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Success Rates With Low Dose Misoprostol Before Induction of Labor for Nulliparas With Severe Preeclampsia at Various Gestational Ages

November 11, 2007

By Berkley, Eliza Meng, Chen; Rayburn, William F

Abstract Objective. To assess the efficiency of labor induction using low dose misoprostol for cervical ripening among nulliparous patients with severe preeclampsia.

Methods. This retrospective investigation involved cases gathered from our perinatal database for nulliparous women with severe preeclampsia delivering singleton gestations between January 2002 and May 2006. After a review of 229 hospital records, we selected only those cases (N = 145) that were eligible for a trial of labor and were administered intravaginal misoprostol (25 mcg every 3 to 6 h) for an unfavorable cervix. Primary outcomes related to the success and timing of vaginal deliveries. Secondary outcomes involved maternal and neonatal morbidity rates. Statistical evaluations included Chi-square testing and regression analysis.

Results. Vaginal delivery was successful in 95 cases (65.5%). This rate increased from 55.1% in cases at /=37 weeks. Most of those who delivered vaginally did so within 24 h (82 of 95 cases, 86.3%), regardless of gestational age. Vaginal delivery was associated with a shorter postpartum stay (2.5 vs. 3.2 days; p = 0.001) and with less neonatal respiratory distress (4.2% vs. 26.0%; p

Conclusions. Vaginal delivery within 24 h was common, with less morbidity than cesarean delivery, in this nulliparous group presenting with severe preeclampsia and an unfavorable cervix.

Keywords: Severe preeclampsia, induction of labor, misoprostol

Introduction

Preeclampsia affects approximately 8% of all pregnancies, and is one of the main indications for preterm delivery [1]. Timely delivery is warranted, because severe preeclampsia is associated with significant maternal and neonatal morbidity. There is debate, however, about the optimal route of delivery especially when preterm and with an unfavorable cervix. Several investigators recommend cesarean section to avoid prolonged induction, especially when at

It is well known that induction of labor, especially in preterm women with an unfavorable cervix, is difficult and sometimes unsuccessful [7]. Cervical ripening with agents like misoprostol, a synthetic prostaglandin El analog, is often used to enhance success. The American College of Obstetricians and Gynecologists (ACOG) acknowledged the efficacy of misoprostol for pre-induction cervical ripening while recommending a low intravaginal dose (25 mcg) [1]. Nahar and colleagues demonstrated the efficacy of misoprostol for cervical ripening and labor induction in patients with severe preeclampsia [8]. However, they did not reveal the dosing of misoprostol or the parity of their patients.

The objective of this retrospective study was to assess the efficiency of labor induction using low-dose misoprostol for pre- induction cervical ripening for nulliparous patients with an unfavorable cervix and with severe preeclampsia. Efficiency involved the success with vaginal delivery and the duration of labor. This group represents the greatest risk of failure to induction. Secondary outcome measures included maternal and neonatal morbidity.

Methods

Approval for this study was obtained from our human research and review committee. We performed a chart review of 229 consecutive cases of nulliparous patients with the diagnosis of severe preeclampsia. These cases involved singleton gestations obtained from our perinatal database from January 1, 2002 (shortly after release of the ACOG Committee Opinion) to June 1, 2006 [1]. One hundred and forty-five cases met eligibility criteria: (1) diagnosis of severe preeclampsia, (2) singleton gestation, (3) nulliparity, and (4) an unfavorable cervix (Bishop score =4) [9]. Only cases eligible for a trial of labor were included in this study. Exclusion criteria included cases in which a cesarean delivery was necessary before labor: fetal malpresentation, placenta previa, active genital herpes, infection, scarred uterus, rapidly worsening maternal condition, non-reassuring fetal heart rate (FHR) pattern before induction of labor, other active medical or obstetrical complications, and the presence of fetal anomalies.

Criteria for severe preeclampsia followed written ACOG guidelines (Table I) [1]. Confirmation of the diagnosis was made by a maternal- fetal medicine specialist. According to our written protocols, platelet counts and serum liver function tests were obtained every 6 h. Blood pressures were monitored at least every 30 min. Invasive hemodynamic monitoring was required only among women with severe cardiac disease, renal disease, refractory hypertension, pulmonary edema, or unexplained oliguria.

Upon diagnosis, all patients received intravenous magnesium sulfate for seizure prophylaxis using a 4-g bolus followed by 2 g/ h. Betamethasone, 12 mg intramuscularly for two doses, was given to those patients at

Table I. Criteria for severe preeclampsia.

We complied with guidelines from the ACOG Committee on Obstetric Practice on prescribing misoprostol for cervical ripening and labor induction [10]. These guidelines were based on published series and a detailed review of adverse outcomes reported to the Food and Drug Administration (FDA). One quarter of a 100-mcg tablet (Cytotec(R); Searle, Chicago, IL, USA) was the initial intravaginal dose. We anticipated the need to redose every 3-6 h. Oxytocin was infused when a Bishop score became >/=6 or if there were >/=6 contractions per hour. Infusion was started at or beyond 4 h after the last misoprostol dose. The starting dose of oxytocin was 2 mU/min and increased by 2 mU/min every 15 min until contractions came every 2- 3 min lasting 45-60 s [11].

Our written criteria for labor arrest that requires delivery were according to ACOG recommendations [12]. In nearly all cases, an intrauterine pressure catheter was placed. Minimally effective uterine activity was defined as three contractions per 10 min, averaging greater than 25 mmHg above the baseline. A goal of a maximum of five contractions in a 10-min period with resultant cervical dilation was considered adequate. Uterine hyperstimulation was denned either as a persistent pattern of more than five contractions in 10 min, or as contractions lasting 2 min or more [12]. Hyperstimulation syndrome was uterine hyperstimulation accompanied with a non-reassuring FHR recording [13]. An arrest disorder was diagnosed in the first stage of labor using two criteria: (1) the latent phase was completed, and (2) a uterine contraction pattern exceeded 200 Montevideo units for 2 h without cervical change. In our nulliparous women, the diagnosis of a prolonged second stage was considered when the second stage exceeded 3 h if regional anesthesia was administered or 2 h if no regional anesthesia was used.

The cases were divided into three standard subgroups according to gestational age: /=37 weeks 0 days. Maternal demographics included age, ethnicity, and predose Bishop score. The percentage of vaginal deliveries and the duration of labor were calculated for each gestational age group.

The primary outcomes were the success with vaginal deliveries and the duration of labor. As secondary outcomes, we evaluated postpartum morbidities associated with routes of deliveries. Measures of maternal morbidity included post-delivery length of hospital stay, maternal fever (>/=38[degrees]C on two occasions with maternal tachycardia), transfusion, antihypertensive therapy at hospital discharge, and readmission to the hospital. Neonatal morbidity included 5-min Apgar scores =3 and =6, select umbilical artery pH

A sample size of total patients needed to detect a 25% difference in the overall vaginal and cesarean delivery rates was 128, with a power of 0.8 and a type I error probability of 0.05. Statistical analysis was performed using SPSS 13.0 software (SPSS Inc., Chicago, IL, USA). Continuous variables that were normally distributed were compared with Student’s t-tests. Categorical variables were compared with Chi-square tests. For all tests, a p value less than 0.05 was considered to be statistically significant.

Results

During the 53-month study period, 145 women with severe preeclampsia underwent a trial of labor and were eligible for inclusion in this investigation. The numbers of cases in each gestational age group were 49 at between 28 and 33 weeks, 45 at between 34 and 36 weeks, and 51 at >/=37 weeks. Misoprostol was typically administered as two or three doses (range 1-6). Augmentation with oxytocin was used in all cases. No adverse effects from such low doses of local misoprostol (drug reaction, hemorrhage, febrile morbidity, or diarrhea) were recorded. Demographic data for those patients who either underwent a vaginal delivery or a cesarean delivery are shown in Table II. The two groups were not different except for patients at between 34 and 36 weeks of gestation being slightly older when a cesarean delivery was considered necessary. Although pre-induction Bishop scores were higher with increasing gestational age, there was no statistical difference as to the route of delivery for each gestational age subgroup and the pre-induction Bishop score. Elements of labor efficiency are shown in Figures 1 and 2. Vaginal delivery rates ranged from 55.1% in cases at between 28 weeks 0 days and 33 weeks 6 days of gestation to 68.9% of cases at between 34 weeks 0 days and 36 weeks 6 days, and to 72.5% in cases at >/=37 weeks 0 days (Figure 1). Vaginal delivery occurred within 24 h in 86.3% (82 of 95) cases. This 24-h period from initial misoprostol insert until vaginal delivery did not vary significantly between gestational age subgroups (Figure 2). Primary indications for cesarean delivery (N =50) were for fetal intolerance of labor in 34 cases (68%) and for failure to progress in 12 cases (24%).

The postpartum period was associated with gradual recovery and low maternal morbidity. The mean length of hospital stay was shorter after a vaginal than cesarean delivery (2.5 vs. 3.2 days; p = 0.001). The shorter hospital stay after vaginal delivery was most apparent at >/=37 weeks (Table III). Transfusion was necessary in one case (1.1%) after vaginal delivery. No eclamptic seizures were observed with discontinuation of intravenous magnesium sulfate approximately 24 h postpartum. Treatment for a postpartum fever with suspected endomyometritis also occurred less often (5.4% vs. 35.7%; p = 0.013) after a vaginal delivery (at least >/=37 weeks). Approximately one-third of all patients required oral antihypertensive therapy at discharge. There was no significant difference, according to gestational age or route of delivery, in the prescribing of antihypertensive medications at hospital discharge.

Table II. Maternal demographics for those who delivered either vaginally or by cesarean after labor.

Figure 1. Percent deliveries that were vaginal according to gestational age.

Figure 2. Mean time to vaginal delivery according to gestational age.

Neonatal outcomes are shown in Table III. Attendance at delivery by our neonatal team occurred in all cases. A 5-min Apgar score =6 was seen in nine (6.2%) cases, with eight being preterm. There were no cases with an umbilical artery pH /=34 weeks. Antibiotics were prescribed commonly, and reported sepsis was rare.

Table III. Maternal and neonatal morbidity according to gestational age and route of delivery.

Discussion

Consistent with our practice protocols, women with severe preeclampsia who met eligibility criteria underwent a labor induction. Our reported experience comprises the largest number of nulliparas with severe preeclampsia who were eligible for a trial of labor. We chose 145 consecutive nulliparous women, and induction was successful (i.e., resulted in vaginal delivery) in 65.5% of cases. This success rate varied by gestational age, with vaginal delivery occurring in 55.1% of women induced at less than 34 weeks compared with 72.5% induced at or beyond 37 weeks. These rates are similar or better than other reports that failed to distinguish between parity, gestational age group, and condition of the cervix [4-6,8]. Furthermore, those studies used protocols that did not comply with more current ACOG guidelines.

Our data also demonstrate that a large percentage of vaginal deliveries occur within 24 h despite an original unfavorable Bishop score. Although the duration of induction was slightly longer at an earlier gestational age, vaginal delivery occurred within 24 h in 85.2% of cases at

Initiating labor in the third trimester of pregnancy is performed by different methods such as oxytocin administration, hygroscopic balloon dilation of the cervix, extra-amniotic balloon catheters, and the use of prostaglandins and prostaglandin analogs. We chose to investigate outcomes with the use of misoprostol since it is easily available, inexpensive, stable, and easy to store. A feature of the study is compliance with recent ACOG guidelines using a low dose regimen of 25 [mu]g initially and repeated every 3-6 h, knowing that the half-life of misoprostol is 4.5 h [10]. In our experience, we infrequently administered more than three doses consecutively. Misoprostol alone did not achieve effective uterine contractions in many cases, so we often used oxytocin to augment labor.

Studying the effects of labor and routes of delivery on preterm fetuses not only requires a large data set, but also necessitates controlling for several potentially confounding therapies that affect neonatal neurologic morbidity. Uniform intrapartum written protocols were used in the current investigation, and potentially confounding variables were minimized. Magnesium sulfate was used to prevent eclampsia, and all fetuses at

Although our study is limited by its retrospective design, our findings are consistent with others that promote the general safety of induction of labor in cases of severe preeclampsia. Our investigation did not include cases at less than 28 weeks of gestation, since there was a very small number eligible to undergo a trial of labor. In addition, we did not compare overall morbidity with morbidity from elective cesareans performed in a similar group with severe preeclampsia.

Findings reported here should enhance counseling about the relative merits of a trial of labor in this high-risk group who require a timely delivery. Vaginal delivery within 24 h was common, with less morbidity than a cesarean delivery, in this nulliparous group presenting with severe preeclampsia. It appears to be appropriate to employ low-dose misoprostol in the presence of an unfavorable cervix for those cases meeting eligibility criteria to attempt a vaginal delivery. The fetuses appeared to tolerate labor and have less respiratory distress as newborn premature infants. The length of postpartum hospitalization was shortened with vaginal delivery, possibly because of fewer cases of endomyometritis and less anemia requiring transfusion.

Acknowledgements

This research was partially funded by the Seligman Perinatal Research Fund.

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ELIZA BERKLEY, CHEN MENG, & WILLIAM F. RAYBURN

Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, School of Medicine, University of New Mexico, Albuquerque, New Mexico, USA

(Received 12 April 2007; revised 10 July 2007; accepted 16 July 2007)

Correspondence: Eliza Berkley, MD, Department of Obstetrics and Gynecology, University of New Mexico School of Medicine, MSC 10 5580, 1 University of New Mexico, Albuquerque, NM 87131, USA. Tel: +1 505 272 6269. Fax: +1 505 272 3918. E-mail: eberkley@salud.unm.edu

Copyright Taylor & Francis Ltd. Nov 2007

(c) 2007 Journal of Maternal – Fetal & Neonatal Medicine. Provided by ProQuest Information and Learning. All rights Reserved.




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