- Email: [email protected]
Ripening of the human cervix with porcine ovarian relaxin
Hill et al. Am.
tiona! age, for IUGR and thereby delineate a group who are at risk for perinatal morbidity and mortality. REFERENCES I. McBurney, R. D.: The undernourished full-term infant: A case report, West. ]. Surg. Obstet. Gynecol. 55:363, 1947. 2. Lugo, G., and Cassady, G.: Intrauterine growth retardation: Clinicopathologic findings in 233 consecutive infants, AM.]. Ossn:T. GYNECOL 109:615, 197l. 3. Mann, L. I., Tejani, N. A .. and Weiss, R. R.: Antenatal diagnosis and management of the small-for-gestational age fetus, AM.]. 0BSTET. GYNECOL. 120:995, 1974. 4. Manning, F. A., Hill, L. M., and Platt, L. D.: Qualitative amniotic fluid volume determination by ultrasound: Antepartum detection of intrauterine growth retardation. AM. J. 0BSTET. GYNECOL. 139:254. 1981. 5. Fitzhardinge, P. M., and Steven, E. M.: The small-for-
6.
7. 8.
9.
10.
ll.
Oct()ber 15, 1983 Gynecol.
J. Obstet.
date infant. II. Neurological and intellectual sequelae, Pediatrics 50:50, 1972. Whetham. J. C. G., Muggah, H., and Davidson, S.: Assessment of intrauterine growth retardation by diagnostic ultrasound, AM. J. OBSTF,T. GYNECOL. 125:577, 1976. Campbell, S.: Physical methods of assessing size at birth, Ciba Found. Symp. 27:275, 1974. Tanner,]. M., and Thomson, A.M.: Standards for birth weight at gestation periods from 32 to 42 weeks, allowing for maternal height and weight. Arch. Dis. Child. 45:566, 1970. Dubowitz, L. M.S., Dubowitz, V., and Goldberg, C.: Chnical assessment of gestational age in the newborn infant, J. Pediatr. 77:1. 1970. Wladimiroff, .J. W., and Campbell, S.: Fetal urine-production rates in normal and complicated pregnancy, Lancet 1:151, 1974. Cohn. H. E.. Piasecki, G.J., and jackson, B. T.: The effect of fetal heart rate on cardiovascular function during hypoxemia. AM. J. OBSTET. GYNECOL 138:1190, 1980.
Ripening of the human cervix with porcine ovarian relaxin Mark I. Evans, M.D., Malia~Beth Dougan,* Atef H. Moawad, M.D., Wendy J. Evans, M.P.H., Gillian D. Bryant-Greenwood, Ph.D., and Frederick C. Greenwood, Ph.D. Chicago, Illinois, and Honolulu, Hawaii Recent experience has suggested that porcine ovarian relaxin may promote cervical changes. We have performed two double-blind randomized studies: (1) comparing cervical changes with relaxin versus placebo during oxytocic labor induction and (2) as outpatients in postdates pregnancies. In the induction study, cervical changes were speeded up by both 2 and 4 mg doses of relaxin, and times to delivery were decreased. In the outpatient study, 2 mg doses of relaxin produced greater cervical changes than did control or 4 mg doses. We conclude that relaxin may have benefit in ripening of the cervix. Since relaxin works directly on the cervix and not through uterine contractions, relaxin may have advantages in cervical ripening of pregnancies in which stress to the fetus is an issue. (AM. J. Oasrer. GYNECOL. 147:410, 1983.)
The unripe cervix in the patient who needs to be delivered has remained an obstetric enigma for decades. Such patients are at very high risk for obstetric complications (fetal compromise or cesarean section) regardless of the underlying cause of the necessity for From the Department of Obstetrics and Gynecology and the Perinatal Center, The University of Chicago Pritzker School of Medicine, The Chicago Lying In Hospital, and the Pacific Biomedical Research Center and the Department of Anatomy and Reproductive Biology, Univenity of Hawaii. The supply of pregnant porcine ovaries and the isolation of purified relaxin were part of a separate studyfunded by The Leahi Foundation of Honolulu, Hawaii. Received for publication january 13, 1983. Revised April6, 1983. Accepted june 1, 1983. Reprint requests: Mark I. Evans, M.D., National Institutes of Health, Building 10, Room 8C429, Bethesda, Maryland 20205. *M.B.S. undergraduate research student supported by Grant No. RR08125-09. 410
immediate delivery (be it postdatism, preeclampsia, ruptured membranes, or medical complications of pregnancy, etc.). The inability to deliver certain pa· tients in a reasonable time period without undue stress to a possibly compromised fetus has undoubtedly contributed to the dramatically increasing cesarean section rate in the United States and abroad. 1 At present, chang·es in the quality. consistency, effacement, and dilatation of the cervix are accomplished by spontaneous labor or labor induced through the use of intravenous oxytocin, prostaglandins applied in several fashions, laminaria, or estradiol. HI In most cases pari of the action reflects mechanical force of the presenting part against the cervix. Effacement can occur independently of uterine action as documented by Stys and associates, 6 but most of the evidence concerning the above agents suggests that their action is intimately involved with uterine contractions.
Volume 147 Number 4
The existence of relaxin has been known for more than 50 years, and in the mid-1950s, crude extracts were used as a potential tocolytic agent in several studies.7· 8 These crude extracts were found to be clinically ineffective, and interest in relaxin waned over a 20year period. The availability of a method for obtaining purified relaxin permitted a reevaluation of the effects of relaxin upon the human cervix in late pregnancy. 9 Two clinical studies were performed by MacLennan and associates in Australia. 10 • 11 In these double-blind studies the effect of relaxin applied in a tylose gel to the cervix at one dose level and also in combination with other hormones prior to induction was noted with encouraging results. The purpose of the present doubleblind studies was to examine the effect of porcine ovarian relaxin applied against the cervix in 2 or 4 mg doses during induction of labor. In addition, we have attempted to evaluate changes in cervical effacement in patients who received a topical application of relaxin 5 to 7 days before anticipated induction for patients with postdated pregnancies.
Material and methods Relaxin was obtained from pregnant sow ovaries and purified by the method of Sherwood and O'Byrne9 with minor modifications as described by Kwok and associates. 12 Four batches were prepared and compared radioimmunologically with standard CM-a relaxin in our laboratory. Batches were within 3% of the standard. The purified relaxin used was equivalent to the CM-a, CM-a 1, and CM-b peaks described by Sherwood and O'Byrne 9 and shown by various authors to be equivalent in bioassays or immunoassays. Suppository placebo pellets were made from an 80% Carbowax 400, 20% Carbowax 6000 (Union Carbide polyethylene glycol) compound melted and formed in sterile molds. To make the relaxin pellets, the Carbowax pellets were then individually melted, the appropriate amount of relaxin was added, and the pellets were remolded. Microbiologic cultures of samples from each batch of pellets were all negative. The assignment of pellets to patients was by consecutive entry into either of the studies (explaining differing numbers of control subjects versus relaxin patients) with a code that remained unknown to the authors until after the study was completed and all patient data were computed. Induction study. Subjects for the induction study were drawan from the population undergoing oxytocin induction of labor who had achieved at least 35 weeks' gestation. Subjects were at least 18 years old, and informed consent was obtained. For patients consenting to the study, pellets were inserted into the cervical canal at the time of initiation of oxytocin induction. When lack of cervical dilatation prevented the insertion of a pellet into the cervical canal, the pellet was placed
Ripening of cervix with porcine relaxin
411
closely against the cervix. In all patients a cervical diaphragm (Ortho Pharmaceutical Corp., Raritan, New Jersey) was placed behind the pellet to maintain the position of the pellets which melted in approximately 30 minutes. Management of the patients was conducted according to usual standards (e.g., cervical examinations and rupture of membranes) as clinically indicated without regard to the research. Intravenous oxytocin induction was performed to achieve a contraction pattern of approximately every 3 minutes with contractions of 40 to 50 mm Hg. Whenever appropriate scalp clips and internal pressure cathethers were used to monitor fetal and uterine status. Outpatient study. Patients who had reached 41 weeks' gestation by the best clinical information available were eligible for the outpatient study. A pellet was inserted against the cervix with a retaining diaphragm as described previously, and the patient was allowed to go home. The standard management protocol of estriols three times per week and nonstress tests once or twice per week was followed. If the patient reached 42 weeks' gestation, she was admitted for postdates induction. No patient received relaxin twice. In evaluating the effects of the drug on the cervix, two questions were asked: (1) Do the cervical changes prior to active labor differ significantly in the relaxintreated groups? (2) Is cervical progression to complete dilation significantly affected? In order to measure these effects, we decided to use the cervical coefficient (dilatation x% effacement) as described by Hendricks and associates 13 rather than the Bishop 14 score, because the latter score considers factors other than, and in addition to, the cervical changes. The rate of change in the cervical coefficient was calculated as follows: (1) Changes per hour from the insertion of the pellet to the beginning of the active phase of labor (defined as 3.5 em of dilatation and 90% effacement) were designated as the "effacement rate"; (2) changes per hour from the insertion of the pellet to the end of the first stage of labor (cervical coefficient= 1,000) were designated at the "rate of total cervical change"; (3) in the outpatient study (when the pellets were inserted 5 to 7 days before the anticipated onset of labor or induction) the rate of change in the cervical coefficient was calculated per day (rather than per hour) and was designated as the "outpatient effacement rate." Minimal dilatation was defined as 0.5 em and minimal effacement as 10%. A maximal initial coefficient of 350 (3.5 em x 100%) was allowed if the patient was admitted in labor with a cervical coefficient >350. Cervical examinations were performed as clinically indicated usually by the same examiner. It was felt that the Hendricks coefficient would be less subject to interexaminer variability than the Bishop score.
412 Evans et al. Am.
October 15, 1983 Gynecol.
J. Obstet.
Table I. Induction study: Cervical changes Control subjects
Relaxin, 2 mg
Relaxin, 4 mg
Total N Effacement rate*
46 18.7 :': 14.1
23 50.0t :': 41.8
26 42.9t :': 33.0
Total cervical change ratet
47.1 :!: 35.0
95.3t :!: 73.9
61.7t :!: 38.4
Time
delivery (primiparas)§
29.1 :': 10.8
16.3t ::':: 12.4
22.6
Initial cervical coefficient (primiparas) n (primiparas) Time to delivery (multiparas)§
59.5 :': 41.4 24 31.7 ::':: 26.6
62.3 ± 36.4
36.0 :': 40.7
11
II
Initial cervical coefficient (multiparas) n (multiparas)* Cesarean sections
56.3 ± 28.4 22 9/46 (19.6%)
to
10.3t
7.8
61.0 :': 32.1
12 J/23 (4.3%)
17.3
:t
:t
Difference
x' = 26.8 p < 0.001 x'"' 10.1 p < 0.01 x' = 15.5 p < 0.01
17.1
x'= NS
x' 6.4 p < 0.05 xz = 6.4
8.1
42.9 ± 24.0 1.5 4/26 (15.4%)
x'= NS
*Change per hour in cervical coefficient from insertion to at least 3.5 cm/90%. tStatistically significant difference at p < 0.05 from control subjects by x'. tChange per hour in cervical coefficient from insertion to complete dilatation. §Includes only patients who were delivered vaginally.
Table II. Induction study: Fetal and maternal data Control :;ubjed'
Total N Birth weight (gm) 5 min Apgar score Gestational age (wk) Pari tv Mate'rnal age (yr)
46
3,033 ± 444 8.5:!: 1.0 40.0 ± 2.2 I.:~ ± 2.0 22.6 4.8
All statistical manipulations were performed before the code was broken. Data for effacement rate, total cervical change rate, outpatient effacement rate, time to delivery, initial cervical coefficients, number of patients admitted in labor, and parities were analyzed by the extension of the median test (x 2 ). When a statistically significant (p < 0.05) extension of the median test was found among the three groups (control subjects, 2 mg of relaxin patients, and 4 mg of relaxin patients), pairwise comparisons between groups were performed by the median test (x 2 ). Data for birth weight, Apgar scores, gestational age, and maternal age were analyzed by one-way analyses of variance.
Results
Induction study. Ninety-five patients were entered into the induction study, including 46 control subjects who received placebo, 23 who received 2 mg relaxin pellets, and 26 who received 4 mg relaxin pellets. Patients who received either the 2 or 4 mg relaxin pellets had cervical effacement rates very highly significantly greater than control subjects. There was no significant difference between the 2 mg and 4 mg pellets (Table l). Total cervical change rates were similarly increased by
Relaxin, 2 mg
23 2,981 :': 8.8:!: 38.9 = 0.8 :!: 23.2
521 0.8 2.8 1.0 4.3
Relaxin, 4mg
26 2,923 :!: 667 8.7 :': 0.7 39.0 ± 3.9 1.2 ± 1.6
24.2:!: .5.7
DiffeTence F = NS F = NS F = NS NS F NS
X~
relaxin. Time to delivery was reduced from an average of 29.1 hours for control patients to 16.3 hours for the 2 mg patients (p < 0.05) and 22.6 hours for the 4 mg patients. There were no statistical differences in initial cervical coefficients, although the 4 mg patients had the least favorable cervices at relaxin insertion. For multiparous pi!tients time to delivery was 31.7 hours for control subject~. 10.3 hours for 2 mg patients, and 17.3 hours for 4 mg patients. Again, although not statistically significant, the 4 mg patients had the least favorable cervices at the beginning of the induction. Nine of 46 control patients ( 19.6%) needed cesarean section, whereas only one of 23 (4.3%) 2 mg patients and four of 26 (15.4%) 4 mg patients required cesarean section. These differences were not statistically significant. Birth weights, Apgar scores, parity, and maternal ages were equivalent (Table II). There were no differences in the incidence of maternal complications (i.e., endometritis) among the groups, and there were no significant fetal complications. Outpatient study. In the outpatient study there were 14 control subjects, 13 patients received 2 mg pellets, and l 0 patients received 4 mg pellets. The outpatient effacement rate for control subjects was 21.1. For 2 mg
Ripening of cervix with porcine relaxin
Volume 147
413
Number 4
Table III. Clinic study: Cervical data
n Outpatient effacement rate* Days to admission No. admitted in labor Time to delivery (hr) Initial cervical coefficient
Control subjects
Relaxin, 2 mg
Relaxin, 4 mg
14 21.1 ± 31.7
13 53.3t ± 46.2
10 23.6:j: ± 12.2
x'
4.6 ± 1.6 3 /10 11.3 ± 7.2 38.0 ± 44.5
p < 0.001 x' = NS x' = NS x' = NS x' = NS
5.3 ± 2.1 6/14 14.8 ± 12.2 70.0 ± 62.6
5.3 ± 2.2 7/13 7.7 ± 5.0 49.6 ± 44.4
Difference =
26.8
*Change in cervical coefficient from insertion to admission divided by number of days. tStatistically significant at p < 0.05 from control subjects (X'). :j:Statistically significant at p < 0.05 from relaxin, 2 mg tx').
Table IV. Clinic study: Fetal and maternal data Control subjects
Birth weight (gm) 5 min Apgar score
Gestational age at insertion (wk) Pari tv Mate'rnal age (yr)
3,245 9.0 41.1 l.J 21.3
± 479 ± 0.4 ± 0.2
± 0.9 ± 4.4
patients it was 53.3 and for 4 mg patients it was 23.6. The effect of the 2 mg pellets was very highly significantly greater than both placebo and 4 mg pellets. Mean times to admission of the patient were comparable for the three groups as well as the proportion admitted in labor. The time to delivery for the 2 mg patients was approximately half that of control subjects, although the number of patients was small, and the results were not significant statistically (Table III). Data for initial cervical coefficients, birth weight, Apgar scores, gestational age, parity, and maternal age were comparable among all the groups (Table IV). There were no significant differences in complications among the groups.
Comment With the advent of sophisticated means of monitoring fetal status, powerful antibiotics, intensive care nurseries, and a shift in philosophy from a maternal safety priority to that of a fetal well-being priority, obstetric management has changed markedly over the past several years. Frequently cesarean section is performed for primarily fetal indications when vaginal delivery cannot be accomplished relatively quickly. Patients who require delivery but have unripe cervices are at particularly high risk for cesarean section. At the University of Chicago Chicago Lying In Hospital, the primary cesarean section rate for all patients is approximately 6% (low by national standards). However, for patients requiring induction, the primary cesarean section rate is approximately 20%, thus attesting to the high-risk status of such patients. A pharma-
Relaxin, 2 mg 3,256 9.0 41.2 1.2 23.3
± 613
± 0.4 ± 0.3
± 1.1 ± 5.4
Relaxin, 4 mg 3,113 8.6 41.0 1.0 26.0
± 447 ± 1.2 ± 0.2
± 1.2 ± 5.7
Difference F = NS F = NS F = NS
x'
F
= =
NS NS
cologie agent capable of accelerating vaginal delivery without subjecting the baby to undue stress from strong labor could potentially reduce the overall cesarean section rate. Oxytocin and prostaglandin affect the cervix via uterine contractions and secondary mechanical force of the presenting part upon the cervix. Relaxin appears to exert a direct effect upon cervical tissue and thus may have the advantage of achieving cervical change without stress upon the fetus. There was no evidence of increased uterine activity following relaxin administration. In fact, Sarosi and Weiss 1•5 have shown in vitro that relaxin potentiated progesteronemediated uterine muscle diminution of electrostimulated contractions. For the induction study, patients receiving 2 mg relaxin pellets had significantly greater cervical effacement rates, total cervical change rates, and decreased time to delivery. Initial cervical coefficients for both primiparous and multiparous women were comparable; control data for fetal well-being were also comparable, and the decrease in cesarean section rate from 19.6% to 4.3% if analyzed separately would have approached significance (p < 0.1 0). Four milligram pellets also demonstrated significantly increased effacement rates and total cervical change rates over placebo. The decrease in time to delivery for primiparous women from 29.1 to 22 hours and for multiparous women from 31.7 to I 7.3 hours was not statistically significant; however, for primiparous patients the initial coefficient of the 4 mg patients were 36.0 as compared to 59.5 for control subjects, and 42.9 versus 56.3 for multiparous patients. Although these differences
414 Evans et al. Am.
were not significant, the 4 mg patients may have been at a serious disadvantage as compared to the other group. In the outpatient study the use of 2 mg relaxin pellets resulted in an increased outpatient effacement rate to 59.3 from 21.1 per day for control subjects. For reasons that are not understood the effect of 4 mg pellets was negligible; again, although not statistically significant, it must be noted that the initial cervical scores of 4 mg patients were the worst of the three groups. lt should also be noted that the number of patients in this part of the study was small (n = :~6).'" In the induction study and for the 2 mg pellets in the clinic study, relaxin appears to have accelerated effacement and dilatation of the cervix and decreased the amount of time needed to deliver patients. From this study and those of MacLennan and associates 10 • 11 it appears that porcine ovarian relaxin applied to the cervix may be of use in accelerating changes in the cervix and perhaps decreasing the time of labor and the number of patients who require cesarean section. Further studies will be necessary to confirm these results and refine dosage and administration protocols. and to clarify whether the differences between 2 mg and 4 mg doses are related to small numbers, a downregulation effect of "overdosing." or a disadvantageous starting point for the 4 mg patients. We acknowledge the help of Ms. Sandra Yamamoto, Marily Ueno, and Dr. Austin Leach for the preparation of relaxin, Mark Miller, Pat Bagnara, Julie Esclamado, and Morris Bartot for preparation of the pellets, Drs. Eric Poon, Gary Loy, and Michael Zinaman for help in patient management, and Mrs. Debbie Kirk and Ms. Regina Stewart for preparation of the manuscript. REFERENCES 1. Cesarean Childbirth: United States Department of Health and Human Services. Public Health Service, National In-
2. 3. 4. :'>.
6. 7. 8. 9. 10. II.
12.
13. 14. 15.
October 15. 19H:l Obstet. Gvneu>l.
J.
stitutes of Health, NIH Publication No. 82-2067, Washington, D. C., 1982, Government Printing Office. Weiss, R. R., Tejani, N., Isreali. 1., Evans, M. !., et al.: Priming of the uterine cervix with oral prostaglandin E 2 in the term multigravida. Obstet. Gynecol. 46:181, 197S. MacLennan, A. H., and Green, R. S.: Cervical ripening and induction of labor with intravaginal prostaglandin E 2 , Lancet 1:117, 1979. Tohan. N .. Tejani, N. A., Varanasi, M., et al.: Ripening of the term cervix with Laminaria, Obstet. Gynecol. 54:588, 1979. Ellwood, D. A.. ~1itchell, M.D .. Anderson, A. B. M .. et al.: Oestrogens. prostaglandins, and cervical ripening, Lancet 1:376, 1979. Stys, S. J., Clewell, W. H., and Meschia, G.: Changes in cervical compliance at parturition independent of uterine activity. AM. j. 0BSTET. GYNECOL. 130:414, !978. Brvant-Greenwood, G. D.: Relaxin as a new hormone, En'docr. Rev. 3:62, 1982. Stone. M. L., Sedlis, A., and Zuckerman, H.: Relaxin-a critical evaluation, AM. J. 0BSTET. GYNECOL. 76:544, 1958. Sherwood, C. D., and O'Bvrne, E. M.: Purification and characterization of porcine. relaxin, Arch. Biochem. Biophys. 160:185, 1974. MacLennan. A. H., Green, R. C., Bryant-Greenwood. G. D.. eta!.: Ripening of the human cervix and induction of labour with purified relaxin, Lancet 1:220, 1980. ~1acLennan. A. H .. Green. R. C .. Bn·ant-Greenwood, G. D.. et al.: Cervical ripening with combinations of vaginal prostaglandin E 2 • estradiol. and relaxin, Obstet. Gvnecol. 58:601 , 19R I. Kwok, S. C. M., Bryant-Greenwood, G. D., and Niall, H. D.: Evidence for proteolysis during purification of relaxin from pregnant sow ovaries. Endocr. Res. Commun. 7:1, 1980. Hendricks, C. H., Brenner, W. E., and Kraus, G.: Normal cervical dilatation pattern in late pregnancy and labor. AM. J. 0BSTET. GYNECOL. 106:1065, 1970. Bishop, E. H.: Pelvic scoring for elective induction, Obstet. Gynecol. 24:2{)6, 1964. Sarosi, P., and Weiss, G.: Progesterone-relaxin synergism in electro-stimulated isolated rat uterine horn segments, presented at the Twenty-ninth Annual Meeting of the Society for Gynecologic Investigation, Dallas, Texas, March 24-27. 1982.
tiona! age, for IUGR and thereby delineate a group who are at risk for perinatal morbidity and mortality. REFERENCES I. McBurney, R. D.: The undernourished full-term infant: A case report, West. ]. Surg. Obstet. Gynecol. 55:363, 1947. 2. Lugo, G., and Cassady, G.: Intrauterine growth retardation: Clinicopathologic findings in 233 consecutive infants, AM.]. Ossn:T. GYNECOL 109:615, 197l. 3. Mann, L. I., Tejani, N. A .. and Weiss, R. R.: Antenatal diagnosis and management of the small-for-gestational age fetus, AM.]. 0BSTET. GYNECOL. 120:995, 1974. 4. Manning, F. A., Hill, L. M., and Platt, L. D.: Qualitative amniotic fluid volume determination by ultrasound: Antepartum detection of intrauterine growth retardation. AM. J. 0BSTET. GYNECOL. 139:254. 1981. 5. Fitzhardinge, P. M., and Steven, E. M.: The small-for-
6.
7. 8.
9.
10.
ll.
Oct()ber 15, 1983 Gynecol.
J. Obstet.
date infant. II. Neurological and intellectual sequelae, Pediatrics 50:50, 1972. Whetham. J. C. G., Muggah, H., and Davidson, S.: Assessment of intrauterine growth retardation by diagnostic ultrasound, AM. J. OBSTF,T. GYNECOL. 125:577, 1976. Campbell, S.: Physical methods of assessing size at birth, Ciba Found. Symp. 27:275, 1974. Tanner,]. M., and Thomson, A.M.: Standards for birth weight at gestation periods from 32 to 42 weeks, allowing for maternal height and weight. Arch. Dis. Child. 45:566, 1970. Dubowitz, L. M.S., Dubowitz, V., and Goldberg, C.: Chnical assessment of gestational age in the newborn infant, J. Pediatr. 77:1. 1970. Wladimiroff, .J. W., and Campbell, S.: Fetal urine-production rates in normal and complicated pregnancy, Lancet 1:151, 1974. Cohn. H. E.. Piasecki, G.J., and jackson, B. T.: The effect of fetal heart rate on cardiovascular function during hypoxemia. AM. J. OBSTET. GYNECOL 138:1190, 1980.
Ripening of the human cervix with porcine ovarian relaxin Mark I. Evans, M.D., Malia~Beth Dougan,* Atef H. Moawad, M.D., Wendy J. Evans, M.P.H., Gillian D. Bryant-Greenwood, Ph.D., and Frederick C. Greenwood, Ph.D. Chicago, Illinois, and Honolulu, Hawaii Recent experience has suggested that porcine ovarian relaxin may promote cervical changes. We have performed two double-blind randomized studies: (1) comparing cervical changes with relaxin versus placebo during oxytocic labor induction and (2) as outpatients in postdates pregnancies. In the induction study, cervical changes were speeded up by both 2 and 4 mg doses of relaxin, and times to delivery were decreased. In the outpatient study, 2 mg doses of relaxin produced greater cervical changes than did control or 4 mg doses. We conclude that relaxin may have benefit in ripening of the cervix. Since relaxin works directly on the cervix and not through uterine contractions, relaxin may have advantages in cervical ripening of pregnancies in which stress to the fetus is an issue. (AM. J. Oasrer. GYNECOL. 147:410, 1983.)
The unripe cervix in the patient who needs to be delivered has remained an obstetric enigma for decades. Such patients are at very high risk for obstetric complications (fetal compromise or cesarean section) regardless of the underlying cause of the necessity for From the Department of Obstetrics and Gynecology and the Perinatal Center, The University of Chicago Pritzker School of Medicine, The Chicago Lying In Hospital, and the Pacific Biomedical Research Center and the Department of Anatomy and Reproductive Biology, Univenity of Hawaii. The supply of pregnant porcine ovaries and the isolation of purified relaxin were part of a separate studyfunded by The Leahi Foundation of Honolulu, Hawaii. Received for publication january 13, 1983. Revised April6, 1983. Accepted june 1, 1983. Reprint requests: Mark I. Evans, M.D., National Institutes of Health, Building 10, Room 8C429, Bethesda, Maryland 20205. *M.B.S. undergraduate research student supported by Grant No. RR08125-09. 410
immediate delivery (be it postdatism, preeclampsia, ruptured membranes, or medical complications of pregnancy, etc.). The inability to deliver certain pa· tients in a reasonable time period without undue stress to a possibly compromised fetus has undoubtedly contributed to the dramatically increasing cesarean section rate in the United States and abroad. 1 At present, chang·es in the quality. consistency, effacement, and dilatation of the cervix are accomplished by spontaneous labor or labor induced through the use of intravenous oxytocin, prostaglandins applied in several fashions, laminaria, or estradiol. HI In most cases pari of the action reflects mechanical force of the presenting part against the cervix. Effacement can occur independently of uterine action as documented by Stys and associates, 6 but most of the evidence concerning the above agents suggests that their action is intimately involved with uterine contractions.
Volume 147 Number 4
The existence of relaxin has been known for more than 50 years, and in the mid-1950s, crude extracts were used as a potential tocolytic agent in several studies.7· 8 These crude extracts were found to be clinically ineffective, and interest in relaxin waned over a 20year period. The availability of a method for obtaining purified relaxin permitted a reevaluation of the effects of relaxin upon the human cervix in late pregnancy. 9 Two clinical studies were performed by MacLennan and associates in Australia. 10 • 11 In these double-blind studies the effect of relaxin applied in a tylose gel to the cervix at one dose level and also in combination with other hormones prior to induction was noted with encouraging results. The purpose of the present doubleblind studies was to examine the effect of porcine ovarian relaxin applied against the cervix in 2 or 4 mg doses during induction of labor. In addition, we have attempted to evaluate changes in cervical effacement in patients who received a topical application of relaxin 5 to 7 days before anticipated induction for patients with postdated pregnancies.
Material and methods Relaxin was obtained from pregnant sow ovaries and purified by the method of Sherwood and O'Byrne9 with minor modifications as described by Kwok and associates. 12 Four batches were prepared and compared radioimmunologically with standard CM-a relaxin in our laboratory. Batches were within 3% of the standard. The purified relaxin used was equivalent to the CM-a, CM-a 1, and CM-b peaks described by Sherwood and O'Byrne 9 and shown by various authors to be equivalent in bioassays or immunoassays. Suppository placebo pellets were made from an 80% Carbowax 400, 20% Carbowax 6000 (Union Carbide polyethylene glycol) compound melted and formed in sterile molds. To make the relaxin pellets, the Carbowax pellets were then individually melted, the appropriate amount of relaxin was added, and the pellets were remolded. Microbiologic cultures of samples from each batch of pellets were all negative. The assignment of pellets to patients was by consecutive entry into either of the studies (explaining differing numbers of control subjects versus relaxin patients) with a code that remained unknown to the authors until after the study was completed and all patient data were computed. Induction study. Subjects for the induction study were drawan from the population undergoing oxytocin induction of labor who had achieved at least 35 weeks' gestation. Subjects were at least 18 years old, and informed consent was obtained. For patients consenting to the study, pellets were inserted into the cervical canal at the time of initiation of oxytocin induction. When lack of cervical dilatation prevented the insertion of a pellet into the cervical canal, the pellet was placed
Ripening of cervix with porcine relaxin
411
closely against the cervix. In all patients a cervical diaphragm (Ortho Pharmaceutical Corp., Raritan, New Jersey) was placed behind the pellet to maintain the position of the pellets which melted in approximately 30 minutes. Management of the patients was conducted according to usual standards (e.g., cervical examinations and rupture of membranes) as clinically indicated without regard to the research. Intravenous oxytocin induction was performed to achieve a contraction pattern of approximately every 3 minutes with contractions of 40 to 50 mm Hg. Whenever appropriate scalp clips and internal pressure cathethers were used to monitor fetal and uterine status. Outpatient study. Patients who had reached 41 weeks' gestation by the best clinical information available were eligible for the outpatient study. A pellet was inserted against the cervix with a retaining diaphragm as described previously, and the patient was allowed to go home. The standard management protocol of estriols three times per week and nonstress tests once or twice per week was followed. If the patient reached 42 weeks' gestation, she was admitted for postdates induction. No patient received relaxin twice. In evaluating the effects of the drug on the cervix, two questions were asked: (1) Do the cervical changes prior to active labor differ significantly in the relaxintreated groups? (2) Is cervical progression to complete dilation significantly affected? In order to measure these effects, we decided to use the cervical coefficient (dilatation x% effacement) as described by Hendricks and associates 13 rather than the Bishop 14 score, because the latter score considers factors other than, and in addition to, the cervical changes. The rate of change in the cervical coefficient was calculated as follows: (1) Changes per hour from the insertion of the pellet to the beginning of the active phase of labor (defined as 3.5 em of dilatation and 90% effacement) were designated as the "effacement rate"; (2) changes per hour from the insertion of the pellet to the end of the first stage of labor (cervical coefficient= 1,000) were designated at the "rate of total cervical change"; (3) in the outpatient study (when the pellets were inserted 5 to 7 days before the anticipated onset of labor or induction) the rate of change in the cervical coefficient was calculated per day (rather than per hour) and was designated as the "outpatient effacement rate." Minimal dilatation was defined as 0.5 em and minimal effacement as 10%. A maximal initial coefficient of 350 (3.5 em x 100%) was allowed if the patient was admitted in labor with a cervical coefficient >350. Cervical examinations were performed as clinically indicated usually by the same examiner. It was felt that the Hendricks coefficient would be less subject to interexaminer variability than the Bishop score.
412 Evans et al. Am.
October 15, 1983 Gynecol.
J. Obstet.
Table I. Induction study: Cervical changes Control subjects
Relaxin, 2 mg
Relaxin, 4 mg
Total N Effacement rate*
46 18.7 :': 14.1
23 50.0t :': 41.8
26 42.9t :': 33.0
Total cervical change ratet
47.1 :!: 35.0
95.3t :!: 73.9
61.7t :!: 38.4
Time
delivery (primiparas)§
29.1 :': 10.8
16.3t ::':: 12.4
22.6
Initial cervical coefficient (primiparas) n (primiparas) Time to delivery (multiparas)§
59.5 :': 41.4 24 31.7 ::':: 26.6
62.3 ± 36.4
36.0 :': 40.7
11
II
Initial cervical coefficient (multiparas) n (multiparas)* Cesarean sections
56.3 ± 28.4 22 9/46 (19.6%)
to
10.3t
7.8
61.0 :': 32.1
12 J/23 (4.3%)
17.3
:t
:t
Difference
x' = 26.8 p < 0.001 x'"' 10.1 p < 0.01 x' = 15.5 p < 0.01
17.1
x'= NS
x' 6.4 p < 0.05 xz = 6.4
8.1
42.9 ± 24.0 1.5 4/26 (15.4%)
x'= NS
*Change per hour in cervical coefficient from insertion to at least 3.5 cm/90%. tStatistically significant difference at p < 0.05 from control subjects by x'. tChange per hour in cervical coefficient from insertion to complete dilatation. §Includes only patients who were delivered vaginally.
Table II. Induction study: Fetal and maternal data Control :;ubjed'
Total N Birth weight (gm) 5 min Apgar score Gestational age (wk) Pari tv Mate'rnal age (yr)
46
3,033 ± 444 8.5:!: 1.0 40.0 ± 2.2 I.:~ ± 2.0 22.6 4.8
All statistical manipulations were performed before the code was broken. Data for effacement rate, total cervical change rate, outpatient effacement rate, time to delivery, initial cervical coefficients, number of patients admitted in labor, and parities were analyzed by the extension of the median test (x 2 ). When a statistically significant (p < 0.05) extension of the median test was found among the three groups (control subjects, 2 mg of relaxin patients, and 4 mg of relaxin patients), pairwise comparisons between groups were performed by the median test (x 2 ). Data for birth weight, Apgar scores, gestational age, and maternal age were analyzed by one-way analyses of variance.
Results
Induction study. Ninety-five patients were entered into the induction study, including 46 control subjects who received placebo, 23 who received 2 mg relaxin pellets, and 26 who received 4 mg relaxin pellets. Patients who received either the 2 or 4 mg relaxin pellets had cervical effacement rates very highly significantly greater than control subjects. There was no significant difference between the 2 mg and 4 mg pellets (Table l). Total cervical change rates were similarly increased by
Relaxin, 2 mg
23 2,981 :': 8.8:!: 38.9 = 0.8 :!: 23.2
521 0.8 2.8 1.0 4.3
Relaxin, 4mg
26 2,923 :!: 667 8.7 :': 0.7 39.0 ± 3.9 1.2 ± 1.6
24.2:!: .5.7
DiffeTence F = NS F = NS F = NS NS F NS
X~
relaxin. Time to delivery was reduced from an average of 29.1 hours for control patients to 16.3 hours for the 2 mg patients (p < 0.05) and 22.6 hours for the 4 mg patients. There were no statistical differences in initial cervical coefficients, although the 4 mg patients had the least favorable cervices at relaxin insertion. For multiparous pi!tients time to delivery was 31.7 hours for control subject~. 10.3 hours for 2 mg patients, and 17.3 hours for 4 mg patients. Again, although not statistically significant, the 4 mg patients had the least favorable cervices at the beginning of the induction. Nine of 46 control patients ( 19.6%) needed cesarean section, whereas only one of 23 (4.3%) 2 mg patients and four of 26 (15.4%) 4 mg patients required cesarean section. These differences were not statistically significant. Birth weights, Apgar scores, parity, and maternal ages were equivalent (Table II). There were no differences in the incidence of maternal complications (i.e., endometritis) among the groups, and there were no significant fetal complications. Outpatient study. In the outpatient study there were 14 control subjects, 13 patients received 2 mg pellets, and l 0 patients received 4 mg pellets. The outpatient effacement rate for control subjects was 21.1. For 2 mg
Ripening of cervix with porcine relaxin
Volume 147
413
Number 4
Table III. Clinic study: Cervical data
n Outpatient effacement rate* Days to admission No. admitted in labor Time to delivery (hr) Initial cervical coefficient
Control subjects
Relaxin, 2 mg
Relaxin, 4 mg
14 21.1 ± 31.7
13 53.3t ± 46.2
10 23.6:j: ± 12.2
x'
4.6 ± 1.6 3 /10 11.3 ± 7.2 38.0 ± 44.5
p < 0.001 x' = NS x' = NS x' = NS x' = NS
5.3 ± 2.1 6/14 14.8 ± 12.2 70.0 ± 62.6
5.3 ± 2.2 7/13 7.7 ± 5.0 49.6 ± 44.4
Difference =
26.8
*Change in cervical coefficient from insertion to admission divided by number of days. tStatistically significant at p < 0.05 from control subjects (X'). :j:Statistically significant at p < 0.05 from relaxin, 2 mg tx').
Table IV. Clinic study: Fetal and maternal data Control subjects
Birth weight (gm) 5 min Apgar score
Gestational age at insertion (wk) Pari tv Mate'rnal age (yr)
3,245 9.0 41.1 l.J 21.3
± 479 ± 0.4 ± 0.2
± 0.9 ± 4.4
patients it was 53.3 and for 4 mg patients it was 23.6. The effect of the 2 mg pellets was very highly significantly greater than both placebo and 4 mg pellets. Mean times to admission of the patient were comparable for the three groups as well as the proportion admitted in labor. The time to delivery for the 2 mg patients was approximately half that of control subjects, although the number of patients was small, and the results were not significant statistically (Table III). Data for initial cervical coefficients, birth weight, Apgar scores, gestational age, parity, and maternal age were comparable among all the groups (Table IV). There were no significant differences in complications among the groups.
Comment With the advent of sophisticated means of monitoring fetal status, powerful antibiotics, intensive care nurseries, and a shift in philosophy from a maternal safety priority to that of a fetal well-being priority, obstetric management has changed markedly over the past several years. Frequently cesarean section is performed for primarily fetal indications when vaginal delivery cannot be accomplished relatively quickly. Patients who require delivery but have unripe cervices are at particularly high risk for cesarean section. At the University of Chicago Chicago Lying In Hospital, the primary cesarean section rate for all patients is approximately 6% (low by national standards). However, for patients requiring induction, the primary cesarean section rate is approximately 20%, thus attesting to the high-risk status of such patients. A pharma-
Relaxin, 2 mg 3,256 9.0 41.2 1.2 23.3
± 613
± 0.4 ± 0.3
± 1.1 ± 5.4
Relaxin, 4 mg 3,113 8.6 41.0 1.0 26.0
± 447 ± 1.2 ± 0.2
± 1.2 ± 5.7
Difference F = NS F = NS F = NS
x'
F
= =
NS NS
cologie agent capable of accelerating vaginal delivery without subjecting the baby to undue stress from strong labor could potentially reduce the overall cesarean section rate. Oxytocin and prostaglandin affect the cervix via uterine contractions and secondary mechanical force of the presenting part upon the cervix. Relaxin appears to exert a direct effect upon cervical tissue and thus may have the advantage of achieving cervical change without stress upon the fetus. There was no evidence of increased uterine activity following relaxin administration. In fact, Sarosi and Weiss 1•5 have shown in vitro that relaxin potentiated progesteronemediated uterine muscle diminution of electrostimulated contractions. For the induction study, patients receiving 2 mg relaxin pellets had significantly greater cervical effacement rates, total cervical change rates, and decreased time to delivery. Initial cervical coefficients for both primiparous and multiparous women were comparable; control data for fetal well-being were also comparable, and the decrease in cesarean section rate from 19.6% to 4.3% if analyzed separately would have approached significance (p < 0.1 0). Four milligram pellets also demonstrated significantly increased effacement rates and total cervical change rates over placebo. The decrease in time to delivery for primiparous women from 29.1 to 22 hours and for multiparous women from 31.7 to I 7.3 hours was not statistically significant; however, for primiparous patients the initial coefficient of the 4 mg patients were 36.0 as compared to 59.5 for control subjects, and 42.9 versus 56.3 for multiparous patients. Although these differences
414 Evans et al. Am.
were not significant, the 4 mg patients may have been at a serious disadvantage as compared to the other group. In the outpatient study the use of 2 mg relaxin pellets resulted in an increased outpatient effacement rate to 59.3 from 21.1 per day for control subjects. For reasons that are not understood the effect of 4 mg pellets was negligible; again, although not statistically significant, it must be noted that the initial cervical scores of 4 mg patients were the worst of the three groups. lt should also be noted that the number of patients in this part of the study was small (n = :~6).'" In the induction study and for the 2 mg pellets in the clinic study, relaxin appears to have accelerated effacement and dilatation of the cervix and decreased the amount of time needed to deliver patients. From this study and those of MacLennan and associates 10 • 11 it appears that porcine ovarian relaxin applied to the cervix may be of use in accelerating changes in the cervix and perhaps decreasing the time of labor and the number of patients who require cesarean section. Further studies will be necessary to confirm these results and refine dosage and administration protocols. and to clarify whether the differences between 2 mg and 4 mg doses are related to small numbers, a downregulation effect of "overdosing." or a disadvantageous starting point for the 4 mg patients. We acknowledge the help of Ms. Sandra Yamamoto, Marily Ueno, and Dr. Austin Leach for the preparation of relaxin, Mark Miller, Pat Bagnara, Julie Esclamado, and Morris Bartot for preparation of the pellets, Drs. Eric Poon, Gary Loy, and Michael Zinaman for help in patient management, and Mrs. Debbie Kirk and Ms. Regina Stewart for preparation of the manuscript. REFERENCES 1. Cesarean Childbirth: United States Department of Health and Human Services. Public Health Service, National In-
2. 3. 4. :'>.
6. 7. 8. 9. 10. II.
12.
13. 14. 15.
October 15. 19H:l Obstet. Gvneu>l.
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stitutes of Health, NIH Publication No. 82-2067, Washington, D. C., 1982, Government Printing Office. Weiss, R. R., Tejani, N., Isreali. 1., Evans, M. !., et al.: Priming of the uterine cervix with oral prostaglandin E 2 in the term multigravida. Obstet. Gynecol. 46:181, 197S. MacLennan, A. H., and Green, R. S.: Cervical ripening and induction of labor with intravaginal prostaglandin E 2 , Lancet 1:117, 1979. Tohan. N .. Tejani, N. A., Varanasi, M., et al.: Ripening of the term cervix with Laminaria, Obstet. Gynecol. 54:588, 1979. Ellwood, D. A.. ~1itchell, M.D .. Anderson, A. B. M .. et al.: Oestrogens. prostaglandins, and cervical ripening, Lancet 1:376, 1979. Stys, S. J., Clewell, W. H., and Meschia, G.: Changes in cervical compliance at parturition independent of uterine activity. AM. j. 0BSTET. GYNECOL. 130:414, !978. Brvant-Greenwood, G. D.: Relaxin as a new hormone, En'docr. Rev. 3:62, 1982. Stone. M. L., Sedlis, A., and Zuckerman, H.: Relaxin-a critical evaluation, AM. J. 0BSTET. GYNECOL. 76:544, 1958. Sherwood, C. D., and O'Bvrne, E. M.: Purification and characterization of porcine. relaxin, Arch. Biochem. Biophys. 160:185, 1974. MacLennan. A. H., Green, R. C., Bryant-Greenwood. G. D.. eta!.: Ripening of the human cervix and induction of labour with purified relaxin, Lancet 1:220, 1980. ~1acLennan. A. H .. Green. R. C .. Bn·ant-Greenwood, G. D.. et al.: Cervical ripening with combinations of vaginal prostaglandin E 2 • estradiol. and relaxin, Obstet. Gvnecol. 58:601 , 19R I. Kwok, S. C. M., Bryant-Greenwood, G. D., and Niall, H. D.: Evidence for proteolysis during purification of relaxin from pregnant sow ovaries. Endocr. Res. Commun. 7:1, 1980. Hendricks, C. H., Brenner, W. E., and Kraus, G.: Normal cervical dilatation pattern in late pregnancy and labor. AM. J. 0BSTET. GYNECOL. 106:1065, 1970. Bishop, E. H.: Pelvic scoring for elective induction, Obstet. Gynecol. 24:2{)6, 1964. Sarosi, P., and Weiss, G.: Progesterone-relaxin synergism in electro-stimulated isolated rat uterine horn segments, presented at the Twenty-ninth Annual Meeting of the Society for Gynecologic Investigation, Dallas, Texas, March 24-27. 1982.