabetes Hypertension Repeated premature infants Total Percentage

29 35

29 93

4 6 8

3 5 5

18 20

13 14

>

Karyopyknotic index 10% No. with abnormal value (> 1)

>

1

1 0

1 0

2

2

3

2

3

Estriol and pregnanediol No. with abnormal value (>I)

Estriol and karyopyknotic index No. with abnormal value (> 1)

1

0 0

3 4 8 9

2 2

2

*Indicates more than one abnormal value in the series.

Table III. Risk of abnormal outcome if cytohormonal evaluation abnormal more than once

Pregnanediol 20 mg./24 hr.

Chorionic ganadotropin 20,000 R.U./24 hr.

No. of patients with abnormal values ( 1) and abnormal outcome

28

13

3

Karyopyknotic index 10% 5

Total No. of patients with abnormal values ( 1)

46

26

5

8

21

7

Per cent of patients with abnormal values ( 1 ) who had abnormal. outcome

61

50

60

62

62

71

Estriol 10 mg./ 24 hr.

<

>

> >

<

The occurrence of abnormal laboratory tests in our high-risk patients who experienced a normal outcome of pregnancy is reviewed in Table II. It is apparent that estriol excretion was abnormal on more than one occasion beyond 30 weeks pregnancy in 20 per cent of these patients. This percentage is lower for the diabetic patient than for the hypertensive patient and much lower than for the repeated premature group. A smaller percentage of patients had repeatedly abnormal pregnanediol and a very small percentage had repeatedly abnormal chorionic

>

>

Estriol and pregnanediol

Estriol and karyopyknotic index

13

5

gonadotropin, KPI, or combinations of tests. With this information available, the predictive risk associated with repeatedly abnormal cytohormonal values can be generally established and is presented in Table III. It can be seen that the obstetric risk associated with abnormal values is about the same for each of the 4 tests as well as the two combinations of tests. The great advantage of estriol is its far greater sensitivity and therefore the smaller number of patients in whom normal values would lend a false sense of security regarding fetal welfare.

60 Aubry and Nesbitt

Comment The endocrinologic state of pregnancy is complex and as yet incompletely understood. It is dear, h0wever, that those hormones produced by the fetoplacental unit reflect to some degree the integrity of that unit and therefore may be useful indices in estimating fetal welfare. Based on the work of many authors, urinary estrogens and estriol, in particular, are sensitive reflectors of fetal welfare, perhaps relating to the maturity and function of the fetal adrenal glands and liver. 1 - 20 Estriol production is dependent to a large extent on the provision by the fetus of androgenic precursors to the placenta which in turn utilizes these compounds as substrate for estrogen production. It seems likely that this fetal-placental interaction explains our findings of a close relationship between estriol excretion and fetal weight, although the correlation is poorer with placental weight. These findings are compatible with those of other investigators. 3 ' 5 ' 8 ' 10 ' 14 Among the problem patients who experienced .a. normal pregnancy outcome, some of our findings are particularly noteworthy. As have others/• 10• 13 we found that uncomplicated diabetics have essentially normal pattems of estriol excretion. However, we found a trend to lower estriol excretion in the more advanced diabetic and hypertensive patients despite a "normal" outcome of pregnancy. When this finding is viewed in conjunction with our frequent observation of depressed estriol excretion among patients with a history of poor reproductive performance, again despite a "normal" outcome, it appears that estriol excretion patterns reflect subtle degrees of fetal deprivation which escape notice in the usual clinical evaluations. Similarly, depressed values have been noted by others among patients with advanced diabetes/ hypertension, 11 and poor obstetric histories,!) and, in addition, our finding of cytohormonal aberrations in patients with the incompetent cervix syndrome has been previ0usly reported, 9 indicating that at least some of these patients have a degree of chronic fetal embarrassment. Despite an

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May 1, 1970 Obstet. Gynec.

apparently normal perinatal outcome, one wonders what effect such subtle jeopardy might have on the future growth and development of these infants. Thus, just as there is need to broaden and intensify our programs for prenatal investigation, longitudinal studies of newborn infants, particularly those from vulnerable mothers, are likewise mandatory. Estriol excretion has also been found to be diminished in many circumstances of more severe fetal compromise; impending or actual fetal death, 3 • 5 • 6 • 12 • 15 • 18 • 20 dysmaturity states/• 7 • 10 • 11 • 14 • 15 premature labors, 13 toxemia of pregnancy/• 5 • 13 • 15 • 17 • 19 etc. Our findings lend support to these previous observations. Fetal death was found to be accompanied by low or falling estriol excretion in essentially all of our cases. Estriol excretion also was frequently found to be depressed in patients wh0 were destined to experience premature labor and even further depressed in those patients who were delivered of infants showing the results of chronic intrauterine deprivation, i.e., dysmaturity. The values among patients with hypertension were depressed only in the more severe cases and/or those in whom intrauterine deprivation of a recognizable degree was occurring. Decreased estriol clearance in the hypertensive patient has been suggested as a partial explanation for these lower values, 44 and decreased in vitro placental conversion of androgenic precursors to estrogens has been noted in these toxemias by others. 45 However, neither of these two theses would completely explain these low levels in toxemias, since we found that the correlation of estriol excretion to newborn weight was fairly good in these patients. This is also of interest in view of the observation by others14 that dysmature states themselves are associated with lower estriol excretion than would be expected for fetal weight, a finding we could not corroborate. It has been felt that pregnanediol excretion is chiefly a reflection of placental rather than fetal status. A fair correlation with placental weight has been observed.u Preg-

Volume 107 Numb,~r 1

nanediol has been found by some to be a poor reflector of fetal status,1 1 • 46 but others have found it to be fairly good. 21 " 25 • 47 -49 Indeed, some have found it to be almost as reliable as estriol excretion. 2 • 12 • 15 From Cassmer's48 observation of a relatively slow decrea:;e in pregnanediol excretion after abrupt clamping of the cord of an intact fetus, it seems likely that pregnanediol may not be as sensitive a reflector of rapid changes in fetal status as is estriol. This may explain some of the discrepancies in the literature since the degree of correlation would depend on what type of clinical problem is threatening fetal welfare, chronic: or relatively acute. Our findings lend support to such a concept. Pregnanediol excretion was below the normal range in those fetal deaths that took place in circumstances of chronic fetal deprivation, i.e., chronic hypertension. It also was depressed in many patients who experienced premature labor and in most of those patients who delivered low birth weight infants at term. It was not, however, greatly disturbed in nonhypertensive diabetic patients who experienced no acute problems, even when the pregnancy resulted in fetal death. Chorionic gonadotropin excretion is commonly accepted as a reflector of purely placental function. It has been found to be very useful in assessing early pregnancy problems. Some of the earliest reports of the use of endocrine excretory products as guidelines to late pregnancy status indicated that there was an increase in chorionic gonadotropin excretion when the pregnancy was threatened. 26 " 31 • 50 Occasional reports since then have supported this view 32 • 33 ; however, others have not found it useful. Our findings indicate that chorionic gonadotropin is an insensitive reflector of fetoplacental welfare for the types of problems presented in this report. In those exceptional cases in which clearly abnormal values occurred, it was, however, equally as predictive as the other assays of impending problems. Vaginal hormonocytology theoretically might be expected to be the most accurate of all since it could be thought of as the patient's own bioassay of the current endocrine

High-risk obstetrics 61

milieu of the pregnancy. It also has had much use in assessing early pregnancy problems. Reports of its use in late pregnancy problems have been quite conflicting. An increasing cornification index or a preterm smear has been described as occurring prelabor and some have found the occurrence of this pattern other than at term to be a sign of severe fetal jeopardy. 3 4-3 7 , 51 Others, however, have been unable to corroborate these findings. 52 Our findings reveal that, in general, the KPI is an insensitive reflection of pregnancy status. However, in circumstances of impending fetal death and/or premature labor, particularly in the chronic hypertensiv.e group, the KPI was often in the abnormal range. This relationship is even more striking when the total pregnancy pattern of KPI is observed in the patients who had these problems. The interrelationship of the hormonal environment to the KPI in these problem cases is the subject of a separate report. Over-all clinical utility

Our experiences with these four means of assessing pregnancy status, in the types of problems presented, leads us to certain conclusions regarding the practical use of these assays in clinical practice. Quantitative chorionic gonadotropin excretion seems to be insufficiently sensitive to be of any practical value in these particular problem cases. Pregnanediol excretion is almost as good as estriol in terms of reflecting chronic states of fetoplacental deprivation but is not quite as sensitive, nor as quickly responsive to rapidly changing fetal status as is estriol excretion. Pregnanediol is also not as closely correlated with fetal weight nor is it as broadly applicable to all three problem areas, especially the diabetic, as is estriol. Estriol is the most sensitive reflector of fetal status in states of both chronic and acute stress. However, the relatively high incidence of borderline or low levels in pregnancies which spontaneously result in a normal outcome makes it obligatory to not only have serial values on each patient but to relate these to standard curves determined in each laboratory

62

Aubry and Nesbitt

based on assessment of a broad population base. Vaginal hormonal cytology as we have determined it by the KPI is a relatively insensitive reflection of fetal welfare. However, the findings in those patients who experienced premature labor or fetal death, especially among the hypertensive group is provocative and warrants further study in a larger series. Inferences regarding endocrinologic antecedents and accompaniments of fetal deprivation and/or death. Among the special problem groups which we studied, only the nonhypertensive diabetic appeared to spare the fetus chronic stress. When stress occurred, it appa.rently was of the acute type since such insults were not reflected in deteriorating cytoho:rmonal patterns. The rna jority of the data from all of the other problem categories suggest very strongly that when fetal deprivation occurs, it occurs in a chronic fashion and probably from at least as early as midpregnancy. This is suggested by the trend to early lowering of estriol and pregnanediol excretion in the group who were delivered prematurely and among those with low birth weight infants at term and the hypertensive patients who experienced fetal death. That many patients who experience a "normal fetal outcome" (defined as > 2,500 grams birth weight and > 36 weeks' gestational age) in these problem groups are also being subjected to subclinical stress is suggested by the lowered estriol in the more severe chronic hypertensive and the patients with a history of repeated prematures. The ensemble of information thus suggests that in these problem categories the preconceptional maternal status plus the integrity of early placentation are major determinants of pregnancy outcome. Possible impact on perinatal mortality and morbidity. It has been the hope of almost all investigators in this field that the prognostic significance of cytohormonal data might lead to programs of management which would significantly contribute to a lowering of perinatal mortality and morbidity. 44 • 45, Go, 5s, 5 4 , 5 5, 56 Unfortunately, this goal has not been realized. Some investigators

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May 1, !970 Obstet. Gynec.

have not found estriol, at least, to be of much practical clinical utility in achieving this end. 57 • 58 In our series of 133 high-risk patients, only 7 experienced fetal death in utero at or beyond the thirty-fourth gestational week. Of these, only 3 could conceivably have been delivered alive. These were all hypertensives and the low levels of estriol preceding fetal death were not a dramatic change from prior values. In addition, even if the fetal status had been perfectly judged, the healthy survival of the neonatal period would not have been assured. Moreover, our clinic policy of early delivery of diabetic patients and most patients with significant hypertensive disorders, usually as soon as feasible after the thirty-sixth gestational week, limits the use of cytohormonal data as an indication for pregnancy termination to early periods of gestation when neonatal survival could not be anticipated in more than guarded terms. The 2 successful inductions in our series illustrates the uncommon but occasionally valuable use of these assays. They were, however, both hypertensive and at or beyond 3 7 weeks and would probably have been induced shortly even if no assays had been done. However, the high sensitivity of estriol excretion as a reflection of fetal stress may more frequently help in another way. It has been an extremely useful tool in conjunction with other clinical guides to decide which patients do not require early termination of pregnancy. In 19 patients ( 12 with hypertension, 7 with diabetes) normal values allowed us more safely to postpone inductions to achieve greater fetal maturity. In all patients, live healthy infants at later delivery justified the delay and corroborated the normal cytohormonal assessment. Our experience, therefore, indicates that in this manner cytohormonal assessments may be of significance in decreasing neonatal mortality, since premature and illadvised intervention is attended by unnecessary risks to the newborn infant. The use of these assays in caring for the problem of premature labor or states of chronic sublethal states of fetal deprivation remains to be evaluated. The neonatal mor-

Volume 107 Number l

bidity in terms of neurological sequelae has been found to be high for infants born to mothers who experienced low estriol excretion.16 It is not known, moreover, what precise impact such clinically applicable methods as enforced bed rest, psychological sup-

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High-risk obstetrics 63

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64 Aubry and 1\lesbitt

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