Placental passage of the oxytocin antagonist atosiban

Placental passage of the oxytocin antagonist atosiban Guillermo J. Valenzuela, Mary L. Holland, PhD San Bernardino,

OBJECTIVE: antagonist,

MD>

b Jan Craig,”

Mark

D. Bernhardt,

MD,” and

California

We wanted to determine the degree of placental transfer in pregnant women at term. We also assessed the effects

of atosiban (Antocin), an oxytocin of the infusion on umbilical cord

blood gases at birth and the maternal hematocrit drop after cesarean section. STUDY DESIGN: Eight women undergoing elective cesarean section at term were studied. Each received an infusion of 300 kg/min of atosiban over 208 to 443 minutes; the infusion was continued up to the time of cord clamping. Uterine vein and umbilical blood samples were obtained simultaneously. They were assayed by specific radioimmunoassay. Cord blood gases were obtained and compared with those from a control group of women undergoing elective cesarean section. RESULTS: The mean (i SD) maternal uterine vein concentration was 331.9 + 42.9 rig/ml, compared with 42 c 13 rig/ml in the umbilical vein @I < 0.05). The mean maternal/fetal ratio was 12 i 0.03, which was not affected by the length of infusion. There was no significant difference in the hematocrit drop between the cesarean delivery groups: 5.9 f 0.4 for the control group versus 5.8 i- 1 .l for the atosiban group @ > 0.1). The mean cord pH was 7.27 for the atosiban group versus 7.27 for the control group (II = 141) (p > 0.1). One year follow-up of the infants (n = 7) was normal. CONCLUSIONS: Our results show minimal placental transfer of atosiban. Drug levels did not increase with longer infusions, and no effect was seen on umbilical cord gases, Administration of atosiban even at high doses up to the time of delivery did not increase maternal blood loss at cesarean section. (AM J OBSTET GYNECOL 1995;172:1304-6.)

Key words:

Premature

labor, oxytocin

antagonist,

postpartum

Preliminary studies on the use of the oxytocin antagonist atosiban (Antocin, PRI, Raritan, N.J.) to treat premature labor have been encouraging.lm3 The compound appears to effectively abolish uterine contractions with minimal maternal side effects. Currently used tocolytics such as ritodrine are known to cross the placenta, and fetal levels have been reported to reach 20% to 1OO%4 of maternal levels. Its use is associated with a number of maternal and fetal side effects and complications.’ The purpose of the current study was to simultaneously determine plasma levels of atosiban in the maternal and newborn circulations at term and to assess the effect of the infusion on arterial umbilical blood gases. Material

and methods

This study was conducted in eight pregnant undergoing elective cesarean section at term.

women Patients

From the Deflartment of Obstetrics and Gynecology, San Bernardino County Medical Center,” the Center of Perinatal Biology, Loma Linda University,b and the R. W. Johnson Pharmaceutical Research Institute.” Funded by the San Bernardino County Medical Research Foundation. Received for publication January 6, 1994; revised June 13, 1994; accepted September 17, 1994. Reprint requests: Guillermo J. Valenzuela, MD, San Bernardino County Medical Center, Department of Obstetrics and Gynecology, 780 E. Gilbert St., San Bernardino, CA 92415.0935. Copyright 0 1995 by Mosby-Year Book, Inc. 0002-9378/95 $3.00 + 0 6/l/60684

hemorrhage

in the oxytocin atosiban [ 1-deamino-2-D-n-y (OEt)-4thr-8-orn-vasotocinioxytocin] group were those who had received an infusion of the agent for 208 to 443 minutes before delivery. The protocol was approved by the Human Research Committee at the San Bernardino County Medical Center. Atosiban was infused at a rate of 300 u,g/min, and the infusion was continued until the umbilical cord was clamped. Arterial umbilical blood gases were collected at delivery. At surgery blood samples were obtained from the uterine vein and fetal umbilical vessels, as described in detail previously.6 Samples were collected in precooled syringes and centrifuged immediately at 4” C. Plasma was stored at -70" C until assayed. Data were collected regarding the decrease in maternal hematocrit after cesarean section and compared with data from a group of matched controls undergoing elective cesarean section (n = 60).

Atosihan assay. The assay consisted of solid-phase cartridge extraction of atosiban from plasma followed by radioimmunoassay (RIA). The Ferring rabbit antibody used in this study did not cross-react with endogenous peptide hormones such as oxytocin or vasopressin (cross-reactivity < 0.00001) but did show affinity for atosiban metabolites. The solid-phase extraction procedure separated atosiban from cross-reactive metabolites, allowing reliable quantitation of parent drug in the RIA. Atosiban was shown to be stable in plasma

Volume 172, Number

4, Part 1

Valenzuela et al.

Am J Obstet Gynecol

1305

0.25 1

150

1

I

I

250

350

450

Time (min) Fig. 1. Ratio between fetal and maternal concentration of atosiban are expressed against duration of maternal infusion. Fetal sample was taken at delivery, after cord clamp but before delivery of placenta.

from pregnant and nonpregnant females during the conditions of the assay procedure and through at least four freeze-thaw cycles. Extraction. From 100 to 500 ~1 plasma was applied to conditioned solid-phase extraction cartridges (Baker bond SPE cartridge diol, Baker, Chicago). They were rinsed with water and methanol. The atosiban fraction was eluted with 4% trifluoroacetic acid in methanol and dried with a nitrogen stream. The sample was then reconstituted with bovine serum albumin and phosphate-buffered saline solution buffer solution for RIA. Recovery through the cartridge extraction procedure was monitored with tritiated atosiban and found to be > 98%. RZA. On the first day of the RIA the extracted samples were diluted appropriately, and a 100 JLI aliquot was added to a test tube. Iodine 125-labeled atosiban was then added to the tube, followed by the first antibody (Ferring rabbit Ab9 11004). The tube was covered, vortex mixed, and incubated for 1 hour. After this period the second antibody (Bio-Rad Immunobead Reagent, Bio-Rad, Palo Alto, Calif.) was added, and the tube was covered, vortex mixed, and incubated overnight at room temperature. On the second day the tube was vortex mixed and centrifuged for 15 to 30 minutes (3000 revolutions/min). The supernatant was aspirated and the pellet washed with buffer solution (bovine serum albumin and phosphate-buffered saline solution). The supernatant was again aspirated and the pellet counted in a y counter. Logit transformation was used to linearize the data. The quantitation range of the RIA was 0.05 to 5.0 rig/ml, with interassay and intraassay coefficients of variation of I 7%. The accuracy of the assay, on the basis of the analysis of extracted quality control samples, was within f 13%. Dilutional linearity was evaluated with spiked controls

and actual subject samples and was found to be excellent. Data analysis. The ratio between the maternal uterine vein and fetal umbilical vein concentrations was calculated for each patient. Average t SD concentrations for mother and fetus were compared by paired t test. Mean 2 SD values for blood gases obtained in these infants were compared with those from a control group of elective cesarean sections (n = 141).

Results The mean 2 SD concentration for atosiban in maternal serum was 331.9 -I- 42.9 rig/ml, whereas the concentrations in umbilical vein were 42 t 13 ngiml. The average ratio (i-SD) for the fetal versus maternal compartment was 0.124 ? 0.025. There was not a significant change in the slope of the line relating maternal and fetal concentrations over time (Fig. l), suggesting that the drug does not accumulate in the fetus. The individual plasma values are presented in Table I. There was no significant difference between the drop in hematocrit after cesarean section in various cesarean delivery groups: 5.9 t 0.4 for controls and 5.8 + 1.1 for the oxytocin antagonist @ > 0.1). The umbilical arterial gases for the atosiban and control groups are presented in Table II; they were not significantly different.

Comment Preliminary reportslm3 suggest that atosiban has the same effectiveness as ritodrine7 but with a much lower incidence of maternal side effects. Our finding of a relatively low placental transfer of atosiban without apparent accumulation m the fetal circulation is encouraging. The half-life of atosiban is 17 minutes, whereas that of ritodrine is 150 minutes. Fetal ritodrine

1306

Valenzuela

Table

I. Paired

maternal-fetal

atosiban

plasma levels Uterine

340 279 281 416

36 29 24 52

ii 7 8

290 327 380 443

353 359 292 347

51 58 31 50

were

obtained

at cesarean

umbilical

Atosiban Control

blood

section:

7.27 7.27

sample

receiving

calcium

18.7 15.9 treated

channel

2 5.76 c 6.2 and

59.4 59.5

control

groups

blockers,‘,

’ another

compound that has been used as a tocolytic.” There were no observable antidiuretic effects in the newborns and all fed appropriately. In seven of eight newborns we have follow-up to 1 year of age; general physical examinations, developmental testing (Bayley), and neurologic examinations were all normal at that time. One concern with any uterine relaxant is the possibility of uterine atony with subsequent postpartum hemorrhage. It is possible that an oxytocin antagonist interfere

with

the

normal

postdelivery

process

of

uterine contraction. Another concern was the phenomenon observed in a study in the pregnant sheep in which a larger decrease in arterial pressure in response to hemorrhage was seen in those animals also receiving atosiban.” We found no such increase in postpartum hemorrhage, although one of the patients had postpartum hemorrbage that responded well to methylergonovine maleate (Methergine, Sandoz, East Hanover, N.J.) 15-methyl-prostaglandin

Kalamazoo, more

frequently

ever,

the

rate

F,, in control

of hematocrit

was similar to that in atosiban was administered of delivery.

(Hemabate,

Upjohn,

Mich.). We used methylergonovine than

drop

uterine

vein

Pco,

PO2

between

from

and newborn

from

umbilical

vein.

gases

F 0.04 k 0.06

was no difference

maternal

concentrations have been reported as 20% to 100% of the maternal level; these authors also found an accumulation of ritodrine in the fetus with time.4 Both these factors suggest that ritodrine has more chances to affect the fetus or newborn infant. Arterial umbilical cord blood gases were the same as for a group of similar patients undergoing elective cesarean section. This compares favorably with the finding of fetal acidemia in rhesus monkeys and sheep

and

vein (@ml)

200 225 226 275

PH

might

Umbilical

1 2 3 4

II. Arterial

fetuses

(nglml)

Time (min)

levels

There

vein

No.

Plasma

Table

April 1995 Am J Obstet Gynecol

etal.

cesarean within

maleate

sections; the

the control group, in high doses up

study

howgroup

although to the time

Base excess -1.15 -0.07

-+ 8.2 AI 10.6

t f

Apgar

2.03 2.96

score

No.

8.9 zt 0.5 8.7 k 1.1

8 141

(p > 0.1).

In

conclusion,

this

to atosiban

posed experienced increase

no in maternal

study

for

deleterious blood

showed

several

effects, loss

that

hours

newborns

before and

there

ex-

delivery was

no

at delivery.

REFERENCES 1. Goodwin TM, Paul R, Valenzuela GJ, et al. A description of the course of preterm labor during a standard infusion of the oxytocin antagonist atosiban. AM J OBSTET GYNECOL 1994;170:474-8. 2. Aukerlund M, Stromberg P, Hauksson A, et al. Inhibition of uterine contractions in premature labor with oxytocin analogue. Results form a pilot study. Br J Obstet Gynaecol 1987;94: 1040-4. 3. Andersen LF, Lyndrup J, Aukerlund M, et al. Oxytocin receptor blockade: a new principle in the treatment of preterm labor? Am J Perinatol 1989;6:196-9. 4. Gross TL, Kuhnert BR, Rosen MG, Kazzi NJ. Maternal and fetal plasma concentrations of ritodrine. Obstet Gynecol 1985;65:793-7. 5. Briggs GG, Freeman RK, Jaffe SJ. Drugs in pregnancy and lactation. 3rd ed. Baltimore: Williams & Wilkins, 1990: 566-7 1. 6. Valenzuela GJ, Harper MJK, Hayashi R. Uterine venous, peripheral venous, and radial arterial levels of prostaglandins E and F in women with pregnancy-induced hypertension AM J OBSTET GYNECOL 1983;145:11-4. 7. Canadian Preterm Investigator Group. The treatment of preterm labor with beta-adrenergic agonist ritodrine. N Engl J Med 1992;327:308-12. 8. Ducsay CA, Thompson JS, Wu AT, Navy MJ. Effects of a calcium channel blocker (nicarpidine) tocolysis in rhesus macaques: fetal plasma concentrations and cardiorespiratory changes. AM J OBSTET GYNECOL 1987;157:1482-6. 9. Harake B, Gilbert RD, Ashwal S, Power G. Nifedipine: effects on fetal and maternal hemodynamics in pregnant sheep. AM J OBSTET GYNECOL 1987;157:1003-8. 10. Ducsay CA. Calcium channels: role in myometrial contractility and pharmacological applications of calcium entry blockers. In: Carlsten ME, Miller JD, eds. Uterine function. New York: Plenum, 1990: 169-94. 11. Greig PC, Massman AG, Demarest KT, et al. Maternal and fetal cardiovascular effects and placental transfer of the oxytocin antagonist atosiban in late-gestation pregnant sheep. AM J OBSTET GWECOL 1993;163:897-902.