Dickinson, Jan E. MD*†
Prenatal diagnosis is an accepted component of contemporary obstetric practice and has permitted the detection of many fetal abnormalities before birth. An option for women with a prenatally detected lethal or severe fetal anomaly is interruption of the pregnancy. In the circumstance of pregnancy termination following the detection of a fetal anomaly, pathologic evaluation of the fetus is frequently required to assist in definitive diagnosis. In this setting destructive termination techniques may be inappropriate because the nature of the procedure can render autopsy studies impossible or incomplete. Therefore, in the situation of a fetal anomaly, medical termination of pregnancy is often performed. The usual agents employed to induce a medical termination of pregnancy in the second trimester are prostaglandin preparations.1,2 The synthetic prostaglandin misoprostol is commonly used as an abortifacient in this situation.
The frequency of cesarean birth continues to increase. There remains uncertainty as to the most appropriate mode of pregnancy interruption in the second trimester when a fetal anomaly is diagnosed in women with prior cesarean deliveries. It is unlikely that any single method will be risk-free in the setting of previous uterine surgery. In the second trimester of pregnancy, there is limited information on the safety profile of misoprostol in women with prior cesarean births. Case reports of uterine rupture have been published with the use of misoprostol in both the scarred3,4 and unscarred uterus.5 Although case series have been published investigating the use of prostaglandins, including misoprostol, for second-trimester pregnancy termination in women with prior cesarean deliveries, all studies have been very small.6–9
The aim of this study was to compare the safety profile of misoprostol as an abortifacient in women with and those without a prior cesarean delivery scar who underwent a second-trimester pregnancy interruption for the indication of a fetal anomaly.
MATERIALS AND METHODS
All women admitted to King Edward Memorial Hospital, Perth, Western Australia, for pregnancy interruption with a prenatally identified fetal abnormality between January 1997 and July 2004 were identified using the institutional obstetric database. The medical records of those women identified within this cohort with a gestation of 14–28 weeks were then specifically reviewed to develop 2 contemporaneous cohorts based on the presence or absence of past cesarean birth. The information regarding the pregnancy termination was collected and collated. Specific data recorded included maternal demographic information, pregnancy gestation, indication for pregnancy termination, duration of termination, and procedure-related complications (blood loss, blood transfusion, placental retention, failed medical termination, uterine rupture, hysterectomy). This investigational protocol was approved by the Institutional Ethics Committee before commencement of the study.
Since 1997 misoprostol has been adopted as the standard abortifacient for second-trimester pregnancy interruption in our institution. Before 1997 extra-amniotic prostaglandin F2α (PGF2α), instilled via a transcervical Foley catheter, was the standard method of inducing second-trimester pregnancy termination for all women. The dose of misoprostol was not uniform during the study period, with 2 randomized controlled clinical trials conducted and completed.10,11 Since 2001 the standard dosage regimen for misoprostol has been 400 μg intravaginally every 6 hours, for a maximum total prostaglandin administration period of 48 hours. During the entire study period, all women who were undelivered after 48 hours received a transcervical Foley catheter with extra-amniotic PGF2α instillation every 2 hours or high-concentration intravenous oxytocin (5 IU/h), depending on the cervical status and amniotic membrane integrity. No prophylactic medications were used to prevent the gastrointestinal adverse effects of misoprostol. Routine placental curettage was not performed. Spontaneous expulsion of the placenta within 60 minutes of delivery was awaited, with digital exploration of the uterine cavity and blunt curettage reserved for those cases where expulsion did not occur or was incomplete on the basis of clinical signs and symptoms.
The data were analyzed using univariate and multivariable statistical techniques within the SigmaStat 2.0 statistical software program (SYSTAT Software Inc, Point Richmond, CA). Analyses were 2-tailed, with the significance level set at .05 for all tests. Numeric variables are presented as mean (standard deviation) or median (interquartile range) and were compared using analysis of variance or the Kruskal-Wallis χ2 test for variables when the assumption of normality was not satisfied. Group testing of categorical data are presented as number (%) and were compared with Fisher exact test or χ2 test.
Seven hundred twenty consecutive women underwent a medical termination of pregnancy for prenatally diagnosed fetal abnormalities during the 7.5-year study period from January 1997 through July 2004. One hundred one women (14%) within this cohort gave a history of at least 1 prior cesarean birth. Seventy-eight (77.2%) women reported 1, 19 women (18.8%) 2, and 4 women (4%) 3 prior cesarean deliveries.
All pregnancy terminations were for fetal abnormality, and all fetuses were alive at, or just before, the commencement of the termination process. The principal fetal anomalies for which termination of pregnancy was conducted were karyotypic anomalies (36.5%), neural tube defects (15.6%), cardiac anomalies (9.2%), cerebral anomalies (7.6%), skeletal dysplasias (7.1%), and renal abnormalities (6.9%). During the study, 6 dosage regimens for misoprostol were in use: 200 μg intravaginally every 6 hours (n = 85, 11.8%); 400 μg loading dose followed by 200 μg intravaginally every 6 hours (n = 35, 4.9%); 600 μg loading dose followed by 200 μg intravaginally every 6 hours (n = 30, 4.1%); 600 μg intravaginal loading dose followed by 200 μg orally every 3 hours (n = 30, 4.2%); 400 μg orally every 3 hours (n = 29, 4%); and 400 μg vaginally every 6 hours (n = 511, 71%). There was no significant difference in the distribution of the misoprostol dosage regimens between women with prior uterine surgery and those without (P = .689). The total dose of misoprostol administered to achieve pregnancy termination, regardless of the specific regimen used, was not different between the 2 groups (1,200 μg [interquartile range 800–1,600] versus 1,100 μg [800–1,600], no prior cesarean birth versus cesarean birth, respectively, P = .066).
There was a significant difference in the maternal age of those women with and those without a prior cesarean delivery, most likely because of the nature of the requirement for a prior birth in the former group (Table 1). Predictably, this consequence was also extended to a gravidity and parity effect. Gestational age was assigned on the basis of certain menstrual dates with confirmatory ultrasound examination, or ultrasound dating if the menstrual dates were uncertain or varied significantly from the menstrual dates. For both groups the median gestational age at delivery was 19 weeks (Table 1).
There was no significant difference in the median time to achieve delivery between the 2 groups (Table 2). Delivery was achieved in a median of 14.5 hours in those women with a prior cesarean delivery compared with 16.6 hours in those women with no prior cesarean delivery (P = .07). There was, however, no difference in the proportion of women who delivered in less than 24 hours from misoprostol commencement (76.1% versus 82.2%, no prior cesarean birth versus cesarean birth, respectively, P = .22) or in prolonged delivery interval beyond 48 hours (Table 2).
Transcervical Foley catheter insertion and extra-amniotic PGF2α instillation were required in 2.1% (n = 13) of women with no prior cesarean birth and 3.0% (n = 3) of women with a prior cesarean birth (P = .85). Adjunctive intravenous oxytocin use was uncommon in our series, being required in 0.8% (n = 5) of women with no prior cesarean delivery and 1% (n = 1) of those with a prior cesarean delivery. One woman in the unscarred group required a hysterotomy to effect delivery because of a failed medical induction. There was no case of hysterotomy in the prior cesarean birth group. There was no case of uterine rupture or hysterectomy in either group.
The progressive increase in the incidence of cesarean birth has been a notable feature of contemporary obstetric practice. In 2001 the cesarean delivery rate in the United States was 24.4%,12 and cesarean delivery is now the most frequent major surgical procedure performed in obstetrics and gynecology. With the expanding subpopulation of women with prior cesarean births, second-trimester pregnancy termination in the scenario of a prior cesarean delivery has become an increasingly common circumstance facing obstetricians. There is limited information on the safety profile of any termination technique in the setting of prior uterine surgery, and no method is risk free. The technique used for second-trimester termination is probably influenced more by physician opinion and expertise than objective outcome data.
Prostaglandins are commonly used to induce medical abortion in the second trimester, and the prostaglandin E1 analogue misoprostol is increasingly being used for this purpose. In the third trimester, induction of labor with misoprostol has been associated with an increased frequency of uterine rupture in women with prior uterine surgery compared with other induction techniques.13–15 In the second trimester of pregnancy, however, uterine rupture associated with the use of misoprostol does not appear to occur with such frequency as that observed at term. There have been a few case reports published of uterine rupture associated with the use of misoprostol in the setting of second-trimester medical termination in women with prior cesarean delivery.3–5 Case reports are, however, not an optimal method for assessing frequency of occurrence of an event nor the overall risks of a procedure, frequently reflecting rare single catastrophic events (Level III evidence). Uterine rupture is a recognized complication of pregnancy termination, regardless of the technique, and therefore it is not unexpected that this event has been reported with misoprostol. The more important issue is whether misoprostol is associated with an excess of complications in women with scarred uteri compared with those without. Three small case series have been recently published,6–8 totaling 87 women with at least 1 prior cesarean delivery undergoing second-trimester pregnancy termination with misoprostol. No case of uterine rupture was reported in these small series, but the study numbers remain too small to draw firm conclusions. Our current series is the largest reported to date, with 101 women with at least 1 prior cesarean delivery experiencing a misoprostol pregnancy termination over a 7-year period in a single institution. This is based on a systematic search of the medical literature conducted with MEDLINE (January 1966 to September 2004) and using the following search terms: “misoprostol,” “prostaglandins,” “prostaglandin E1 analogues,” “mifepristone,” “cesarean,” “previous cesarean,” “termination,” “abortion,” “uterine rupture,” and “scar rupture.” We observed no excess of complications in those women with prior uterine surgery compared with the contemporaneous cohort of women without prior surgery. There were no observed differences in any termination outcome between these 2 groups.
This is not a randomized controlled trial, but an observational series, and therefore conclusions about the relative merits of surgical termination compared with medical termination in the second trimester in the presence of prior uterine surgery cannot be made. A recent attempt to pilot such a study was ended early because of poor enrollment rates,16 and this appears to have been a reflection of the widespread use and acceptance of surgical termination abortion practices in the United States. Surgical termination is not available in our institution beyond 14 weeks of gestation, a common scenario in Australia and the United Kingdom. Thus, all women requiring pregnancy interruption beyond the first trimester in our institution undergo a medical induction procedure with prostaglandins. Large series have demonstrated the safety of medical termination of pregnancy with prostaglandins,17 and our data are in accord with these outcomes. Additionally, for institutions such as ours where expertise in dilation and evacuation is not available, information regarding complications of medical termination of pregnancy in the second trimester with misoprostol is important for both women and health care providers.
The published data on outcomes and complications of medical termination of pregnancy in the presence of previous cesarean birth is limited. The true incidence of catastrophic outcomes such as uterine rupture and hysterectomy is uncertain. Before the introduction of misoprostol, 2 large case series evaluating the outcomes of second-trimester medical pregnancy termination in the setting of prior uterine surgery were published.18,19 In 1980 Atienza et al18 reported the outcomes of medical termination of pregnancy in the second trimester using hyperosmolar urea and PGF2α in 1,626 women, of whom 76 had prior cesarean births. There was a single case of uterine rupture, occurring in a woman with a prior cesarean delivery receiving an adjunctive oxytocin infusion. The retrospective case series of Chapman et al19 comparing the outcomes of 606 women undergoing second trimester pregnancy termination demonstrated an increased incidence of uterine rupture (3.8% versus 0.2%) and requirement for blood transfusion (11.4% versus 5.3%) in women with prior cesarean delivery. Several methods were used to facilitate termination, including vaginal PGE2, intravenous concentrated oxytocin and intra-amniotic PGF2α-urea. It is notable that the 4 cases of uterine rupture in this series all involved an oxytocin infusion technique. In our contemporary series, the incidence of severe complications is low, with major hemorrhage and the need for blood transfusion being uncommon events. The incidence of placental retention in our second-trimester termination cohort remains high, and we are currently addressing strategies to decrease this.
The majority of case reports of uterine rupture in the second trimester have occurred in women without a history of prior uterine surgery.20 Three small case reports addressing the impact of misoprostol in women with prior cesarean deliveries have recently been reported.6–8 A total of only 87 women in these series gave histories of prior uterine surgery, and a variety of misoprostol dosage regimens were used. However, these data, combined with those of our series, suggest the incidence of uterine rupture observed at term with the use of misoprostol for labor induction in women with prior uterine surgery does not appear to occur with the same frequency when this agent is used in the second trimester. Misoprostol would appear to be a reasonable option for women with prior uterine surgery when interruption of pregnancy is required in the second trimester. It is, however, important to recognize that there is no technique in this circumstance that is risk-free. Uterine rupture, hemorrhage, and hysterectomy remain uncommon, and probably unavoidable, complications of second-trimester pregnancy termination. There is a suggestion from the literature that uterine rupture associated with second-trimester termination in women with a prior cesarean birth is associated with the use of intravenous high-dose oxytocin. In our series there was a very low requirement for this agent, with the majority of women delivering with the use of misoprostol alone. On the basis of the published data,18,19 it would appear prudent to minimize the use of oxytocin as a uterine stimulant to effect delivery in medical termination of pregnancy in the presence of prior uterine surgery.
Ongoing data collection and audits from institutions using misoprostol as a primary abortifacient in second-trimester pregnancy termination are still required to accumulate sufficient patient numbers to accurately ascertain the drug's safety profile in women with prior uterine surgery.
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