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Intranasal oxytocin in eighteen hundred patients
lntranasal oxytocin in eighteen hundred patients A study on its safety as used in a community
ROBERT Orlando,
T.
HOOVER,
hospital
M.D.
Florida
Of 9,557 deliveries, 1,806 patients received intranasal oxytocin. Thirteen hundred and fifty-seven, or 75 per cent, received it for elective stimulation of labor. Four hundred forty-nine, or 25 per cent, received it for induction of labor. There was a total success rate of induction of 88 per cent. There was an over-all cesarean rate of 1.5 per cent, and there were no major maternal complications. There were II cervical lacerations, no ruptured uteri, and one inversion of the uterus. There was a total of 6 depressed infants, one of whom required prolonged hospitalization. There were 2 fetal deaths which could indirectly be related to the use of intranasal oxytocin.
SINCE THE INTRODUCTION of intranasal oxytocin by Hofbauer and Hoerner5 in 1927, very few studieswere done until the last decade. The notable exception was Bartholomew’sl report in 1945. Since 1960, numerous articles have been published regarding the safety, dosage, and effectiveness of intranasal oxytocin used either in drops or spray. This report is presented to give our experience with its usage in 2 community hospitals over a two-year period of time and to report on its safety and effectiveness.
Methods
All deliveries at 2 community hospitals over a two-year period of time were reviewed. In one (Orange Memorial), there were 8,328 deliveries, and, in the other (Florida), there were 1,229, for a total of 9,557 deliveries. Intranasal oxytocin was used in 1,806 patients for a total of 19 per cent of all the deliveries. From the Department Gynecology, Orange and the Department Gynecology, Florida
of Obstetrics and Memorial Hospital, of Obstetrics and Hospital.
Presented by invitation at the Thirtythird Annual Meeting of the South Atlantic Association of Obstetricians and ~l~;$,~ts, Atlanta, Georgra, February - >
Of this group, 1,357 patients, or 75 per cent, received intranasal oxytocin for elective stimulation of labor or stimulation of prolonged labor. In 449 patients, or 25 per cent, it was used for induction of labor. AS the methods used in both hospitals were comparable, they will be considered as a single unit. The patients were divided into those who had no deliveries, those who had 1 to 3 deliveries, and those who had 4 or more deliveries (Table I). The method of administering oxytocin* was by dropper, with the use of 10 I.U. per cubic centimeter. The drops used contained approximately 0.4 to 0.8 I.U. per drop and were administered with either a glass or plastic dropper. The initial test dose was 1 to 2 drops; then 2 to 4 drops were used at 15 to 20 minute intervals, for a total of 8 to 9 doses.Occasionally, when poor responsewas noted, 6 to 8 drops would be given at each application. The drops were given by the labor room nurse, who is a registered nurse, under the direction of the attending physician or resident physician in the case of service patients. The usual precautions of monitoring ‘Either Michigan,
788
Pituitrin was used.
or Pit&n,
Parke.
Davis
& Co.,
Detroit,
Volume Number
110 6
lntranasal oxytocin
Table I -.Patients Nulliparas Multigravidas Multigravidas - Totals
(1 to 3) (4 to 8)
Induction
Augmentation
Totals
161 251 37
593 635 129
754 886 166
449
1,357
fetal heart rate, uterine contractions, progress of labor were taken.
1,806
and
Results
Induction of labor. Of the 449 patients who were induced, 161 were nulliparous, 251 had 1 to 3 children, and 37 had had 4 or more children. The indications for induction were as follows: elective, 256 (57 per cent) ; irregular uterine contractions which had stopped (false labor), 118 (26 per cent) ; premature rupture of the membranes, 54 (12 per cent) ; toxemia, 12 (3 per cent) ; diabetes, 4 (1 per cent); Rh isoimmunization, 3; nephritis, 1; and eclampsia, 1. If, after one or two series of intranasal oxytocin, labor was not instituted, occasionally additional oxytocin in the intramuscular and/or intravenous form was used. Of the 449 inductions, 366 received intranasal oxytocin only, 60 received intranasal and intramuscular oxytocin, and 23 received intranasal and intravenous oxytocin (Table II ) . Of the 449 patients, 45 failed to deliver and were either returned to the floor for another seriesof oxytocin the following day or discharged. Nine of the patients had cesarean delivery. There were 91 low-forceps and 3 mid-forceps deliveries. This is a total success rate by vaginal delivery of 88 pe’r cent, and, of’ the 449, 331 delivered with intranasal osytocin only for a successrate of 70.2 per rent. The indications for cesareandelivery were: ctxphalopelvic disproportion, 5; toxemia, 1; prolapsed cord in a set of twins, 1; failure of the cervix to dilate with adequate uterine rontractions, 1; and “nonproductive” labor, Dosage. The patients received from 1 to 43 doses. Thirty-two patients received 1 to
789
4,239 received 5 to 12, 132 received 13 to 20, and 46 received 20 or more (Table III). Maternal complications. Maternal complications are shown in Table IV. Of this group, cervical laceration, hemorrhage, and prolapsed cord could be related to the use of the intranasal oxytocin. There were no ruptured uteri. Three cervical lacerations required repair and one prolapsed cord occurred in twins which required cesarean delivery. Fetus. Apgar scoreswere recorded at both 1 and 5 minutes and, with depression, at 10 minutes. Three hundred eighty-six had an Apgar rating at 1 minute of 7 to 10 and above 7 at 5 minutes. Sixteen had an Apgar rating of 0 to 6 at 1 minute, but all were above 7 at 5 minutes. There was one infant with an Apgar score of less than 7 at 5 minutes. This infant did survive and was discharged with the mother on the fifth postpartum day. One infant was stillborn. The mother, gravida 13, para 12, had severe diabetes and received intranasal and intravenous oxytocin. Fetal heart tones were not present on admission (Table V). Augmentation of labor. Intranasal oxytotin was used for stimulation of prolonged labor and elective stimulation of labor in 1,357 patients; and, of this group, 16 had cesarean deliveries for a total of 1.2 per cent. The remainder were delivered vaginally. Table VI shows the relationship between the methods of administration and the incidence of cesareansections. Indications for cesarean delivery were: cephalopelvic disproportion, 8; cephalopelvic disproportion with brow presentation, 3 : uterine dystocia, premature rupture of the membranes, and presence of a breech lie, 1: deep transverse arrest, 2; compound presentation, 1; and amnionitis with fetal distress, 1. Dosage. It is interesting to note that of the 1,357 patients receiving stimulation of labor 808, or approximately 60 per cent, received only 1 to 4 dosesto stimulate labor to an adequate level. Four hundred seventyeight required 5 to 12 doses, 65 patients required 13 to 20, and 6, over 20 doses (Table VII).
Hoover
790
Amer.
July J. Olxtet.
15, 1971 Gynec.
Table II Oxytot Nasal Patients Nulliparas Multigravidas Multigravidas
Total ( 1 to 3) (4 to 8)
Totals CS
= cesarean
1
only
Nasal (
intramuscularly
Failed
CS
Total
121 215 30
9 23 7
5 1 0
32 26 2
1 3 0
1 0 0
Failed
CS
366
39
6
60
4
I
section.
Table III. Doses of intranasal
oxytocin
I Patients Nulliparas Multigravidas Multigravidas
and
(1 to 3) (4 to 8)
Totals
Table IV. Maternal
No.
of doses
l-4
5-12
13-20
I
+20
10 17 5
79 143 17
49 71 12
23 20 3
32
239
132
46
complications Parity
Complication Rupture of uterus Cervical laceration Postpartum bleeding Convulsion Endometritis Amnionitis Infected B. G. cyst Deep venous thrombosis Totals
0
I to 3
4 to 8
0 1 1 1 1 1 0 0
0 2
0 0 0 0 0 0
0
0
:
5
6
0
11
Maternal complications. A number of maternal complications were present in this group of patients (Table VIII). While some of these were incidental to labor and delivery and are in no way related to the use of intranasal oxytocin, certain complications do require closer observation. Of particular interest is the presence of cervical laceration, postpartum hemorrhage, inversion of the uterus, and the cesarean rate. In this group of patients, a cesarean delivery was required in 16 patients and cervical laceration occurred in 11 patients. Ten of these required repair, but one was extensive and extended into the broad ligament,
A 0 0 1 2
Totals
z 1 1 1
requiring repair which was done from the vaginal route (incomplete rupture) . There were 302 low-forceps and 24 mid-forceps deliveries. Postpartum hemorrhage was present in 3 primigravidas requiring 3, 2, and 1 U. of blood, respectively. One inversion of the uterus was present. Fetus. In analyzing the effect upon the fetus, 1,304 of the 1,357 had an Apgar rating of 7 to 10 at one minute. An Apgar rating of 0 to 6 at one minute but above 7 at 5 minutes was present in 41 infants. There were 5 depressed infants with Apgar ratings of less than 7 at 5 minutes, of which one required extended hospital stay (Table IX).
V~hme Number
lntranasal
110 6
7’otalr Nasal
and
Total 0 1; 5 -_
intravenously
oxytocin
791
---_-~_
. ~. -... ~-
---
.-._ --.-Vaginal delilrery
cs
Failed
CS
Total
1 0
20 0
251 161 37
:5 7
(11%) (7%) (20%)
81 0
(5%) (4%)
2
2
449
45
(10%)
9
(2%) ~----~~_ 395 -.. -~.-. ( 88%, ~- .-j
23
Failed
223 142 30
(88%) (89%) (77%)
Table V. Fetal results __-Apgar Patients Nulliparas Multigravidas Multigravidas
score
7-10
O-6
141 217 28
;
386 0
(1 to 3) (4 to 8)
Totals Depression
F&al I <7
or 5 min.
.-.---
status L‘Of.7
Premature
1
1 0 0
2 2 2
0 0 1
16 16
1 1
6
1
Table VI I
Oxytocin Nasal No.
Patients Nulliparas Multigravidas Multigravidas
(1 to 3) (4 to 8)
Totals
547 597 123 1,267
Table VII. Doses of intranasal
only )
I
Nasal f fntramuscularly CS
6 5 1 12 (1%)
No.
/
Nasal + intravenously CS
No.
1
Totals CS
31 30 4
2 0 0
17 6 2
1 1 0
65
2 (3%)
25
2 (8%) -____---.-.
No.
-_._____ 1 CS i %
595 633 129
9 6 1
1.5 1.0 0.8
1,357
16
- ._1.2 ~-
oxytocin ---_-.-.--
I Patients
I
l-4
I
5-12
H-20
( 1 to 3)
313 392
Multigravidas
(t4)
103
19
7
808
478
65
There was a fetal loss of 7 infants. Of this one had hyaline membrane disease grow, associated with prematurity and premature rupture of the membranes. This mother received 12 doses of intranasal oxytocin of 4 drops each. Anencephalia was present in 2
240 219
I
Nulliparas Multigravidas
Totals
-
Dose.r I
Orier
36 22
20 4 ',i 0
---.-.-.
6
.--.-
-
infants of primigravidas, one mother receiving 19 doses of oxytocin and the other 8 doses. One infant died secondary to placental dysfunction with a small infarcted placenta. This mother had received 9 doses of intranasal oxytocin. One stillborn infant had a
792
Hoover
Table VIII.
Amer.
,July 15. l!liI J. Obstet. Gyncc.
Maternal complications
Complication
Multigravidas (1 to 3)
Primiparas
Premature rupture of membranes Cepbalopelvic disproportion Cervical laceration Cervical laceration with extension Postpartum hemorrhage Abruptio placentae Amnionitis Eclampsia Diabetes Epilepsy Inversion of uterus Thrombophlebitis
71 5 5 1 3 3 0 2 1 1 1 0
69 5 4 0 0 0 1 0 0 2 0 1
Multigravidas (+4)
Total 164 11 10 1 3 4 2 3 1 3 1 1
24 1 1 0 0 1 1 1 0 0 0 0
Table IX. Fetal results Apgar Patients Nulliparas Multigravidas Multigravidas Totals
status
O-6
Less than 7 or 5 min.
561 623 120
27 11 3
2 0 3
0 4 2
3 1 3
1,304
41
5
6
7
7-10 (1 to 3) (+4)
Fetal
score
true knot in the cord that had obstructed the blood supply of the infant. The mother was a grand multipara who had received one dose of 2 drops of intranasal oxytocin. In one infant, whose mother had received one dose of 4 drops, there was occult prolapse of the cord with compression.The seventh loss was due to erythroblastosis fetalis and hydropic change in the infant. This mother had received 4 dosesof 4 drops of intranasal oxytotin. Comment
Intranasal oxytocin has been used in the Orlando area in 2 of the community hospitals for many years. Two years’ experience is reviewed from July, 1968, through July, 1970. During this period of time, intranasal oxytocin was used on 1,806 patients, or 19 per cent of the total deliveries, 449 being for induction and 1,357 being for enhancement of labor. There was a total cesarean rate of 1.5 per cent with a hospital rate of 3.6 per cent for all deliveries. Maternal complica-
Premature
Loss
tions consisted primarily of 14 cervical lacerations, one of which extended into the broad ligament which required extensive repair from below, 5 postpartum hemorrhages (2 requiring 1 U. of blood, 2 requiring 2 U. of blood, and 1 requiring 3 U. of blood). There were no ruptured uteri and one inversion of the uterus. There were 6 depressedinfants, of which one was severe and required extended hospitalization; long-term follow-up is not known. There were 8 stillbirths and neonatal deaths, of which oxytocin could possibly be implicated in 2. Intranasal oxytocin in the dosagesused is equivalent approximately to intravenous oxytocin at the rate of 1 to 2 mu. per minute continuously. Uterine tetany did not occur in any of these 1,806 patients during this two-year period of time, and oxytocin was discontinued in 2 patients becauseof irregularity of the fetal heart rates. The findings in this study are consistent with those of Clement and associates,2Hendricks and Gabel,4 and De Voe and col-
Volume 110 Number 6
leagues,3 in that intranasal oxytocin is a gentle stimulant to labor and can be used effectively for the augmentation of prolonged labor, elective stimulation of labor, and induction of labor. Intranasal oxytocin does not replace the
lntranasal
oxytocin
793
intravenous route, particularly when used with the infusion pump, but is a compliment to this method; and, because of its apparent ease, simplicity, and safety, its continued use is indicated, and further study and evaluation are in order.
REFERENCES
I. Bartholomew, R. A.: J. Med. Ass. Georgia 34: 110, 1945. 2. Clement, J. E., Harwell, V. D., and McCain, J. R.: AMER. J. OBSTET. GYNEC. 83: 778, 1962. %. De Voe, K., Rigsby, W. C., and McDaniels,
Discussion H. HENDRICKS, Chapel Hill, North Carolina. Dr. Hoover is reporting on the safety of intranasal oxytocin as it was used in 2 community hospitals from 1968 to 1970. One cannot make a specific judgment about the safety factor, since we have not been informed of the incidence of such complications as cervical lacerations, uterine ruptures, perinatal deaths, and depressed infants among the total number of patients who were delivered during the same time that the intranasal oxytocin patients were being studied but who did not receive intranasal oxytocin. Nor have we been informed as to the incidence of complications among patients whose labors were induced or augmented by means other than intranasal oxytotin. Nevertheless, it is appropriate for physicians to continue to be concerned about safety factors whenever labor is to be induced or augmented. One uterine rupture occurred in the augmented labor group, although the author reported this as a cervical laceration extending into the broad ligament. By definition, this should be considered as an incomplete uterine rupture, despite the fact that this particular rupture was successfully repaired from below. Whether the rupture resulted from a difficult delivery or the use of oxytocin or was inevitable is impossible to determine. Another serious uterine complication, inversion of the uterus, certainly cannot be blamed upon the use of oxytocin; such an unfortunate happening should be extremely rare under modern obstetric conditions. It is difficult to make an accurate assessment DR.
CHARLES
B. A.: AMER. J. OBSTET. GYNEC. 97: 208, 1967. 4. Hendricks, C. H., and Gabel, R. A.: AMER. J. OBSTET. GYNEC. 79: 780, 1960. 5. Hofbauer, J., and Hoerner, J.: Abren. J. OBSTET. GYNEC. 14: 137, 1927.
of the role of intranasal oxytocin in producing the relatively few depressed infants in these inductions and augmentations done for a wide spectrum of indications. At least it is gratifying that in the induction group there was no fetal death after the induction was begun. Of the 7 infants who died in the augmentation group, 3 (the 2 anencephalic deaths and the erythroblastosis death) were probably inevitable by the time labor began, For the remaining 4 cases, in none of which excessively large doses of intranasal oxytocin was used, it would probably be unfair to incriminate oxytotin as a major contributing factor. These 4 tragic cases represent a spectrum of unexpected fetal losses : death from hyaline membrane disease where labor was induced after premature rupture of the membranes, death from what was believed to be placental dysfunction, one death from a true knot in the cord, and another from occult prolapse of the cord. One might raise the question as to whether these infants died as the result of labor rather than from the use of oxytocin per se. While all labors were monitored in this series, it still was not possible in these cases to identify the point in labor when the infant was getting into trouble and where immediate cesarean section was indicated. Some added comment about drugs and dosage is in order. Part of the patients received Pituitrin rather than oxytocin. It was surprising to learn that this preparation of whole pituitary extract is still being employed in modern obstetric hospitals. The ready availability of precisely standardized totally synthetic preparations
794
July 15, 1971 Amer. J. Ohstet. Gynnc.
Hoover
of oxytocin (sold commercially as Syntocinon and Pitocin) makes obsolete any indication for the use of Pituitrin. The drops were administered by a trained nurse. No mention is made as to whether hospital rules rcquirc the presence of a physician on the labor floor when oxytocin is being used. At best, the intranasal route is a somewhat inefficient way of administering oxytocin. It may be, however, perfectly sufficient when only a small stimulus is needed to induce or to augment labor. In many ways, the first one or two doses of intranasally applied oxytocin drops serve not only as a therapeutic but also as a diagnostic and prognostic test. The physician learns quite promptly whether or not an adequate enhancement of uterine contractility can be obtained by this simple means. If the response is insufficient, he naturally tends to consider other things, including the delivery of oxytocin by the intramuscular or the intravenous route as was done in the series reported here. From my own experience with this method of administration of oxytocin, I concluded that if a few applications of intranasal oxytocin failed to elicit adequate labor, it was preferable to change to the intravenous infusion route. The author’s report that 5 per cent of the augmented patients and 40 per cent of the induced patients received more than 12 doses intranasally is a tribute to the persistence of the obstetricians in using this method, but perhaps most of these patients would have benefited from an earlier initiation of intravenous oxytocin infusion. DR. GEORGE L. PITTMAN, Burlington, North Carolina (by invitation). Intranasal oxytocin has long been used for induction and enhancement of labor in the Atlanta area, and two studies have been published from Atlanta. The first was in 1945 by Bartholomew1 and the second one was by Clement, Harwell, and McCain2 in 1962. The only other area which has been as productive was Case Western Reserve University where Dr. Hendricks?? 4 published two studies in 1960. The present study by Dr. Hoover is the largest series of cases which has been reported and serves to further the concept that intranasal oxytocin represents probably the safest method of administration for this potentially powerful drug. There were some patients of
rather high parity in the present study, but there were no maternal deaths. The safety of oxytocin is, of course, related directly to the dosage in any given method of administration. Only a small amount of the oxytocin placed intranasally is absorbed, and this amount could vary a great deal depending on local factors. It has been estimated that the same dose given intravenously would be one hundred times more potent.3 An indication of the safety of intranasal oxytocin is that there has been only one case report of a ruptured uterus.5 Jt would seem to be a matter of terminology as to whether, in the present report, the cervical laceration which extended into the broad ligament should be considered a tear of the lower uterine segment. It is unlikely that the safety record of intranasal oxytocin could be matched by any other route of administration in so large a number of cases. There were 45 failures of elective induction with the first course of intranasal oxytocin. This figure is difficult to evaluate, however, because the success or failure of induction depends on many factors and these other factors were not included as a part of the present study. One of the most attractive aspects of Dr. Hoover’s study was that stimulation of labor required only 1 to 4 doses of intranasal oxytocin in 60 per cent of the 1,357 patients. The small amount of medication required here indicates that, in common usage, excessively large doses are frequently employed. Overdosage will in turn lead to increased complications. It is a fact of life that much oxytocin stimulation is carried out in this country without the attending obstetrician being present at the bedside. It is the responsibility of the obstetrician to be present whenever possible, and, if he is not present, the safety factor must outweigh all other considerations. The data presented in this study again indicate the large margin of safety with this method of administration. REFERENCES
1. Bartholomew, R. A.: J. Med. Ass. Georgia 34: 110, 1945. 2. Clement, J. E., Harwell, V. D., and McCain, J. R.: AMER. J. OBSTET. GYNEC. 83: 778, 1962. 3. Hendricks, C. H., and Gabel, R. A.: AMER. J. OBSTET. GYNEC. 79: 780, 1960. 4. Hendricks, C. H.: AMER. J. OBSTET. GYNEC. 79: 789, 1960. 5. Stitchbury, P. C.: New Zealand Med. J. 61: 160, 1962.
ROBERT Orlando,
T.
HOOVER,
hospital
M.D.
Florida
Of 9,557 deliveries, 1,806 patients received intranasal oxytocin. Thirteen hundred and fifty-seven, or 75 per cent, received it for elective stimulation of labor. Four hundred forty-nine, or 25 per cent, received it for induction of labor. There was a total success rate of induction of 88 per cent. There was an over-all cesarean rate of 1.5 per cent, and there were no major maternal complications. There were II cervical lacerations, no ruptured uteri, and one inversion of the uterus. There was a total of 6 depressed infants, one of whom required prolonged hospitalization. There were 2 fetal deaths which could indirectly be related to the use of intranasal oxytocin.
SINCE THE INTRODUCTION of intranasal oxytocin by Hofbauer and Hoerner5 in 1927, very few studieswere done until the last decade. The notable exception was Bartholomew’sl report in 1945. Since 1960, numerous articles have been published regarding the safety, dosage, and effectiveness of intranasal oxytocin used either in drops or spray. This report is presented to give our experience with its usage in 2 community hospitals over a two-year period of time and to report on its safety and effectiveness.
Methods
All deliveries at 2 community hospitals over a two-year period of time were reviewed. In one (Orange Memorial), there were 8,328 deliveries, and, in the other (Florida), there were 1,229, for a total of 9,557 deliveries. Intranasal oxytocin was used in 1,806 patients for a total of 19 per cent of all the deliveries. From the Department Gynecology, Orange and the Department Gynecology, Florida
of Obstetrics and Memorial Hospital, of Obstetrics and Hospital.
Presented by invitation at the Thirtythird Annual Meeting of the South Atlantic Association of Obstetricians and ~l~;$,~ts, Atlanta, Georgra, February - >
Of this group, 1,357 patients, or 75 per cent, received intranasal oxytocin for elective stimulation of labor or stimulation of prolonged labor. In 449 patients, or 25 per cent, it was used for induction of labor. AS the methods used in both hospitals were comparable, they will be considered as a single unit. The patients were divided into those who had no deliveries, those who had 1 to 3 deliveries, and those who had 4 or more deliveries (Table I). The method of administering oxytocin* was by dropper, with the use of 10 I.U. per cubic centimeter. The drops used contained approximately 0.4 to 0.8 I.U. per drop and were administered with either a glass or plastic dropper. The initial test dose was 1 to 2 drops; then 2 to 4 drops were used at 15 to 20 minute intervals, for a total of 8 to 9 doses.Occasionally, when poor responsewas noted, 6 to 8 drops would be given at each application. The drops were given by the labor room nurse, who is a registered nurse, under the direction of the attending physician or resident physician in the case of service patients. The usual precautions of monitoring ‘Either Michigan,
788
Pituitrin was used.
or Pit&n,
Parke.
Davis
& Co.,
Detroit,
Volume Number
110 6
lntranasal oxytocin
Table I -.Patients Nulliparas Multigravidas Multigravidas - Totals
(1 to 3) (4 to 8)
Induction
Augmentation
Totals
161 251 37
593 635 129
754 886 166
449
1,357
fetal heart rate, uterine contractions, progress of labor were taken.
1,806
and
Results
Induction of labor. Of the 449 patients who were induced, 161 were nulliparous, 251 had 1 to 3 children, and 37 had had 4 or more children. The indications for induction were as follows: elective, 256 (57 per cent) ; irregular uterine contractions which had stopped (false labor), 118 (26 per cent) ; premature rupture of the membranes, 54 (12 per cent) ; toxemia, 12 (3 per cent) ; diabetes, 4 (1 per cent); Rh isoimmunization, 3; nephritis, 1; and eclampsia, 1. If, after one or two series of intranasal oxytocin, labor was not instituted, occasionally additional oxytocin in the intramuscular and/or intravenous form was used. Of the 449 inductions, 366 received intranasal oxytocin only, 60 received intranasal and intramuscular oxytocin, and 23 received intranasal and intravenous oxytocin (Table II ) . Of the 449 patients, 45 failed to deliver and were either returned to the floor for another seriesof oxytocin the following day or discharged. Nine of the patients had cesarean delivery. There were 91 low-forceps and 3 mid-forceps deliveries. This is a total success rate by vaginal delivery of 88 pe’r cent, and, of’ the 449, 331 delivered with intranasal osytocin only for a successrate of 70.2 per rent. The indications for cesareandelivery were: ctxphalopelvic disproportion, 5; toxemia, 1; prolapsed cord in a set of twins, 1; failure of the cervix to dilate with adequate uterine rontractions, 1; and “nonproductive” labor, Dosage. The patients received from 1 to 43 doses. Thirty-two patients received 1 to
789
4,239 received 5 to 12, 132 received 13 to 20, and 46 received 20 or more (Table III). Maternal complications. Maternal complications are shown in Table IV. Of this group, cervical laceration, hemorrhage, and prolapsed cord could be related to the use of the intranasal oxytocin. There were no ruptured uteri. Three cervical lacerations required repair and one prolapsed cord occurred in twins which required cesarean delivery. Fetus. Apgar scoreswere recorded at both 1 and 5 minutes and, with depression, at 10 minutes. Three hundred eighty-six had an Apgar rating at 1 minute of 7 to 10 and above 7 at 5 minutes. Sixteen had an Apgar rating of 0 to 6 at 1 minute, but all were above 7 at 5 minutes. There was one infant with an Apgar score of less than 7 at 5 minutes. This infant did survive and was discharged with the mother on the fifth postpartum day. One infant was stillborn. The mother, gravida 13, para 12, had severe diabetes and received intranasal and intravenous oxytocin. Fetal heart tones were not present on admission (Table V). Augmentation of labor. Intranasal oxytotin was used for stimulation of prolonged labor and elective stimulation of labor in 1,357 patients; and, of this group, 16 had cesarean deliveries for a total of 1.2 per cent. The remainder were delivered vaginally. Table VI shows the relationship between the methods of administration and the incidence of cesareansections. Indications for cesarean delivery were: cephalopelvic disproportion, 8; cephalopelvic disproportion with brow presentation, 3 : uterine dystocia, premature rupture of the membranes, and presence of a breech lie, 1: deep transverse arrest, 2; compound presentation, 1; and amnionitis with fetal distress, 1. Dosage. It is interesting to note that of the 1,357 patients receiving stimulation of labor 808, or approximately 60 per cent, received only 1 to 4 dosesto stimulate labor to an adequate level. Four hundred seventyeight required 5 to 12 doses, 65 patients required 13 to 20, and 6, over 20 doses (Table VII).
Hoover
790
Amer.
July J. Olxtet.
15, 1971 Gynec.
Table II Oxytot Nasal Patients Nulliparas Multigravidas Multigravidas
Total ( 1 to 3) (4 to 8)
Totals CS
= cesarean
1
only
Nasal (
intramuscularly
Failed
CS
Total
121 215 30
9 23 7
5 1 0
32 26 2
1 3 0
1 0 0
Failed
CS
366
39
6
60
4
I
section.
Table III. Doses of intranasal
oxytocin
I Patients Nulliparas Multigravidas Multigravidas
and
(1 to 3) (4 to 8)
Totals
Table IV. Maternal
No.
of doses
l-4
5-12
13-20
I
+20
10 17 5
79 143 17
49 71 12
23 20 3
32
239
132
46
complications Parity
Complication Rupture of uterus Cervical laceration Postpartum bleeding Convulsion Endometritis Amnionitis Infected B. G. cyst Deep venous thrombosis Totals
0
I to 3
4 to 8
0 1 1 1 1 1 0 0
0 2
0 0 0 0 0 0
0
0
:
5
6
0
11
Maternal complications. A number of maternal complications were present in this group of patients (Table VIII). While some of these were incidental to labor and delivery and are in no way related to the use of intranasal oxytocin, certain complications do require closer observation. Of particular interest is the presence of cervical laceration, postpartum hemorrhage, inversion of the uterus, and the cesarean rate. In this group of patients, a cesarean delivery was required in 16 patients and cervical laceration occurred in 11 patients. Ten of these required repair, but one was extensive and extended into the broad ligament,
A 0 0 1 2
Totals
z 1 1 1
requiring repair which was done from the vaginal route (incomplete rupture) . There were 302 low-forceps and 24 mid-forceps deliveries. Postpartum hemorrhage was present in 3 primigravidas requiring 3, 2, and 1 U. of blood, respectively. One inversion of the uterus was present. Fetus. In analyzing the effect upon the fetus, 1,304 of the 1,357 had an Apgar rating of 7 to 10 at one minute. An Apgar rating of 0 to 6 at one minute but above 7 at 5 minutes was present in 41 infants. There were 5 depressed infants with Apgar ratings of less than 7 at 5 minutes, of which one required extended hospital stay (Table IX).
V~hme Number
lntranasal
110 6
7’otalr Nasal
and
Total 0 1; 5 -_
intravenously
oxytocin
791
---_-~_
. ~. -... ~-
---
.-._ --.-Vaginal delilrery
cs
Failed
CS
Total
1 0
20 0
251 161 37
:5 7
(11%) (7%) (20%)
81 0
(5%) (4%)
2
2
449
45
(10%)
9
(2%) ~----~~_ 395 -.. -~.-. ( 88%, ~- .-j
23
Failed
223 142 30
(88%) (89%) (77%)
Table V. Fetal results __-Apgar Patients Nulliparas Multigravidas Multigravidas
score
7-10
O-6
141 217 28
;
386 0
(1 to 3) (4 to 8)
Totals Depression
F&al I <7
or 5 min.
.-.---
status L‘Of.7
Premature
1
1 0 0
2 2 2
0 0 1
16 16
1 1
6
1
Table VI I
Oxytocin Nasal No.
Patients Nulliparas Multigravidas Multigravidas
(1 to 3) (4 to 8)
Totals
547 597 123 1,267
Table VII. Doses of intranasal
only )
I
Nasal f fntramuscularly CS
6 5 1 12 (1%)
No.
/
Nasal + intravenously CS
No.
1
Totals CS
31 30 4
2 0 0
17 6 2
1 1 0
65
2 (3%)
25
2 (8%) -____---.-.
No.
-_._____ 1 CS i %
595 633 129
9 6 1
1.5 1.0 0.8
1,357
16
- ._1.2 ~-
oxytocin ---_-.-.--
I Patients
I
l-4
I
5-12
H-20
( 1 to 3)
313 392
Multigravidas
(t4)
103
19
7
808
478
65
There was a fetal loss of 7 infants. Of this one had hyaline membrane disease grow, associated with prematurity and premature rupture of the membranes. This mother received 12 doses of intranasal oxytocin of 4 drops each. Anencephalia was present in 2
240 219
I
Nulliparas Multigravidas
Totals
-
Dose.r I
Orier
36 22
20 4 ',i 0
---.-.-.
6
.--.-
-
infants of primigravidas, one mother receiving 19 doses of oxytocin and the other 8 doses. One infant died secondary to placental dysfunction with a small infarcted placenta. This mother had received 9 doses of intranasal oxytocin. One stillborn infant had a
792
Hoover
Table VIII.
Amer.
,July 15. l!liI J. Obstet. Gyncc.
Maternal complications
Complication
Multigravidas (1 to 3)
Primiparas
Premature rupture of membranes Cepbalopelvic disproportion Cervical laceration Cervical laceration with extension Postpartum hemorrhage Abruptio placentae Amnionitis Eclampsia Diabetes Epilepsy Inversion of uterus Thrombophlebitis
71 5 5 1 3 3 0 2 1 1 1 0
69 5 4 0 0 0 1 0 0 2 0 1
Multigravidas (+4)
Total 164 11 10 1 3 4 2 3 1 3 1 1
24 1 1 0 0 1 1 1 0 0 0 0
Table IX. Fetal results Apgar Patients Nulliparas Multigravidas Multigravidas Totals
status
O-6
Less than 7 or 5 min.
561 623 120
27 11 3
2 0 3
0 4 2
3 1 3
1,304
41
5
6
7
7-10 (1 to 3) (+4)
Fetal
score
true knot in the cord that had obstructed the blood supply of the infant. The mother was a grand multipara who had received one dose of 2 drops of intranasal oxytocin. In one infant, whose mother had received one dose of 4 drops, there was occult prolapse of the cord with compression.The seventh loss was due to erythroblastosis fetalis and hydropic change in the infant. This mother had received 4 dosesof 4 drops of intranasal oxytotin. Comment
Intranasal oxytocin has been used in the Orlando area in 2 of the community hospitals for many years. Two years’ experience is reviewed from July, 1968, through July, 1970. During this period of time, intranasal oxytocin was used on 1,806 patients, or 19 per cent of the total deliveries, 449 being for induction and 1,357 being for enhancement of labor. There was a total cesarean rate of 1.5 per cent with a hospital rate of 3.6 per cent for all deliveries. Maternal complica-
Premature
Loss
tions consisted primarily of 14 cervical lacerations, one of which extended into the broad ligament which required extensive repair from below, 5 postpartum hemorrhages (2 requiring 1 U. of blood, 2 requiring 2 U. of blood, and 1 requiring 3 U. of blood). There were no ruptured uteri and one inversion of the uterus. There were 6 depressedinfants, of which one was severe and required extended hospitalization; long-term follow-up is not known. There were 8 stillbirths and neonatal deaths, of which oxytocin could possibly be implicated in 2. Intranasal oxytocin in the dosagesused is equivalent approximately to intravenous oxytocin at the rate of 1 to 2 mu. per minute continuously. Uterine tetany did not occur in any of these 1,806 patients during this two-year period of time, and oxytocin was discontinued in 2 patients becauseof irregularity of the fetal heart rates. The findings in this study are consistent with those of Clement and associates,2Hendricks and Gabel,4 and De Voe and col-
Volume 110 Number 6
leagues,3 in that intranasal oxytocin is a gentle stimulant to labor and can be used effectively for the augmentation of prolonged labor, elective stimulation of labor, and induction of labor. Intranasal oxytocin does not replace the
lntranasal
oxytocin
793
intravenous route, particularly when used with the infusion pump, but is a compliment to this method; and, because of its apparent ease, simplicity, and safety, its continued use is indicated, and further study and evaluation are in order.
REFERENCES
I. Bartholomew, R. A.: J. Med. Ass. Georgia 34: 110, 1945. 2. Clement, J. E., Harwell, V. D., and McCain, J. R.: AMER. J. OBSTET. GYNEC. 83: 778, 1962. %. De Voe, K., Rigsby, W. C., and McDaniels,
Discussion H. HENDRICKS, Chapel Hill, North Carolina. Dr. Hoover is reporting on the safety of intranasal oxytocin as it was used in 2 community hospitals from 1968 to 1970. One cannot make a specific judgment about the safety factor, since we have not been informed of the incidence of such complications as cervical lacerations, uterine ruptures, perinatal deaths, and depressed infants among the total number of patients who were delivered during the same time that the intranasal oxytocin patients were being studied but who did not receive intranasal oxytocin. Nor have we been informed as to the incidence of complications among patients whose labors were induced or augmented by means other than intranasal oxytotin. Nevertheless, it is appropriate for physicians to continue to be concerned about safety factors whenever labor is to be induced or augmented. One uterine rupture occurred in the augmented labor group, although the author reported this as a cervical laceration extending into the broad ligament. By definition, this should be considered as an incomplete uterine rupture, despite the fact that this particular rupture was successfully repaired from below. Whether the rupture resulted from a difficult delivery or the use of oxytocin or was inevitable is impossible to determine. Another serious uterine complication, inversion of the uterus, certainly cannot be blamed upon the use of oxytocin; such an unfortunate happening should be extremely rare under modern obstetric conditions. It is difficult to make an accurate assessment DR.
CHARLES
B. A.: AMER. J. OBSTET. GYNEC. 97: 208, 1967. 4. Hendricks, C. H., and Gabel, R. A.: AMER. J. OBSTET. GYNEC. 79: 780, 1960. 5. Hofbauer, J., and Hoerner, J.: Abren. J. OBSTET. GYNEC. 14: 137, 1927.
of the role of intranasal oxytocin in producing the relatively few depressed infants in these inductions and augmentations done for a wide spectrum of indications. At least it is gratifying that in the induction group there was no fetal death after the induction was begun. Of the 7 infants who died in the augmentation group, 3 (the 2 anencephalic deaths and the erythroblastosis death) were probably inevitable by the time labor began, For the remaining 4 cases, in none of which excessively large doses of intranasal oxytocin was used, it would probably be unfair to incriminate oxytotin as a major contributing factor. These 4 tragic cases represent a spectrum of unexpected fetal losses : death from hyaline membrane disease where labor was induced after premature rupture of the membranes, death from what was believed to be placental dysfunction, one death from a true knot in the cord, and another from occult prolapse of the cord. One might raise the question as to whether these infants died as the result of labor rather than from the use of oxytocin per se. While all labors were monitored in this series, it still was not possible in these cases to identify the point in labor when the infant was getting into trouble and where immediate cesarean section was indicated. Some added comment about drugs and dosage is in order. Part of the patients received Pituitrin rather than oxytocin. It was surprising to learn that this preparation of whole pituitary extract is still being employed in modern obstetric hospitals. The ready availability of precisely standardized totally synthetic preparations
794
July 15, 1971 Amer. J. Ohstet. Gynnc.
Hoover
of oxytocin (sold commercially as Syntocinon and Pitocin) makes obsolete any indication for the use of Pituitrin. The drops were administered by a trained nurse. No mention is made as to whether hospital rules rcquirc the presence of a physician on the labor floor when oxytocin is being used. At best, the intranasal route is a somewhat inefficient way of administering oxytocin. It may be, however, perfectly sufficient when only a small stimulus is needed to induce or to augment labor. In many ways, the first one or two doses of intranasally applied oxytocin drops serve not only as a therapeutic but also as a diagnostic and prognostic test. The physician learns quite promptly whether or not an adequate enhancement of uterine contractility can be obtained by this simple means. If the response is insufficient, he naturally tends to consider other things, including the delivery of oxytocin by the intramuscular or the intravenous route as was done in the series reported here. From my own experience with this method of administration of oxytocin, I concluded that if a few applications of intranasal oxytocin failed to elicit adequate labor, it was preferable to change to the intravenous infusion route. The author’s report that 5 per cent of the augmented patients and 40 per cent of the induced patients received more than 12 doses intranasally is a tribute to the persistence of the obstetricians in using this method, but perhaps most of these patients would have benefited from an earlier initiation of intravenous oxytocin infusion. DR. GEORGE L. PITTMAN, Burlington, North Carolina (by invitation). Intranasal oxytocin has long been used for induction and enhancement of labor in the Atlanta area, and two studies have been published from Atlanta. The first was in 1945 by Bartholomew1 and the second one was by Clement, Harwell, and McCain2 in 1962. The only other area which has been as productive was Case Western Reserve University where Dr. Hendricks?? 4 published two studies in 1960. The present study by Dr. Hoover is the largest series of cases which has been reported and serves to further the concept that intranasal oxytocin represents probably the safest method of administration for this potentially powerful drug. There were some patients of
rather high parity in the present study, but there were no maternal deaths. The safety of oxytocin is, of course, related directly to the dosage in any given method of administration. Only a small amount of the oxytocin placed intranasally is absorbed, and this amount could vary a great deal depending on local factors. It has been estimated that the same dose given intravenously would be one hundred times more potent.3 An indication of the safety of intranasal oxytocin is that there has been only one case report of a ruptured uterus.5 Jt would seem to be a matter of terminology as to whether, in the present report, the cervical laceration which extended into the broad ligament should be considered a tear of the lower uterine segment. It is unlikely that the safety record of intranasal oxytocin could be matched by any other route of administration in so large a number of cases. There were 45 failures of elective induction with the first course of intranasal oxytocin. This figure is difficult to evaluate, however, because the success or failure of induction depends on many factors and these other factors were not included as a part of the present study. One of the most attractive aspects of Dr. Hoover’s study was that stimulation of labor required only 1 to 4 doses of intranasal oxytocin in 60 per cent of the 1,357 patients. The small amount of medication required here indicates that, in common usage, excessively large doses are frequently employed. Overdosage will in turn lead to increased complications. It is a fact of life that much oxytocin stimulation is carried out in this country without the attending obstetrician being present at the bedside. It is the responsibility of the obstetrician to be present whenever possible, and, if he is not present, the safety factor must outweigh all other considerations. The data presented in this study again indicate the large margin of safety with this method of administration. REFERENCES
1. Bartholomew, R. A.: J. Med. Ass. Georgia 34: 110, 1945. 2. Clement, J. E., Harwell, V. D., and McCain, J. R.: AMER. J. OBSTET. GYNEC. 83: 778, 1962. 3. Hendricks, C. H., and Gabel, R. A.: AMER. J. OBSTET. GYNEC. 79: 780, 1960. 4. Hendricks, C. H.: AMER. J. OBSTET. GYNEC. 79: 789, 1960. 5. Stitchbury, P. C.: New Zealand Med. J. 61: 160, 1962.