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A comparison of misoprostol with and without laminaria tents for induction of second-trimester abortion
A comparison of misoprostol with and without laminaria tents for induction of second-trimester abortion John K. Jain, MD, and Daniel R. Mishell, Jr., MD
Los Angeles, California OBJECTIVE: Our purpose was to determine whether intracervical placement of laminaria tents would improve the effectiveness of the prostaglandin analog misoprostol for the elective termination of pregnancies in the second trimester. STUDY DESIGN: Sixty-eight women between 12 and 22 weeks of gestation with either an intrauterine fetal death (n = 40) or medical or genetic indications for pregnancy termination (n = 30) were randomized to receive 200 gg of misoprostol administered vaginally every 12 hours with or without intracervical placement of laminaria concurrently with the first dose of misoprostoi. RESULTS: The rate of abortion 24 hours after initiation of treatment was 69.7% in the 33 women receiving misoprostol alone and 68.6% in the 35 women treated with misoprostol and laminaria. The abortion rates 48 hours after initiation of treatment were 84.8% and 91.4%, respectively, an insignificant difference. The complete abortion rate was also similar between women receiving misoprostol alone (39.3%) and the group receiving misoprostol and laminaria (37.5%). There were no significant differences in the incidence of fever, vomiting, diarrhea, or pain. The mean interval from initiation of treatment to abortion was also similar, t5.7 hours in those receiving misoprostol alone and 17.4 hours in those treated with misoprostol and laminaria. In both groups women who had live fetuses at the start of the procedure had a higher failure rate of abortion and a longer time interval to abortion than women whose fetus was dead. CONCLUSIONS: Laminaria tents inserted concurrently with the first dose of misoprostol do not significantly improve the abortifacient effect of vaginal misoprostol in the second trimester of pregnancy. (Am J Obstet Gynecol 1996;175:173-7.)
Key words: Misoprostol, laminaria, abortion
Technologic advances in imaging modalities and more aggressive screening programs to detect genetically abnormal fetuses increase the need for safe methods of performing second-trimester abortion. In the hands of an experienced operator surgical means of abortion, such as dilation and evacuation, have been reported by the Centers for Disease Control to be safer than instillation of materials into the amniotic fluid. ~ However, most gynecologists are inadequately trained to perform second-trimester dilation and evacuation, and thus the need for safe, alternative medical means of abortion is more important than ever. 2 We recently reported the successful use ofintravaginal administration ofmisoprostol (DL-methyl-110~,16-dihydroxy16-methyl-9-oxoprost-13E-en-l-oate) for second-trimester pregnancy termination? Laminaria tents have been
From the Department of Obstetrics and Gynecology, University of Southern California School of Medicine. Received for publication July 31, 1995; revisedJanuary 8, 1996; acceptedJanuary 16, 1996. Reprint requests:John K. Jain, MD, Department of Obstetrics and Gynecology, Women's and Children's Hospital, Los Angeles CountyUniversity of Southern California Medical Center; 1240 North Mission Road, Room LlO09, Los Angeles, CA 90033. Copyright © 1996 by Mosby-Year Book, Inc. 0002-9378/96 $5.00+ 0 6/1/71901
used as an adjunct for pregnancy termination for many years. Data from an earlier study of second-trimester pregnancy termination with intraamniotic prostaglandin F ~ indicated that concurrent, not prior, use oflaminaria tents resulted in shorter intervals between initiation and completion of abortion as compared with intervals for procedures in which laminaria was not used, as well as fewer women failing to abort within 48 hours. 4Therefore a prospective randomized study was undertaken to investigate whether the concurrent use of laminaria tents would improve the rate of abortion, as well as the rate of complete abortion, a n d / o r shorten the time interval between initiation and completion of abortion in women requesting pregnancy termination between 12 and 22 weeks of gestation. One group of subjects received 200 pg ofmisoprostol administered vaginally every 12 hours without intracervical laminaria whereas the second group received the same medication and had laminaria tents placed in the cervical canal for the first 12 hours of treatment. Material and methods Seventy pregnant women with a gestational age of 12 to 22 weeks with either an intrauterine fetal death (n = 40) or medical or genetic indications for pregnancy termina173
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don (n = 30) were enrolled in this study. Women with a previous uterine incision or a history of pulmonary, hepatic, renal, or cardiovascular disease were excluded from the study, as were women who had signs or symptoms of infection or any evidence of cervical dilatation. Of the 30 women with a live fetus at the start of the procedure (herein referred to as live fetuses), 3 underwent termination of pregnancy for maternal medical indications (one for acquired immunodeficiency syndrome, another for a seizure disorder, and a third for traumatic brain injury). The remaining 27 underwent termination for fetal genetic abnormalities as determined by ultrasonographic examination a n d / o r karyotyping of fetal ceils harvested by amniocentesis. Two of the 70 women were disqualified from the study. One with an intrauterine fetal death who was receiving misoprostol alone refused to continue with the study after receiving the second dose of misoprostol and was successfully treated with laminaria and prostaglandin E 2 suppositories. The other, who also had an intrauterine fetal death and was being treated with misoprostol and laminaria, failed to abort after 48 hours of treatment. An interstitial ectopic pregnancy was found and was treated by surgical resection. The mean maternal age, parity, and gestational age in the two treatment groups were similar (Table I). Of the 33 women receiving misoprostol alone, 18 had an intrauterine fetal death and 15 had a live fetus. Of the 35 women who received misoprostol and laminaria, 20 had an intrauterine fetal death and 15 had a live fetus. An ultrasonographic examination was performed on all subjects with use of a vaginal probe and an Uhramark 4 Plus (Advanced Technology Laboratories, Bothell, Wash.) machine. Gestational age was estimated by measuring the biparietal diameter of the fetal head and correlating this measurement with a standard table of gestational age as described by Shepard et al. ~According to a random number table, subjects were randomized to receive either 200 pg of misoprostol (Cytotec, Searle, Chicago), administered as two 100 lag tablets placed deep in the posterior vaginal fornix every 12 hours with or without the use of laminaria tents (Laminaria japonica, [Dilaterial Milex, Chicago]) for the first 12 hours of treatment. In patients randomized to receive laminaria tents varying in size from extra thin to extra thick the procedure was as follows: The cervix was first cleansed with a 10% povidone-iodine solution and dried with cotton sponges. T h e n as many laminaria tents as could be easily accommodated in the cervical canal were inserted and secured in place by one 4 x 4 gauze pad. After placement of the laminaria but before placement of the gauze pad, two tablets of misoprostol were placed deep in the posterior vaginal fornix in a m a n n e r similar to that for the other treatment group. The misoprostol tablets and laminaria were both placed by house officers, and all subjects were hospitalized and remained at bed rest for the duration of treatment. Vital signs were taken every 4 hours, and the
July 1996 AmJ Obstet Gynecol
occurrence of any adverse signs and symptoms including fever (temperature >38 ° C), vomiting, diarrhea, and pain were recorded. Subjects were treated for side effects only if symptoms required. Diphenoxylate plus atropine (Lomotil, Searle) 5.0 mg orally was used to treat diarrhea, acetaminophen (Tylenol, McNeil, Raritan, NJ.) 650 mg orally to treat fever (temperature >38 ° C), prochlorperazine 10 mg intramuscularly to treat vomiting, and meperidine 50 mg intramuscularly to treat uterine pain. To prevent mandatory postnatal resuscitative efforts in infants with severe chromosomal or morphologic anomalies, live infants received a lethal intracardiac injection of 1 to 4 ml of potassium chloride (2 m m o l / m l ) given by a 20-gauge spinal needle with uhrasonographic guidance approximately 4 hours before the first misoprostol treatment. Treatment failure was defined as failure of abortion to occur by 48 hours after the administration of the initial dose of misoprostol or systemic signs and symptoms deemed severe enough to withhold additional medication. After expulsion of the fetus, whether the placenta was or was not expelled, all subjects received an intravenous infusion of oxytocin administered as 30 units in 1 L of dextrose-lactated Ringer's solution. All women had a bimanual pelvic examination and an ultrasonographic examination of the uterine cavity within 6 hours after expulsion of the fetus to determine whether retained products of conception were present. Women with retained products of conception then underwent curettage of the uterus. Immediately before curettage, each woman received an intravenous bolus of 50 mg ofmeperidine and 25 mg of promethazine for sedation and an intracervical injection of 10 ml of a 0.5% solution of lidocaine for local anesthesia. Subjects who failed to abort within 48 hours of initial treatment either underwent a surgical dilation and evacuation procedure or received one or more intramuscular injections of 250 tag of 15-methyl prostaglandin F2~ (Hemabate, Upjohn, Kalamazoo, Mich.) administered every 2 hours. All women were discharged from the hospital with 9 tablets of 0.2 mg of methylergonovine maleate (Methergin e, Sandoz, East Hanover, N.J.) with instructions that they be taken orally every 8 hours. The study was approved by the Institutional Review Board of the Los Angeles County-Universityof Southern California Medical Center, and each of the subjects signed a written informed consent form. Statistical methods used included Student t test for interval from treatm e n t to abortion and Fisher's exact test to assess abortion rate, complete abortion rate, side effects, and characteristics of treatment failures. The analyses were carried out with the Primer (McGraw-Hill, New York) software package, and all reported values are two-sided. Results In 28 of the 33 (84.8%) women receiving misoprostol alone and 32 of the 35 (91.4%) women treated with misoprostol and laminaria, the pregnancies aborted within 48
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175
Table I. Characteristics of study groups
Misoprostolplus laminaria (n = 35)
Misoprostol (n = 33) Maternal age (yi; mean and range) Nulliparous (No.) Gestational age (wk, mean and range) Live fetus Dead fetus Overall
26.4 (16-38) 13 (39.4%)
26.4 (15-42) 15 (42.9%)
18.5 (14-22) (n = 15) 16.0 (12-21)(n=18) 17.2 (12-22)
19.3 (12-22)(n= 15) 15.8 (12-22) (n = 20) 17.3 (12-22)
Table II. Abortion rate
24 hr Intrauterine fetal death
Live fetus
Misoprostol Significance Misoprostolplus laminaria
15/18 (83.3%)
8/15 (53.3%)
15/20 (75.0%)
9/15 (60.0%)
TOTAL
30/38 (78.9%) 17/30 (56.7%) p = 0.07
Significance
48 hr I
Intrauterine fetal death
Total
I
Live fetus
23/33 (69.7%) p = 1.0 24/35 (68.6%)
16/18 (88.9%)
12/I5 (80.0%)
19/20 (95.0%)
13/15 (86.7%)
47/68 (69.1%)
35/38 (92.1%) 25/30 (83.3%) p = 0.45
hours (p = 0.47). A m o n g the 33 women receiving misoprostol alone, abortion occurred in 23 (69.7%) within 24 hours of initial treatment, whereas of the 35 women treated with misoprostol and laminaria, 24 (68.6%) aborted within 24 hours of initial treatment. Four of the five women who failed to abort by 48 hours with misoprostol alone underwent successful termination of pregnancy with two to five doses of intramuscular 15-methyl prostaglandin F2c~ within an additional 13 hours. The fifth woman underwent surgical dilation and evacuation without complication. Of the three women treated with misoprostol and laminaria in whom abortion did not occur within 48 hours, one aborted spontaneously 2 hours later without further intervention, the second underwent dilation and evacuation after failing to abort with three injec6ons of 15-methyl prostaglandin F2~,, and the third underwent dilation and evacuation without additional prostaglandin. The abortion rate of live fetuses in both groups within 24 hours of initial treatment (17/30) was lower than the rate of abortion of dead fetuses (30/38) (p= 0.07); however, after 48 hours of treatment the rates of abortion in these two categories were similar (25/30 and 35/38, p = 0.45) (Table II). O f the 8 women who failed to abort within 48 hours, 5 had a live fetus and 3 a dead fetus. Of the 33 women treated with misoprostol only, 5 (15.2%) failed to abort versus 3 of 35 (8.6%) of the women treated with misoprostol and laminaria (p = 0.47). Among the women who failed to abort, 4 were nulliparous (14.3% of the 28 nulliparous women in the study) and 4 were multiparous (10.0% of the 40 multiparous women in the study) (p= 0.71). O f the 30 live fetuses 11 (36.7%) had either anencephaly or acrania. Of these 11 fetuses 3 (27.3%) failed to abort compared with 2 of the 19 (10.5%) remaining live fetuses (p = 0.33). The abortion rate at different
Total 28/33 (84.8%) p = 0.47 32/35 (91.4%) 60/68 (88.2%)
gestation al ages was similar, with 2 of 14 ( 14.3 % ) fetuses of early gestational age (12 to 14 weeks), 3 of 26 (11.5%) fetuses of intermediate gestational age (15 to 18 weeks), and 3 of 25 ( 12.0 % ) fetuses of late gestational age ( 19 to 22 weeks) failing to abort by 48 hours of treatment. The mean number of laminaria tents used was 3.2 (range 1 to 7) in nulliparous women and 3.8 (range 2 to 9) in parous women. The overall mean interval from initiation of treatment to abortion was not significantly different between the two groups of subjects, 15.7 hours in those receiving misoprostol only a n d 17.4 hours in those treated with misoprostol and laminaria (p = 0.54). In both study groups women with a live fetus aborted later than those with an intrauterine fetal death; the mean interval from initial treatment to abortion was 20.0 hours and 12.4 hours, respectively, among women receiving misoprostol only and 21.3 and 14.7 hours among women treated with misoprostoI and laminaria. The complete abortion rate, defined as the simultaneous passage of both the fetus and the placenta, was similar in the two groups; 11 of 28 (39.3 %) women who aborted with misoprostol alone and 12 of the 32 (37.5%) who aborted with misoprostol and laminaria. The complete abortion rate did not differ significantly between those with earlier gestations and those with later gestations, between those with live and those with dead fetuses, or between nulliparous and parous women (Table III). The side effect profile was similar between the two study groups with diarrhea, fever, and vomiting occurring 0nly occasionally in both groups (Table IV). Moderate pain necessitating analgesic medication occurred in approximately two thirds of the women in both groups. Pain necessitating more than one injection of meperidine occurred m o r e often in the group treated with misoprostol and laminaria but did
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dain and Mishell
Table III. Complete abortion
Gestational age 12-16 wk Misoprostol Significance Misoprostolplus laminaria Significance TOTAL
Significance
Type of gestation
Parity 17-22 wk
Nulliparous
Intrauterine fetal death
Parous
Therapeutic abortion
6/12 (50.0%) 5/16 (31.2%) p = 0.44 6/13 (46.2%) 6/19 (31.6%)
5/11 (45.4%) 6/17 (35.3%) p = 0.70 5/14 (35.7%) 7/18 (38.9%)
7/16 (43,8%) 4/12 (33.3%) p = 0.70 8/19 (42,1%) 4/13 (30.8%)
p = 0.47 12/25 (48.0%) 11/35 (31,4%) p = 0.28
p = 1.0 10/25 (40.0%) 13/35 (52.0%) p = 1.0
p = 0.71 15/35 (42.8%) 8/25 (32.0%) p = 0.43
Table IV. Side effects-
I Vomiting Diarrhea Fever (temperature >38° C) Moderate pain* Severe painJ"
Misoprostol 2/33 0/33 1/33 19/33 5/33
I
Significance
(6.1%) (0%) (3.0%) (57.6%) (15.2%)
p= 1.0 p= 1.0 p= 0.20 p= 0.62 p=0.09
MisoprostolplusLaminaria I 3/35 1/35 5/35 23/35 12/35
(8.6%) (2,8%) (14.3%) (65.7%) (34.3%)
Total 5/68 1.68 6/68 42/68 17/68
(7.9%) (1.5%) (8.8%) (61.8%) (25.0%)
*One dose of analgesic medication. tMore than one dose of analgesic medication.
not reach statistical significance. The estimated blood loss was <500 ml in all women and no woman required a transfusion,
Comment Our experience with the use of intravaginal misoprostol for second-trimester pregnancy termination was recently reported. In that study we found misoprostol to be as effective as prostaglandin E 2 suppositories but with less cost and fewer side effects. The effect of adding laminaria tents to misoprostol was the subject of this investigation. The results of this study indicate that placement of intracervical laminaria tents at the time of the initial misoprostol administration does not significantly improve the rate of abortion within 24 or 48 hours of initial treatment nor does it increase the rate of complete abortion, shorten the interval from initiation of treatment to abortion, or improve the side effect profile. In contrast to our original study, in which 89% of 28 women aborted by 24 hours and 100% within 48 hours, only 69.7% of the 33 women in this study receiving misoprostol alone aborted by 24 hours and 84.8% by 48 hours. Potential causes of abortion failure such as fetuses with a cranial defect (anencephaly or acrania), nulliparity, gesrational age, presence of a live fetus, and method of abortion (with or without laminaria) were analyzed and not found to be significantly different. Although live fetuses with a cranial defect failed to abort more often, because of small numbers the nearly threefold difference was not significant. However, larger studies may indicate that lack of a fetal skull is a risk factor for misoprostol failure. Misoprostol compares favorably with other prostaglan-
dins used for midtrimester abortions. In a recent study by Borgida et al. 6women between 14 and 24 weeks' gestation were prospectively randomized to receive either intramuscular 15-methyl prostaglandin F2~ or prostaglandin E2 vaginal suppositories. Sixty-nine percent of the women receiving 15-methyl prostaglandin F2~ aborted by 24 hours. This incidence is slightly lower than the rate of 79.3% reported by The World Health Organization with use of the same agent. 7Borgida et al. reported that women receiving prostaglandin E 2 suppositories had a 96% abortion rate within 24 hours. This incidence is higher than that found by Surrago and Robins~ and Owen et alY who reported abortion rates of 85% and 86%, respectively, by 24 hours. Ferguson et al. 1° reported that the use of intraamniotic 15(S)-15-methyl prostaglandin F2a in combination with urea and laminaria yielded a 97% abortion rate within 24 hours. In the current study the rate of complete abortion in those women receiving misoprostol alone (39.3%) was similar to that in our initial study (43%) and did not differ significantly between women with earlier and later gestations, between nulliparous and parous women, or between live and dead fetuses. The complete abortion rate associated with other prostaglandin agents including 15-methyl prostaglandin F2c~ and prostaglandin E 2 has been reported to range between 35% and 85%. e~8,lO Unfortunately, the definitions of complete abortion vary, and thus it is difficult to establish meaningful comparisons of these agents to misoprostol. This study confirms the extremely low incidence of side effects with intravaginal misoprostol, with only a few patients experiencing fever, vomiting, or diarrhea that frequently occurs with prostaglandins such as prostaglandin
Volume 175, Number 1 AmJ Obstet Gynecol
E z and 15-methyl prostaglandin F2ce 6-1° T h e one patient with an u n d i a g n o s e d interstitial ectopic pregnancy illustrates the i m p o r t a n c e of considering the presence of this c o n d i t i o n in the event prostaglandins fail to t e r m i n a t e a pregnancy. Currently, medical a b o r t i o n with prostaglandin agents is c o n d u c t e d in a hospital setting and usually requires a 24-hour admission. Even t h o u g h misoprostol is inexpensive in c o m p a r i s o n to o t h e r agents, the r e q u i r e m e n t for inpatient t r e a t m e n t adds considerably to the cost of the abortion. Surgical methods, such as dilation and evacuation, are usually p e r f o r m e d on an outpatient basis. In Los Angeles a second-trimester a b o r t i o n by dilation and evacuation costs between $800 and $2300, whereas a 24h o u r admission to the hospital, including use of o p e r a t i n g r o o m facilities, may cost considerably more. Future studies addressing the possibility of outpatient medical abortion may offer a m e a n s to decrease its cost. In conclusion, it appears that laminaria administered at the time o f the initial misoprostol tablets do n o t significantly improve the abortifacient effect of rnisoprostol in the second trimester. If the laminaria are placed several hours before p l a c e m e n t of the first mis0prostol dose, they may cause cervical dilatation before prostaglandin t r e a t m e n t and shorten the t r e a t m e n t - t o - a b o r t i o n interval. F u r t h e r investigation is also n e e d e d to define the optimal dose and interval of administration of this agent to maximize the effectiveness of this m e t h o d of pregnancy termination.
Jain and Mishel!
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REFERENCES
1. Atrash HK, Mackay HT, Binkin NJ, Hogue CJR. Legal abortion mortality in the United States: 1972 to 1982. Am J Obstet Gynecol 1987;156:605-12. 2. Grimes DA. Clinicians who pro~fide abortion: the thinning ranks. Obstet Gynecol 1992;80:719-23. 3. Jain JK, Mishell DR Jr. A comparison of intravaginal misoprostol with prostaglandin E 2 for termination of second trimester pregnancy. N EnglJ Med 1994;331:290-3. 4. Duenhoelter JH, Gant NF, Jiminez JM. Concurrent use of prostaglandin F2c~and laminaria tents for induction of midtrimester abortion. Obstet Gynecol 1976;47:469-72. 5. Shepard MJ, Richards VA, Berkowitz RL, WarsofSL, Hobbins JC. An evaluation of two equations for predicting fetal weight by ultrasound. Am J Obstet Gynecol 1982;142:47-54. 6. Borgida AF, Rodis JF, Hanlon W, Craffey A, Ciarleglio L, Campbell WA. Second.-trimester abortion by intramuscular 15-methyl-prostaglandin F2c~ or intravaginal prost@andin E 2 suppositories: a randomized triM. Ohstet Gynecol 1995; 85:697-700. 7. World Health Organization Task Force on the use of prostaglandins for the regulation of fertility. Prostaglandins and abortion. I. Intramuscular administration of 15-methyl prostaglandin F2~ for induction of abortion in weeks 10 to 20 of pregnancy. Am J Obstet Gynecol 1977:129:593-6. 8. Surrago EJ, Robins J. Midtrimester pregnancy termination by intravaginal administration of prostaglandin E~. Contraception 1982:26:285-94. 9. OwenJ, HauthJC, WinNer CL. Gray SE. Midtrimester pregnancy termination: a randomized trim of prostaglandin E2 versus concentrated oxytocin. Am I Obstet Gynecol 1992; 167:1112-6. 10. Ferguson J E I I , Burkett BJ, Pinkerton JV, Thiagarajah S. Flather MM. Martel MM. et al. Intraamniotic 15(S)-15methyl prostaglandin F2~ and termination of middle and late second-trimester pregnancy for genetic indications: a contemporary approach. Am J Obstet Gynecot 1993;169: 332-40.
Make researching easier with the Ten-Year Cumulative Index (1978-1987) to the American Journal o f Obstetrics and Gynecology T h e Ten-Year Cumulative I n d e x is a c o m p l e t e guide to m o r e than 30,000 pages of original articles, case reports, letters, and editorials published in the A m e r i c a n J o u r n a l of Obstetrics and Gynecology from 1978 t h r o u g h 1987 (volumes 130 to 157). N u m b e r i n g m o r e than 800 pages, the Cumulative I n d e x includes both a subject and an a u t h o r index. This hard-cover v o l m n e is $64.50 ($69.00 international). Prices include shipping. Payment must accompany all orders and must be in U.S. funds, drawn on a U.S. bank. Contact Mosby-Year Book, Inc., Subscription Services, 11830 Westline Industrial Drive, St. Louis, MO 63146-3318, USA; p h o n e (314)453-4351. In the U.S., call toll-free: (800) 453-4351. Please allow six weeks for delivery.
Los Angeles, California OBJECTIVE: Our purpose was to determine whether intracervical placement of laminaria tents would improve the effectiveness of the prostaglandin analog misoprostol for the elective termination of pregnancies in the second trimester. STUDY DESIGN: Sixty-eight women between 12 and 22 weeks of gestation with either an intrauterine fetal death (n = 40) or medical or genetic indications for pregnancy termination (n = 30) were randomized to receive 200 gg of misoprostol administered vaginally every 12 hours with or without intracervical placement of laminaria concurrently with the first dose of misoprostoi. RESULTS: The rate of abortion 24 hours after initiation of treatment was 69.7% in the 33 women receiving misoprostol alone and 68.6% in the 35 women treated with misoprostol and laminaria. The abortion rates 48 hours after initiation of treatment were 84.8% and 91.4%, respectively, an insignificant difference. The complete abortion rate was also similar between women receiving misoprostol alone (39.3%) and the group receiving misoprostol and laminaria (37.5%). There were no significant differences in the incidence of fever, vomiting, diarrhea, or pain. The mean interval from initiation of treatment to abortion was also similar, t5.7 hours in those receiving misoprostol alone and 17.4 hours in those treated with misoprostol and laminaria. In both groups women who had live fetuses at the start of the procedure had a higher failure rate of abortion and a longer time interval to abortion than women whose fetus was dead. CONCLUSIONS: Laminaria tents inserted concurrently with the first dose of misoprostol do not significantly improve the abortifacient effect of vaginal misoprostol in the second trimester of pregnancy. (Am J Obstet Gynecol 1996;175:173-7.)
Key words: Misoprostol, laminaria, abortion
Technologic advances in imaging modalities and more aggressive screening programs to detect genetically abnormal fetuses increase the need for safe methods of performing second-trimester abortion. In the hands of an experienced operator surgical means of abortion, such as dilation and evacuation, have been reported by the Centers for Disease Control to be safer than instillation of materials into the amniotic fluid. ~ However, most gynecologists are inadequately trained to perform second-trimester dilation and evacuation, and thus the need for safe, alternative medical means of abortion is more important than ever. 2 We recently reported the successful use ofintravaginal administration ofmisoprostol (DL-methyl-110~,16-dihydroxy16-methyl-9-oxoprost-13E-en-l-oate) for second-trimester pregnancy termination? Laminaria tents have been
From the Department of Obstetrics and Gynecology, University of Southern California School of Medicine. Received for publication July 31, 1995; revisedJanuary 8, 1996; acceptedJanuary 16, 1996. Reprint requests:John K. Jain, MD, Department of Obstetrics and Gynecology, Women's and Children's Hospital, Los Angeles CountyUniversity of Southern California Medical Center; 1240 North Mission Road, Room LlO09, Los Angeles, CA 90033. Copyright © 1996 by Mosby-Year Book, Inc. 0002-9378/96 $5.00+ 0 6/1/71901
used as an adjunct for pregnancy termination for many years. Data from an earlier study of second-trimester pregnancy termination with intraamniotic prostaglandin F ~ indicated that concurrent, not prior, use oflaminaria tents resulted in shorter intervals between initiation and completion of abortion as compared with intervals for procedures in which laminaria was not used, as well as fewer women failing to abort within 48 hours. 4Therefore a prospective randomized study was undertaken to investigate whether the concurrent use of laminaria tents would improve the rate of abortion, as well as the rate of complete abortion, a n d / o r shorten the time interval between initiation and completion of abortion in women requesting pregnancy termination between 12 and 22 weeks of gestation. One group of subjects received 200 pg ofmisoprostol administered vaginally every 12 hours without intracervical laminaria whereas the second group received the same medication and had laminaria tents placed in the cervical canal for the first 12 hours of treatment. Material and methods Seventy pregnant women with a gestational age of 12 to 22 weeks with either an intrauterine fetal death (n = 40) or medical or genetic indications for pregnancy termina173
174
dain and Mishell
don (n = 30) were enrolled in this study. Women with a previous uterine incision or a history of pulmonary, hepatic, renal, or cardiovascular disease were excluded from the study, as were women who had signs or symptoms of infection or any evidence of cervical dilatation. Of the 30 women with a live fetus at the start of the procedure (herein referred to as live fetuses), 3 underwent termination of pregnancy for maternal medical indications (one for acquired immunodeficiency syndrome, another for a seizure disorder, and a third for traumatic brain injury). The remaining 27 underwent termination for fetal genetic abnormalities as determined by ultrasonographic examination a n d / o r karyotyping of fetal ceils harvested by amniocentesis. Two of the 70 women were disqualified from the study. One with an intrauterine fetal death who was receiving misoprostol alone refused to continue with the study after receiving the second dose of misoprostol and was successfully treated with laminaria and prostaglandin E 2 suppositories. The other, who also had an intrauterine fetal death and was being treated with misoprostol and laminaria, failed to abort after 48 hours of treatment. An interstitial ectopic pregnancy was found and was treated by surgical resection. The mean maternal age, parity, and gestational age in the two treatment groups were similar (Table I). Of the 33 women receiving misoprostol alone, 18 had an intrauterine fetal death and 15 had a live fetus. Of the 35 women who received misoprostol and laminaria, 20 had an intrauterine fetal death and 15 had a live fetus. An ultrasonographic examination was performed on all subjects with use of a vaginal probe and an Uhramark 4 Plus (Advanced Technology Laboratories, Bothell, Wash.) machine. Gestational age was estimated by measuring the biparietal diameter of the fetal head and correlating this measurement with a standard table of gestational age as described by Shepard et al. ~According to a random number table, subjects were randomized to receive either 200 pg of misoprostol (Cytotec, Searle, Chicago), administered as two 100 lag tablets placed deep in the posterior vaginal fornix every 12 hours with or without the use of laminaria tents (Laminaria japonica, [Dilaterial Milex, Chicago]) for the first 12 hours of treatment. In patients randomized to receive laminaria tents varying in size from extra thin to extra thick the procedure was as follows: The cervix was first cleansed with a 10% povidone-iodine solution and dried with cotton sponges. T h e n as many laminaria tents as could be easily accommodated in the cervical canal were inserted and secured in place by one 4 x 4 gauze pad. After placement of the laminaria but before placement of the gauze pad, two tablets of misoprostol were placed deep in the posterior vaginal fornix in a m a n n e r similar to that for the other treatment group. The misoprostol tablets and laminaria were both placed by house officers, and all subjects were hospitalized and remained at bed rest for the duration of treatment. Vital signs were taken every 4 hours, and the
July 1996 AmJ Obstet Gynecol
occurrence of any adverse signs and symptoms including fever (temperature >38 ° C), vomiting, diarrhea, and pain were recorded. Subjects were treated for side effects only if symptoms required. Diphenoxylate plus atropine (Lomotil, Searle) 5.0 mg orally was used to treat diarrhea, acetaminophen (Tylenol, McNeil, Raritan, NJ.) 650 mg orally to treat fever (temperature >38 ° C), prochlorperazine 10 mg intramuscularly to treat vomiting, and meperidine 50 mg intramuscularly to treat uterine pain. To prevent mandatory postnatal resuscitative efforts in infants with severe chromosomal or morphologic anomalies, live infants received a lethal intracardiac injection of 1 to 4 ml of potassium chloride (2 m m o l / m l ) given by a 20-gauge spinal needle with uhrasonographic guidance approximately 4 hours before the first misoprostol treatment. Treatment failure was defined as failure of abortion to occur by 48 hours after the administration of the initial dose of misoprostol or systemic signs and symptoms deemed severe enough to withhold additional medication. After expulsion of the fetus, whether the placenta was or was not expelled, all subjects received an intravenous infusion of oxytocin administered as 30 units in 1 L of dextrose-lactated Ringer's solution. All women had a bimanual pelvic examination and an ultrasonographic examination of the uterine cavity within 6 hours after expulsion of the fetus to determine whether retained products of conception were present. Women with retained products of conception then underwent curettage of the uterus. Immediately before curettage, each woman received an intravenous bolus of 50 mg ofmeperidine and 25 mg of promethazine for sedation and an intracervical injection of 10 ml of a 0.5% solution of lidocaine for local anesthesia. Subjects who failed to abort within 48 hours of initial treatment either underwent a surgical dilation and evacuation procedure or received one or more intramuscular injections of 250 tag of 15-methyl prostaglandin F2~ (Hemabate, Upjohn, Kalamazoo, Mich.) administered every 2 hours. All women were discharged from the hospital with 9 tablets of 0.2 mg of methylergonovine maleate (Methergin e, Sandoz, East Hanover, N.J.) with instructions that they be taken orally every 8 hours. The study was approved by the Institutional Review Board of the Los Angeles County-Universityof Southern California Medical Center, and each of the subjects signed a written informed consent form. Statistical methods used included Student t test for interval from treatm e n t to abortion and Fisher's exact test to assess abortion rate, complete abortion rate, side effects, and characteristics of treatment failures. The analyses were carried out with the Primer (McGraw-Hill, New York) software package, and all reported values are two-sided. Results In 28 of the 33 (84.8%) women receiving misoprostol alone and 32 of the 35 (91.4%) women treated with misoprostol and laminaria, the pregnancies aborted within 48
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Table I. Characteristics of study groups
Misoprostolplus laminaria (n = 35)
Misoprostol (n = 33) Maternal age (yi; mean and range) Nulliparous (No.) Gestational age (wk, mean and range) Live fetus Dead fetus Overall
26.4 (16-38) 13 (39.4%)
26.4 (15-42) 15 (42.9%)
18.5 (14-22) (n = 15) 16.0 (12-21)(n=18) 17.2 (12-22)
19.3 (12-22)(n= 15) 15.8 (12-22) (n = 20) 17.3 (12-22)
Table II. Abortion rate
24 hr Intrauterine fetal death
Live fetus
Misoprostol Significance Misoprostolplus laminaria
15/18 (83.3%)
8/15 (53.3%)
15/20 (75.0%)
9/15 (60.0%)
TOTAL
30/38 (78.9%) 17/30 (56.7%) p = 0.07
Significance
48 hr I
Intrauterine fetal death
Total
I
Live fetus
23/33 (69.7%) p = 1.0 24/35 (68.6%)
16/18 (88.9%)
12/I5 (80.0%)
19/20 (95.0%)
13/15 (86.7%)
47/68 (69.1%)
35/38 (92.1%) 25/30 (83.3%) p = 0.45
hours (p = 0.47). A m o n g the 33 women receiving misoprostol alone, abortion occurred in 23 (69.7%) within 24 hours of initial treatment, whereas of the 35 women treated with misoprostol and laminaria, 24 (68.6%) aborted within 24 hours of initial treatment. Four of the five women who failed to abort by 48 hours with misoprostol alone underwent successful termination of pregnancy with two to five doses of intramuscular 15-methyl prostaglandin F2c~ within an additional 13 hours. The fifth woman underwent surgical dilation and evacuation without complication. Of the three women treated with misoprostol and laminaria in whom abortion did not occur within 48 hours, one aborted spontaneously 2 hours later without further intervention, the second underwent dilation and evacuation after failing to abort with three injec6ons of 15-methyl prostaglandin F2~,, and the third underwent dilation and evacuation without additional prostaglandin. The abortion rate of live fetuses in both groups within 24 hours of initial treatment (17/30) was lower than the rate of abortion of dead fetuses (30/38) (p= 0.07); however, after 48 hours of treatment the rates of abortion in these two categories were similar (25/30 and 35/38, p = 0.45) (Table II). O f the 8 women who failed to abort within 48 hours, 5 had a live fetus and 3 a dead fetus. Of the 33 women treated with misoprostol only, 5 (15.2%) failed to abort versus 3 of 35 (8.6%) of the women treated with misoprostol and laminaria (p = 0.47). Among the women who failed to abort, 4 were nulliparous (14.3% of the 28 nulliparous women in the study) and 4 were multiparous (10.0% of the 40 multiparous women in the study) (p= 0.71). O f the 30 live fetuses 11 (36.7%) had either anencephaly or acrania. Of these 11 fetuses 3 (27.3%) failed to abort compared with 2 of the 19 (10.5%) remaining live fetuses (p = 0.33). The abortion rate at different
Total 28/33 (84.8%) p = 0.47 32/35 (91.4%) 60/68 (88.2%)
gestation al ages was similar, with 2 of 14 ( 14.3 % ) fetuses of early gestational age (12 to 14 weeks), 3 of 26 (11.5%) fetuses of intermediate gestational age (15 to 18 weeks), and 3 of 25 ( 12.0 % ) fetuses of late gestational age ( 19 to 22 weeks) failing to abort by 48 hours of treatment. The mean number of laminaria tents used was 3.2 (range 1 to 7) in nulliparous women and 3.8 (range 2 to 9) in parous women. The overall mean interval from initiation of treatment to abortion was not significantly different between the two groups of subjects, 15.7 hours in those receiving misoprostol only a n d 17.4 hours in those treated with misoprostol and laminaria (p = 0.54). In both study groups women with a live fetus aborted later than those with an intrauterine fetal death; the mean interval from initial treatment to abortion was 20.0 hours and 12.4 hours, respectively, among women receiving misoprostol only and 21.3 and 14.7 hours among women treated with misoprostoI and laminaria. The complete abortion rate, defined as the simultaneous passage of both the fetus and the placenta, was similar in the two groups; 11 of 28 (39.3 %) women who aborted with misoprostol alone and 12 of the 32 (37.5%) who aborted with misoprostol and laminaria. The complete abortion rate did not differ significantly between those with earlier gestations and those with later gestations, between those with live and those with dead fetuses, or between nulliparous and parous women (Table III). The side effect profile was similar between the two study groups with diarrhea, fever, and vomiting occurring 0nly occasionally in both groups (Table IV). Moderate pain necessitating analgesic medication occurred in approximately two thirds of the women in both groups. Pain necessitating more than one injection of meperidine occurred m o r e often in the group treated with misoprostol and laminaria but did
176
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dain and Mishell
Table III. Complete abortion
Gestational age 12-16 wk Misoprostol Significance Misoprostolplus laminaria Significance TOTAL
Significance
Type of gestation
Parity 17-22 wk
Nulliparous
Intrauterine fetal death
Parous
Therapeutic abortion
6/12 (50.0%) 5/16 (31.2%) p = 0.44 6/13 (46.2%) 6/19 (31.6%)
5/11 (45.4%) 6/17 (35.3%) p = 0.70 5/14 (35.7%) 7/18 (38.9%)
7/16 (43,8%) 4/12 (33.3%) p = 0.70 8/19 (42,1%) 4/13 (30.8%)
p = 0.47 12/25 (48.0%) 11/35 (31,4%) p = 0.28
p = 1.0 10/25 (40.0%) 13/35 (52.0%) p = 1.0
p = 0.71 15/35 (42.8%) 8/25 (32.0%) p = 0.43
Table IV. Side effects-
I Vomiting Diarrhea Fever (temperature >38° C) Moderate pain* Severe painJ"
Misoprostol 2/33 0/33 1/33 19/33 5/33
I
Significance
(6.1%) (0%) (3.0%) (57.6%) (15.2%)
p= 1.0 p= 1.0 p= 0.20 p= 0.62 p=0.09
MisoprostolplusLaminaria I 3/35 1/35 5/35 23/35 12/35
(8.6%) (2,8%) (14.3%) (65.7%) (34.3%)
Total 5/68 1.68 6/68 42/68 17/68
(7.9%) (1.5%) (8.8%) (61.8%) (25.0%)
*One dose of analgesic medication. tMore than one dose of analgesic medication.
not reach statistical significance. The estimated blood loss was <500 ml in all women and no woman required a transfusion,
Comment Our experience with the use of intravaginal misoprostol for second-trimester pregnancy termination was recently reported. In that study we found misoprostol to be as effective as prostaglandin E 2 suppositories but with less cost and fewer side effects. The effect of adding laminaria tents to misoprostol was the subject of this investigation. The results of this study indicate that placement of intracervical laminaria tents at the time of the initial misoprostol administration does not significantly improve the rate of abortion within 24 or 48 hours of initial treatment nor does it increase the rate of complete abortion, shorten the interval from initiation of treatment to abortion, or improve the side effect profile. In contrast to our original study, in which 89% of 28 women aborted by 24 hours and 100% within 48 hours, only 69.7% of the 33 women in this study receiving misoprostol alone aborted by 24 hours and 84.8% by 48 hours. Potential causes of abortion failure such as fetuses with a cranial defect (anencephaly or acrania), nulliparity, gesrational age, presence of a live fetus, and method of abortion (with or without laminaria) were analyzed and not found to be significantly different. Although live fetuses with a cranial defect failed to abort more often, because of small numbers the nearly threefold difference was not significant. However, larger studies may indicate that lack of a fetal skull is a risk factor for misoprostol failure. Misoprostol compares favorably with other prostaglan-
dins used for midtrimester abortions. In a recent study by Borgida et al. 6women between 14 and 24 weeks' gestation were prospectively randomized to receive either intramuscular 15-methyl prostaglandin F2~ or prostaglandin E2 vaginal suppositories. Sixty-nine percent of the women receiving 15-methyl prostaglandin F2~ aborted by 24 hours. This incidence is slightly lower than the rate of 79.3% reported by The World Health Organization with use of the same agent. 7Borgida et al. reported that women receiving prostaglandin E 2 suppositories had a 96% abortion rate within 24 hours. This incidence is higher than that found by Surrago and Robins~ and Owen et alY who reported abortion rates of 85% and 86%, respectively, by 24 hours. Ferguson et al. 1° reported that the use of intraamniotic 15(S)-15-methyl prostaglandin F2a in combination with urea and laminaria yielded a 97% abortion rate within 24 hours. In the current study the rate of complete abortion in those women receiving misoprostol alone (39.3%) was similar to that in our initial study (43%) and did not differ significantly between women with earlier and later gestations, between nulliparous and parous women, or between live and dead fetuses. The complete abortion rate associated with other prostaglandin agents including 15-methyl prostaglandin F2c~ and prostaglandin E 2 has been reported to range between 35% and 85%. e~8,lO Unfortunately, the definitions of complete abortion vary, and thus it is difficult to establish meaningful comparisons of these agents to misoprostol. This study confirms the extremely low incidence of side effects with intravaginal misoprostol, with only a few patients experiencing fever, vomiting, or diarrhea that frequently occurs with prostaglandins such as prostaglandin
Volume 175, Number 1 AmJ Obstet Gynecol
E z and 15-methyl prostaglandin F2ce 6-1° T h e one patient with an u n d i a g n o s e d interstitial ectopic pregnancy illustrates the i m p o r t a n c e of considering the presence of this c o n d i t i o n in the event prostaglandins fail to t e r m i n a t e a pregnancy. Currently, medical a b o r t i o n with prostaglandin agents is c o n d u c t e d in a hospital setting and usually requires a 24-hour admission. Even t h o u g h misoprostol is inexpensive in c o m p a r i s o n to o t h e r agents, the r e q u i r e m e n t for inpatient t r e a t m e n t adds considerably to the cost of the abortion. Surgical methods, such as dilation and evacuation, are usually p e r f o r m e d on an outpatient basis. In Los Angeles a second-trimester a b o r t i o n by dilation and evacuation costs between $800 and $2300, whereas a 24h o u r admission to the hospital, including use of o p e r a t i n g r o o m facilities, may cost considerably more. Future studies addressing the possibility of outpatient medical abortion may offer a m e a n s to decrease its cost. In conclusion, it appears that laminaria administered at the time o f the initial misoprostol tablets do n o t significantly improve the abortifacient effect of rnisoprostol in the second trimester. If the laminaria are placed several hours before p l a c e m e n t of the first mis0prostol dose, they may cause cervical dilatation before prostaglandin t r e a t m e n t and shorten the t r e a t m e n t - t o - a b o r t i o n interval. F u r t h e r investigation is also n e e d e d to define the optimal dose and interval of administration of this agent to maximize the effectiveness of this m e t h o d of pregnancy termination.
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REFERENCES
1. Atrash HK, Mackay HT, Binkin NJ, Hogue CJR. Legal abortion mortality in the United States: 1972 to 1982. Am J Obstet Gynecol 1987;156:605-12. 2. Grimes DA. Clinicians who pro~fide abortion: the thinning ranks. Obstet Gynecol 1992;80:719-23. 3. Jain JK, Mishell DR Jr. A comparison of intravaginal misoprostol with prostaglandin E 2 for termination of second trimester pregnancy. N EnglJ Med 1994;331:290-3. 4. Duenhoelter JH, Gant NF, Jiminez JM. Concurrent use of prostaglandin F2c~and laminaria tents for induction of midtrimester abortion. Obstet Gynecol 1976;47:469-72. 5. Shepard MJ, Richards VA, Berkowitz RL, WarsofSL, Hobbins JC. An evaluation of two equations for predicting fetal weight by ultrasound. Am J Obstet Gynecol 1982;142:47-54. 6. Borgida AF, Rodis JF, Hanlon W, Craffey A, Ciarleglio L, Campbell WA. Second.-trimester abortion by intramuscular 15-methyl-prostaglandin F2c~ or intravaginal prost@andin E 2 suppositories: a randomized triM. Ohstet Gynecol 1995; 85:697-700. 7. World Health Organization Task Force on the use of prostaglandins for the regulation of fertility. Prostaglandins and abortion. I. Intramuscular administration of 15-methyl prostaglandin F2~ for induction of abortion in weeks 10 to 20 of pregnancy. Am J Obstet Gynecol 1977:129:593-6. 8. Surrago EJ, Robins J. Midtrimester pregnancy termination by intravaginal administration of prostaglandin E~. Contraception 1982:26:285-94. 9. OwenJ, HauthJC, WinNer CL. Gray SE. Midtrimester pregnancy termination: a randomized trim of prostaglandin E2 versus concentrated oxytocin. Am I Obstet Gynecol 1992; 167:1112-6. 10. Ferguson J E I I , Burkett BJ, Pinkerton JV, Thiagarajah S. Flather MM. Martel MM. et al. Intraamniotic 15(S)-15methyl prostaglandin F2~ and termination of middle and late second-trimester pregnancy for genetic indications: a contemporary approach. Am J Obstet Gynecot 1993;169: 332-40.
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