Urinary estriol determination in the management of prolonged pregnancy

volume

96 number

December

American

Journal

1,

7 1966

of Obstetrics and Gynecology

OBSTETRICS

Urinary estfiol determination in the management of prolonged pregnancy KAIGHN

SMITH,

JOHN

W.

GREENE,

JOSEPH

C.

Philadelphia,

Pennsylvania

M.D. JR.,

M.D.

TOUCHSTONE,

PH.D.

and pediatricians have a common interest in prolonged pregnancy; yet confusion exists in regard to its effects and treatment. Most authors agree that even in the absence of maternal disease, such as chronic hypertension or diabetes, prolonged pregnancy increases the hazard of infant death,:?, 3, I37 I41 I’, 23 but not all do ~0.~9 15, I63 181” IJnless labor is prolonged, or there is superimposed toxemia, the majority in this country favor watchful waiting rather than

termination of pregnancy.4l 6 13s15-18, 22 On the other hand, it is a common view in England that no pregnancy should be allowed to progress past 42 weeks, and induction of labor is suggested as correct therapy if no maternal complication is present.‘, 23, *4 In a few otherwise normal pregnancies, there is no doubt that placental function may deteriorate.’ Such pregnancies are often past their calculated date of confinement, and the infant, if born alive, may show classical signs of the “postmaturity syndrome.” An antepartum method to assess the adequacy of the fetoplacenta1 complex in these cases would be of great due. Estriol determinations done on 24 hour urine collections have been successful in this regard.’ The present paper reviews the experience of the authors with the use of estriol in the diagnosis and management of prolonged

OBSTETRICIANS

From the Departments Gynecology, Medical of Pennsylvania and Kentucky.

of Obstetrics and Schools, University Universtty of

Supported in part by Grants GM-08419, HD-00539-03, and 3 MO I -FR-40 from the National Institute of Health, United States Public Health Service. Presented Society,

at the Philadelphia Nov. 3, 1965.

Obstetrical 901

902

Smith,

Greene,

and

Touchstone

pregnancy. Previous reports have indicated its usefulness in other complications of pregnancy. A-11, 20, 21 A multiplicity of terms is used to describe prolonged pregnancy and the postmature infant. For purposes of discussion, the following definitions are in order. Prolonged pregnancy is a gestation extending 2 weeks or more beyond the calculated date of confinement. Postdatism represents a condition of prolonged pregnancy in which the patient is 2 weeks or more beyond her calculated date of confinement but exhibits no signs of placental insufficiency. As a result, the fetus may grow to a large size. Postmaturity represents the condition of prolonged pregnancy in which there is clinical or laboratory evidence of placental insufficiency, and in which at delivery the infant is likely to show signs of the “postmaturity syndrome.” The postmaturity syndrome has been adequately described and classified by Clifford.3 It is a pediatric diagnosis. Fetal changes inherent in the syndrome have been described both in the human and in experimental animals, and are probably secondary to hypoxia.l’l lg Materials

and

methods

For several years, the authors have used the estriol determination of 24 hour urinary collections as an assessment of the fetal status in pregnancies complicated by disease entities often associated with placental insufficiency. g-11 Prolonged pregnancy also has been scrutinized. The patients in this group were studied at the Hospital of the University of Pennsylvania from 1960 through 1964. None are included who had a medical or surgical complication of pregnancy. It has not been possible to study every instance in which pregnancy has been prolonged, but every case in which postmaturity has been clinically suspected has been included. Sixtyseven patients have been found, an incidence of 0.6 per cent of the obstetric population during the study. All patients were instructed carefully in the technique of collecting 24 hour urine specimens as outpatients. Those patients in whom estriol was found to be at a borderline level (less than 12.0 mg. per

24 hours) were admitted to the hospital ior daily determinations. If the estriol was nor,. tnal, determinations on outpatient. specimens were continued every other day until delivery was accomplished. No pregnancy was artificially terminated on the basis of one estriol determination. The timing of delivery and method of termination of pregnancy were based on the level of urinary estriol almost entirely in those patients with presumptive evidence of placental insufficiency and fetal jeopardy. In prolonged pregnancy, those with estriol determinations over 12.0 mg. per 24 hours were allowed to continue pregnancy until spontaneous labor ensued unless the responsible physician elected to induce labor. Such normal values (Fig. 1) were not an indication for termination of pregnancy. If serial determinations revealed a borderline value in the high range, termination of pregnancy by induction of labor was considered, particularly if examination revealed that delivery would be easily accomplished. In the presence of falling values, or those with dangerously low values (less than 3. mg. ). interruption of pregnancy by cesarean section was accomplished in the fetal interest. Results A review of the final estriol levels in this group of patients reveals a wide range of values (Table I). High levels were consistent with healthy, mature infants, whereas an estriol less than 4.0 mg. per 24 hours signaled fetal death or, in one case, a severely affected infant with probable residual neurologic damage. Approximately one third of the cases fell into a borderline range of estriol, and one-half of these produced infants showing signs of the postmature syndrome when evaluated by the pediatrician. Except for the 2 infant deaths, all of the affected babies in this middle group thrived in the nursery, gained weight rapidly, and have shown no evidence of mental or nemologic deficit. No correlation bet-n estrGo1 levels and infant weight could be. found, although 4 severely affected babies (one death) weighed

Volume Number

96 7

Management

less than 2,500 grams and had levels less than 6 mg. An analysis of the infant deaths is shown in Table II. The first 3 of these pregnancies had only a single determination of estriol done on an (outpatient specimen, prior to the infant death. The mother of Infant A, a 42year-old para iii, was suspected of having placental insufficiency but refused therapy by either induction or cesarean section. Infant death probably occurred antepartum since no fetal heart tones were found when she was admitted to the hospital in labor. The mother of Infant B was a para i who had a history of prolonged pregnancy with her first gestation, and a deaf infant was born. Within 48 hours following the estriol

Table I. Final

estriol

values

in prolonged

pregnancy Estriol No. of infants

(zgf4 r Over 4-12

12

Less than Total

4

Affected infants

Infant deaths

41 23 3

1 11 3

0 2 2

67

15

4

Table II. Infant

deaths

in prolonged

pregnancy

Infant

Weight (grams)

Final estriol (mg./24 hr.)

A B C D

3,442 2,310 3,20:3 2,806

3.8 5.4 5.4 2.4

Table III. Method

Length of gestation (weeks 63 days) 43 + 5 42 + 4 43+ 1 44+ 1

of delivery

We of death

Antepartum Intrapartum Neonatal Antepartum

in prolonged

pregnancy

$4 Over 4-12

Sp~;rz;~~ous 12

’

Less than 4 Total

Z&c;d

1 C$zr;;

18 9 2

22 6 0

1 8 1

29

28

10

of

prolonged

pregnancy

903

determination in this pregnancy, she went into spontaneous labor. Fetal distress occurred at cervical dilatation of 7 cm., persisted despite oxygen therapy, and she was delivered of a stillborn infant vaginally 20 minutes after the onset of distress. Infant C was born alive with an Apgar rating of 3. Fetal distress occurred late in the first stage of labor in this case as well. Despite all efforts at resuscitation, the infant died within 2 hours of birth. The mother of Infant D was an elderly multipara whose estriol levels remained below 4.0 mg. for 3 days at 44 weeks’ gestation. Her pregnancy was complicated by severe Trichomonas vaginitis, and it was thought that the estriol levels might have been compromised by the amount of pus in the collecting bottle. Unfortunately, this turned out to be a serious mistake, as antepartum death occurred, followed by spontaneous labor within 24 hours. Table III reveals the method of delivery of these patients. One cesarean section in the normal estriol range was carried out for cephalopelvic disproportion in a primigravida with a 4,020 gram infant. Of the 8 cesarean sections in the borderline range, 3 were done because of the development of fetal distress following the onset of spontaneous labor, and one because of fetal distress during an attempted induction of labor. The remaining four cesarean sections were carried out in the fetal interest when estriol levels dropped to borderline levels, indicating that labor was contraindicated. All of the inductions occurred in patients with estri01s over 7.0 mg. per 24 hrs. One cesarean section done on a patient with an extremely low range was carried out after spontaneous labor had started. An estriol level of 2.4 mg. had been obtained 24 hours previously. Fetal distress did not develop, but an amniocentesis failed to obtain fluid. At delivery, the infant was severely depressed, covered by thick meconium, and, as mentioned previously, is presently suspected of having neurologic damage. It is interesting to note that in the entire series, 41 patients were primigravidas, and 18 of these were over the age of 30. Further-

904

Smith,

Greene,

mg./Z& 28-j-

and

Touchstone

hr.

6 10 14 18 Fig. 1. Estriol values in normal pregnancy. AM. J. OBST. & GYNEC. 85: 1, 1963.)

22 26 30 34 38 42 w10. (From Greene, J. W., Jr., and Touchstone, J. C.:

Fig;. 2. Infant of Case E. S., 25-year-old, para i, gravida ii. Previous Ymexpiaiwd” stillbirth at $2 weeks’ gestation. Cesarean section ca&ed out‘at 42 weks + 4 d&a heesuat? of falling estriol levels (see Fig. 3).

Management

pregnancy

905

mg/zJ: hrs.

E.S.

-26

22

T-18 t -14 z ‘-4 1 10 2 s -6t

t

I2 _1

-l--l-l-1 30

of prolonged

34

38

42

wks

Fig. 3. Estriol values of Case E. S. (see Fig. 2) superimposed on normal levels.

more, of those giving birth to infants affected with the postmaturity syndrome, 7 were elderly primigravidas. The photograph (Fig. 2) with its caption is an illustrative case. The serial estriol determinations in this case are superimposed upon normal values in Fig. 3. The infant at birth was tinged by meconium; there was scant amniotic fluid; and it can be seen from the photogra.ph that there was desquamation of the outer skin layer. Comment

From the foregoing results, one must assume that the incidence of fetal death from postmaturity alone in the absence of maternal medical disease is rare. But it certainly exists, and if suspected by the clinician, may be diagnosed antepartum in time to save the infant. Twenty-four hour urinary estriol determinations are of value in making such a diagnosis. Unfortunately, by the time the clinician suspects intrauterine jeopardy from placental senescence, the damage may already have been done, as indicated by our 4 deaths and one damaged baby. Not included are those patients who develop “idiopathic” placental insufficiency before term is reached. These may be the patients who have tragic “unexplained” stillbirths. Urinary estriol is of value in these cases during

all subsequent pregnancies and have saved a few infants as a result9 The management of prolonged pregnancy requires excellent clinical judgment. The vast majority of patients who are more than 2 weeks past their calculated confinement date are either unsure of their last menstrual period, or achieve conception much later than the usual 2 week interval following that period. For such postdate patients, watchful waiting must be carried out. Interference in the form of induction of labor will lead only to prolonged labor, and delivery of premature infants. Rarely, a postdate patient will be truly “overdue,” and in these instances, if the placenta is able to maintain infant development, the fetus may grow to a large size, creating mechanical obstetric difficulties. These must be recognized. Estriol determinations in these situations are uniformly over 12.0 mg. per 24 hours. Even more rarely, as indicated by this series, the fetoplacental complex in a prolonged pregnancy becomes insufficient. This is reflected by falling estriol values. Suspicion of such fetal jeopardy is obtained by decreasing abdominal girth, cessation of fetal growth, and a decrease in amniotic fluid, which becomes meconium-stained. It is confirmed by estriol determinations. Once postmaturity is diagnosed, labor is contraindicated unless a mild form of the disease is indicated by borderline estriol values (7.0 to 12.0 mg. per 24 hours). Uterine contractions under severe conditions probably eliminate the placental reserve remaining for the infant and may result in fetal distress and intrapartum death. Cesarean section is the correct method of delivery under such circumstances. In the presence of a single borderline value, the diagnosis of postmaturity can be confirmed by amniocentesis. A truly postmature infant, in our experience, has been surrounded by meconium-stained amniotic fluid. Therefore, it has recently been the policy to delay cesarean section until amniocentesis confirms the impression obtained by the low urinary estriol. If clear fluid is ob-

906

Smith,

Greene,

and

Touchstone

tained, a gross miscalculation in due date or a urine collection error must be suspected. ‘l’he patient should then have repeated estriol determinations before termination of pregnancy. Furthermore, strict bed rest has insured against an antepartum death during such w-evaluation as long as labor has not ensued. The development of fetal distress in postmaturity occurs late and heralds almost immediate fetal death. Delivery must be accomplished before distress occurs if a healthy baby is ultimately to be obtained.

REFERENCES

1. Bachman, C.: J. Biol. Chem. 131: 463, 1939. 2. McClure Browne, J. C.: AM. J. OBST. & GYNEC. 85: 573, 1963. .“3. 4. W.: AM. T. OBST. & GYNEC. 85: 701. 1963: I-5. r)aichmanr I., and Gold, E. M.: AM. J: 6~s~. & GYNEC. 68: 1129, 1954. 6. Frandsen, V. A., and Stakeman, G.: Danish M. Bul. 7: 95, 1960. 7. Frandsen, V. A., and Stakeman, G.: Danish M. Bul. 7: 98, lQ60. 8. Furuhjelm, M.: Acta obst. et gynec. scandinav. 41: 370, 1962. 9. Greene, J. W., Jr., Fields, H., and Touchstone, J. C.: Obst. & Gynec. 20: 260, 1962. 10. Greene, J. W., Jr., Smith, K., Kyle, G. C.? Touchstone, J. C., and Duhring, J. L.: AM. J. OBST. & GYNEC. 91: 634, 1965. 11. Greene, J. W., Jr., and Touchstone, J. C.: AM. J. OBST. & GYNEC. 85: 1, 1963. 12. Gruenwald, P.: AM. J. OBST. & GYNEC. 89: 503, 1964. 13. Lucas, W. E., Anctil, A. O., and Cal&an, D. A.: Anr. J. OBST. & GYNEC. 91: 241, 1965.

Summary Urinary estriol determinations ha\ t* J)Pcome a valuable aid in the diagnosis of intrauterine fetal jeopardy. Prolonged prqnancy may lead to pIacenta1 senescence in the absence of maternal disease. Such instances may be discovered by the lose of serial urinary rstriol determinations in time to save the infant. Once discovered, ccsarean section is the treatment of choice, particularly if amniocentesis reveals meconium staining.

14.

15.

17. 18. 19. 20. 21.

22. 23. 24.

Macafee, G.: J. 1958.

C. H. G., and Obst. & Gynaec.

Magram,

H.

M., and

Bancroft-Livingston, Brit. Emp. 65:

Cavanagh,

7,

W. V.:

AM. J. OBST. & GYNEC. 79: 216, 1960. Mead, P. B., and Marcus, S. L.: AM. J. OBST. & GYNEC. 89: 495, 1964. Nesbitt, R. E. L., Jr.: Obst. & Gynec 8: 157, 1956. Perlin, I. A.: Aar. J. OBST. & GYNEC. 80: 1, 1960. ROUX, J. F., Romney, S. L., and Dinnerstein? A.: Ass. J. OBST. 8r GYNEC. 90: 546, 1964. Taylor, E. S., Bruns, P. D., and Drose, V. E. : Obst. & Gynec. 25: 177, 1965. Taylor, E. S., Bruns, P. D., Hepner, H. J., and Drose, V. E.: Ax. J. OBST. & GYNEC. 76: 983. 1958. Tucker,’ BI -E., and Benaron, H. B. W.: AM. T. OBST. & GYNEC. 73: 1314. 1957. Walker, J.: AM. J. OBST: & GYNEC. 76: 1231, 1958. walker, J.: J. Obst. & Gynaec. Brit. Emp. 61: 162, 1954. Lankenau Phr’lade&Aia,

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