Pharmacotherapy options for labor induction.

Review

Pharmacotherapy options for labor induction

Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Nyu Medical Center on 07/30/15 For personal use only.

Deborah A Wing† & Lili Sheibani †

University of California Irvine School of Medicine - Obstetrics & Gynecology, Orange, CA, USA

1.

Introduction

2.

Prostaglandins

3.

Oxytocin

4.

Complications and side effects

5.

Alternative methods

6.

Labor induction in women with prior cesarean

7.

Conclusion

8.

Expert opinion

Introduction: Induction of labor remains one of the most commonly performed procedures in the US and in other developed countries around the world. Various agents for cervical ripening are used prior to induction; the most commonly used are prostaglandins and oxytocin. The ideal agent is one that decreases time to vaginal delivery without compromising maternal and/or fetal safety. Areas covered: This article reviews the current pharmacologic methods available for induction of labor. Although these agents have been extensively studied and their safety and efficacy profile are well accepted, there is still ongoing research to determine the safest and most effective method. The article discusses the impact of pharmacogenomics as it relates to the most common induction agents. The dosing, route of administration, and side effects of these agents are reviewed. Expert opinion: Prostaglandins and oxytocin have been proven to be safe and effective methods of induction. However, the optimal medication for induction is yet to be determined. Although there are currently no pharmacogenomic findings that affect dosing of either prostaglandins or oxytocin, this is a growing area of research. In the near future, it may become clear that there is no ‘one regimen for all’ when selecting an induction or cervical ripening agent, or any other pharmaceutical altogether. Keywords: dinoprostone, induction agents, labor, misoprostol, oxytocin, pharmacogenomics, prostaglandins Expert Opin. Pharmacother. (2015) 16(11):1657-1668

1.

Introduction

Labor induction is one of the most commonly performed obstetric procedures in the United States and around the globe. The US rate of labor induction has steadily increased over the last 20 years until it fell slightly in 2011 and again in 2012 (23.3%) [1]. It is a procedure used to stimulate uterine contractions during pregnancy before labor begins on its own and is undertaken when the benefits of delivery either to the mother or fetus outweigh the risks of pregnancy continuation [2]. There are many accepted medical and obstetric indications for labor induction (Table 1). Contraindications to induction of labor are anything that precludes a vaginal delivery (Table 2). Prior to starting induction of labor, the risks, benefits and alternatives should be discussed with the patient. Currently, there is consensus that elective induction should not be done before 39 weeks [3]. Calkins et al. were the first to carry out systematic studies of the factors influencing the duration of the first stage of labor [4]. They concluded that the length, thickness and particularly the consistency of the cervix were important parameters. In 1955, Bishop devised a cervical scoring system for multiparous patients in which 0 -- 3 points are given for each of five factors [5,6]. He determined that when the total score was at least 9, the likelihood of vaginal delivery following labor induction was similar to that observed in patients with spontaneous onset of labor. While the Bishop score has become a classic parameter in obstetrics, several modifications 10.1517/14656566.2015.1060960 © 2015 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

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D. A. Wing & L. Sheibani

Article highlights. .

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Induction of labor is a commonly performed procedure when continuing the pregnancy is associated with greater maternal or fetal risk than delivery. Current pharmacologic agents for induction include various formulations of prostaglandins and oxytocin. When the cervix is unfavorable, prostaglandins can increase the probability of successful labor induction. Oxytocin can increase the success of induction of labor when compared to placebo or no treatment, but the optimal regimen is controversial. For women with prior cesarean delivery, prostaglandins for cervical ripening are not recommended, while oxytocin remains an available pharmacologic agent.

This box summarizes key points contained in the article.

Table 1. Indications for labor induction. Accepted indications Hypertensive disorders Preeclampsia/eclampsia Gestational hypertension Maternal medical conditions Diabetes mellitus Renal disease Chronic pulmonary disease Chronic hypertension Premature rupture of membranes Chorioamnionitis Abruptio placentae Fetal compromise Fetal growth restriction Isoimmunization Nonreassuring antepartum fetal testing Oligohydramnios Multiple gestations Fetal demise previous stillbirth Late term (‡ 41 weeks) or postterm (‡ 42 weeks) pregnancy Data from [2,71].

Table 2. Contraindications to labor induction. Absolute contraindications Vasa previa or complete placenta previa Transverse or oblique fetal lie Umbilical cord prolapse Prior classical uterine incision or transfundal uterine surgery Prior uterine rupture Active genital herpes infection Absolute cephalopelvic disproportion, contracted pelvis Category III fetal heart rate tracing Data from [2].

have been suggested. According to the modified Bishop score, effacement has been replaced by cervical length in centimeters. Additionally, modifiers have been made such that 1658

points are added or subtracted according to special circumstances. For example, a point is added for every previous vaginal delivery while a point is subtracted for nulliparity or postterm pregnancy. In general, if the cervix is considered unfavorable, prostaglandins are an option as the first agent. Misoprostol, a synthetic PGE1 analogue can be administered intravaginally, orally or sublingually. Dinoprostone, PGE2, is approved for cervical ripening; a vaginal insert and a gel are available. When compared with placebo or oxytocin alone, vaginal prostaglandins increase the likelihood of delivery within 24 h, do not reduce the rate of cesarean delivery and increase the risk of tachysystole with associated fetal heart rate changes [7]. Once the cervix is considered favorable, the induction can be continued with oxytocin. Cervical status is a good predictor of likelihood of success when labor is inducted. Any agent is effective in a woman with favorable cervix, whereas no method is highly successful in an unfavorable cervix (i.e., firm, posterior, not effaced, not dilated). When the cervix is unfavorable, a ripening process is generally employed. The two major techniques for cervical ripening are mechanical interventions, such as insertion of a Foley catheter or pharmacological interventions, such as application of prostaglandins. This paper reviews acceptable pharmacological methods for labor induction, especially when cervical ripening is required. These agents include oxytocin and various prostaglandin formulations. It also covers a discussion of safety and efficacy of various agents. 2.

Prostaglandins

Structure and activity Endogenous prostaglandins are 20-carbon eicosanoic fatty acids produced by bodily tissues. The chemical precursor, arachidonic acid, is an essential fatty acid that is present in all cell membranes, including smooth muscle such as the uterus [8]. Most are short-lived when produced endogenously, but some synthetic analogs such as prostaglandin E1 and E2 are stable for use in the process of labor induction. Administration of prostaglandins results in dissolution of collagen bundles and an increase in submucosal water content of the cervix. The collagen fibers of the cervix diminish and separate primarily because of the influence of hydrophilic glycosaminoglycans [9]. These changes in cervical connective tissue at term are similar to those observed in labor. Prostaglandins are endogenous compounds found in the myometrium, decidua and fetal membranes during pregnancy. Prostaglandins play an important role in cervical ripening, onset of labor, rupture of membranes and uterine contractility [10,11]. There is also some research showing that increase in prostaglandin levels occurs after the onset of labor [12]. Regardless, whether as precursors to labor or released after onset of labor, they play a significant role in the labor process. 2.1

Expert Opin. Pharmacother. (2015) 16(11)


Table 3. Prostaglandins for cervical ripening.


Drug name

Dose

Route

Onset of action (min)

Peak plasma level (min)

Plasma half-life (min)

Cost

Prostaglandin E1 Misoprostol Misoprostol

25 -- 50 mcg 25 -- 50 mcg

Oral tablet Vaginal tablet

12 ± 3 20.9 ± 5.3

20 -- 30 60 -- 80

20 -- 40 60

$1.34 $1.34

Prostaglandin E2 Dinoprostone Dinoprostone

0.5 mg in 2.5 ml syringe 10 mg

Endocervical gel Vaginal insert

Rapid onset Rapid onset

60 -- 120 Unknown

Variable Unknown

$314.42 $256.13

Synthetic prostaglandins resemble the ripening action of endogenous prostaglandins [13,14]. They have a longer bioavailability than endogenous ones. The most commonly used prostaglandins are misoprostol and dinoprostone (Table 3). Prostaglandin analogs were first given by intravenous and oral routes. Subsequently, local administration of prostaglandins in the vagina or the endocervix became the route of choice because of fewer side effects and acceptable clinical response. The efficacy of locally applied prostaglandin for cervical ripening and labor induction as compared with oxytocin has been demonstrated in a Cochrane review involving more than 10,000 women [15]. Vaginal prostaglandin E2 compared with placebo reduced the likelihood of vaginal delivery not being achieved within 24 h, the risk of the cervix remaining unfavorable or unchanged, and the need for oxytocin. There was no difference between cesarean section rates, although the risk of tachysystole with fetal heart rate changes was increased. The optimal route, frequency and dose of prostaglandins of all types and formulations for cervical ripening and labor induction have not been determined. Overall, induction with prostaglandins is associated with an increase in successful vaginal delivery within 24 h, a reduction in rate of cesarean delivery, and an increase in rate of tachysystole with fetal heart rate changes [15]. Some contraindications to the use of prostaglandins include hypersensitivity to any components of the drug, when vaginal delivery is contraindicated, unexplained bleeding during current pregnancy, previous cesarean section or abnormal fetal heart rate tracing. Prostaglandin E2 Dinoprostone, synthetic PGE2 is United States Food and Drug Administration (FDA) approved for cervical ripening. One of the first randomized controlled trials using intravaginal prostaglandin was conducted in 1979. Eighty-four term women with singleton pregnancies were assigned to three groups receiving placebo, 0.2 mg, or 0.4 mg PGE2 compound. Labor was established in 48 h in 9.3% of placebo women, 65.4% of women receiving 0.2 mg PGE2 and 85.7% of women receiving 0.4 mg PGE2 [16]. Rayburn 2.2

summarized the experience with more than 3313 pregnancies representing 59 prospective clinical trials in which PGE2 was used for cervical ripening before the induction of labor. He concluded that local administration of PGE2 is effective in enhancing cervical effacement and dilatation, reducing the failed induction rate, shortening the induction to delivery interval, and reducing oxytocin use and cesarean delivery for failure to progress [17]. Currently, there are two PGE2 preparations approved by the FDA for cervical ripening, a cervical gel and a vaginal insert. Because there appears to be no difference in clinical outcomes when comparing intravaginal or intracervical PGE2 preparations, and for ease of administration and patient satisfaction, vaginal administration is recommended [7]. One preparation, Prepidil (Upjohn Pharmaceuticals, Kalamazoo, Michigan), contains 0.5 mg of dinoprostone in 2.5 ml of gel for intracervical administration. The gel must be refrigerated and thawed prior to insertion into the endocervix [18]. The dose can be repeated in 6 -- 12 h if there is inadequate cervical change and minimal uterine activity following the first dose. The manufacturer recommends that the maximum cumulative dose of dinoprostone not exceed 1.5 mg (three doses) within a 24 h period [18]. Oxytocin should not be initiated until 6 -- 12 h after the last dose because of the potential for tachysystole with concurrent administration. Another formulation, Cervidil (Forest Pharmaceuticals, St. Louis, Missouri), is a vaginal insert containing 10 mg of dinoprostone in a timed-release formulation. The vaginal insert administers the medication at 0.3 mg/h and may be left in place for up to 12 h. An advantage of the vaginal insert over the gel formulation is that the insert may be removed with the onset of active labor, with rupture of membranes or with the development of uterine overactivity. This abnormality of uterine contractions is defined as six or more contractions in 10 min for a total of 20 min with concurrent fetal heart rate tracing abnormalities. Per the manufacturer’s recommendations, oxytocin may be initiated 30 -- 60 min after removal of the insert. This formulation must be frozen but does not require thawing prior to vaginal insertion [18]. These two preparations are relatively expensive, require refrigerated storage and become unstable at room


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temperature. Although not approved by the FDA for cervical ripening, there are a variety of other PGE2 compounds such as suppositories available in the United States and tablets available in Europe. Also, pharmacists may prepare their own formulations of PGE2 gel by thawing and re-suspending 20 mg PGE2 suppositories in small amounts of methylcellulose gel. Prostaglandin E1 Misoprostol is a synthetic prostaglandin E1 analog available as 100 and 200 mcg tablets. The current FDA-approved use for misoprostol is for the treatment and prevention of peptic ulcer disease related to chronic nonsteroidal anti-inflammatory use. Misoprostol is considered a safe and effective ‘off-label’ use for cervical ripening [19]. Due to its wide-ranging application in the practice of obstetrics and gynecology, it is on the World Health Organization Model List of Essential Medicines. It is inexpensive and is stable at room temperature. The route of administration includes both oral and vaginal with few systemic side effects. Although not scored, the tablets are usually divided to provide 25 or 50 mcg doses. Multiple studies suggest that misoprostol tablets placed vaginally are either superior to or equivalent in efficacy compared with intracervical PGE2 gel [20]. A meta-analysis of 70 trials revealed the following points regarding the use of misoprostol compared with other methods of cervical ripening and labor induction [21]. Misoprostol improved cervical ripening compared with placebo and was associated with a reduced failure to achieve vaginal delivery within 24 h (RR 0.36; 95% CI 0.19 -- 0.68). Compared with other vaginal prostaglandins for labor induction, vaginal misoprostol was more effective in achieving vaginal delivery within 24 h (RR 0.80; 95% CI 0.73 -- 0.87). Compared with vaginal or intracervical PGE2, oxytocin augmentation was also less common with misoprostol (RR 0.65; 95% CI 0.57 -- 0.73). In this study, uterine tachysystole with fetal heart rate changes (RR 2.04; 95% CI 1.49 -- 2.80) and meconium-stained amniotic fluid (RR 1.42; 95% CI 1.11 -- 1.81) were more common. Although the American College of Obstetricians and Gynecologists (ACOG), based on its review of the existing evidence, recommends 25 mcg dosing every 3 -- 6 h with vaginally applied misoprostol, the optimal dose and timing interval is not known [19]. A meta-analysis comparing 25 mcg with 50 mcg dosing reported that 50 mcg dosing resulted in a higher rate of vaginal delivery within 24 h with higher rates of uterine tachysystole and meconium passage but without compromising in neonatal outcomes. A statistically significant difference in fetal acidosis defined as an umbilical arterial pH of < 7.16 was found in infants of mothers given 50 mcg of intravaginal misoprostol every 3 h compared with those born to mothers given 25 mcg every 3 h [22]. A misoprostol vaginal insert (MVI) containing a controlled release, retrievable polymer chip for gradual delivery of 200 µg over 24 h into the vagina is available in some countries in Western Europe but is currently not available in the US [23,24]. The 200 mcg is released at a mean rate


2.3

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of ~ 7 mcg/h while the insert remains in place, allowing a constant dosing to occur over a 24-h period with the benefit of rapid and easy removal if needed. Oral misoprostol for cervical ripening has also been studied. This method of administration offers more patient comfort, satisfaction and convenience. Studies have compared lower oral doses of misoprostol such as 50 mcg given every 3 -- 6 h and compared them to similar vaginal misoprostol dosing regimens such as 25 -- 50 mcg given every 3 -- 6 h. Although this oral regimen does not appear to be more effective than vaginal administration for achieving vaginal delivery or affecting cesarean rates, it may be associated with less uterine overactivity. There is a dose--response relationship seen between the dosage of oral misoprostol and rate of tachysystole. With the 25 and 50 mcg dosages, there is a lower tachysystole rate while it is higher in those given 200 mcg [25]. Some investigators have described titrating oral misoprostol to its desired effect [26]. This method achieves vaginal delivery rates similar to vaginally administered misoprostol with less tachysystole. Low doses of oral misoprostol were achieved by making a solution (e.g., dissolving a 200 mcg tablet in 200 ml tap water). In a Cochrane review of 76 randomized controlled trials (14,412 women) the authors found that oral misoprostol appeared to be at least as effective as current methods of induction [27]. In 12 trials (3859 women) comparing oral misoprostol with vaginal dinoprostone, women given oral misoprostol were less likely to need cesarean delivery (21% compared with 26% of women). The 37 trials (6417 women) that compared oral and vaginal misoprostol reported similar effectiveness. Nine trials (1282 women) showed that oral misoprostol was equivalent to intravenous oxytocin, but resulted in significantly less cesarean births [27]. Although they found a higher rate of meconium staining of the amniotic fluid in the oral misoprostol group, there were fewer babies in the oral group born with a low Apgar score and there was a decrease in postpartum hemorrhage. This study found that oral misoprostol is effective at achieving vaginal birth, more effective than placebo, as effective as vaginal misoprostol and results in fewer cesarean sections than vaginal dinoprostone or oxytocin. Given the concern for safety, the evidence supports the use of oral regimens [27]. More data are needed to determine the optimal dosing of oral misoprostol for induction. Two systematic reviews suggested misoprostol doses of 20 -- 25 mcg orally at 2-h intervals [27,28]. Other modes of administration include buccal and sublingual. They are believed to have a similar bioavailability to that achieved with vaginal administration. In a randomized controlled trial including 250 women admitted for labor induction, 50 mcg of sublingual misoprostol was compared to 100 mcg of orally administered misoprostol given every 4 h to a maximum of five doses. Sublingual misoprostol appeared to have the same efficacy as oral misoprostol to achieve vaginal delivery within 24 h with no increase in uterine tachysystole. The 100 mcg oral dose of misoprostol had




higher rates of uterine overactivity than 25 mcg administered vaginally [28]. A randomized controlled trial including 152 women received either 200 mcg of buccal misoprostol every 6 h or 50 mcg of misoprostol administered vaginally every 6 h [29]. There was no statistically significant difference in time interval to vaginal delivery, the rate of vaginal delivery, or the rate of uterine tachysystole between the two groups. The buccal route was associated with a trend toward fewer cesarean sections than with the vaginal route. Based on only three small trials included in the Cochrane meta-analysis, sublingual misoprostol appears to be at least as effective as when the same dose is administered orally. However, there are inadequate data to comment on the relative complications and side effects. The standard dosage and regimens for buccal and sublingual routes have not been ascertained, and neither has been the safety, therefore they are not recommended for routine clinical use at present. 3.

Oxytocin

Oxytocin, a polypeptide hormone originating in the hypothalamus and secreted by the posterior lobe of the pituitary gland, is the most commonly used agent for induction [30]. Exogenous oxytocin administration produces periodic uterine contractions first demonstrable at ~ 20 weeks’ gestation, with increasing responsiveness with advancing gestational age due to an increase in myometrial oxytocin-binding sites. There is little change in myometrial sensitivity to this agent from 34 weeks to term; however, once labor begins, the uterine sensitivity to oxytocin increases rapidly. This physiologic mechanism makes oxytocin more effective in augmenting labor as opposed to for cervical ripening. Oxytocin is usually given intravenously. Because the polypeptide is degraded to small, inactive forms by gastrointestinal enzymes, it cannot be given by oral route. The plasma half-life is short, estimated at 3 -- 6 min, and steady-state concentrations are reached within 30 -- 40 min. Synthetic oxytocin is generally diluted by placing 10 units in 1000 ml of an isotonic solution, yielding an oxytocin concentration of 10 mU/ml and usually given by an infusion pump. According to a recent retrospective cohort study of 208,695 electronic medical records from across the United States, oxytocin was the most commonly used induction method, regardless of gestational age, parity or cervical ripeness [31]. Although oxytocin is an effective means of labor induction in women with a favorable cervix, it is less effective as a cervical ripening agent. Many randomized controlled trials comparing oxytocin with various prostaglandin formulations confirm this observation. Lyndrup et al. compared the efficacy of labor induction with vaginal PGE2 with continuous oxytocin infusion in 91 women with an unfavorable cervix [32]. They found PGE2 more efficacious for labor induction in 12 -- 24 h, with fewer women undelivered at

24 h. However, by allowing the inductions to proceed for 48 h, they found no difference in vaginal delivery rates in the two groups. In another study involving 200 women with an unfavorable cervix undergoing induction, vaginal prostaglandin E2 was compared with continuous oxytocin infusion [33]. This study found a shorter time interval to active labor, a significantly greater change in Bishop score and fewer failed inductions with PGE2 compared with oxytocin. In a Cochrane review of 110 trials including more than 11,000 women comparing oxytocin with any vaginal prostaglandin formulation for labor induction, oxytocin alone was associated with an increase in unsuccessful vaginal delivery within 24 h (52 vs 28%, RR 1.85, 95% CI 1.41 -- 2.43), with no difference in cesarean delivery [30]. When intracervical prostaglandins were compared with oxytocin alone for labor induction, oxytocin alone was associated with an increase in unsuccessful vaginal delivery within 24 h (51 vs 35%, RR 1.49, 95% CI 1.12 -- 1.99) and an increase in cesarean delivery (19 vs 13%, RR 1.42, 95% CI 1.11 -- 1.82). The optimal regimen for oxytocin administration is debatable, although success rates for varying protocols are similar. Protocols differ as to the initial dose, incremental time period and steady-state dose [2]. Although a maximum oxytocin dose has not been established, most protocols do not exceed 42 mU/min. In current obstetrics practice, oxytocin is most often used to augment labor in patients with inadequate uterine activity or to induce labor. Satin et al. studied the differences in outcomes when oxytocin was used to augment as opposed to induce labor [34]. These investigators prospectively studied 2788 consecutive women with singleton pregnancies. Indications for oxytocin stimulation were divided into augmentation (n = 1676) and induction (n = 1112). The low-dose regimen consisted of a starting dose of 1 mU/min with incremental increases of 1 mU/min at 20 min intervals until 8 mU/min, then 2 mU/min increases up to a maximum of 20 mU/min, and was used first in 1251 pregnancies. The high-dose regimen consisted of a starting dose of 6 mU/min with increases of 6 mU/min at 20 min intervals up to a maximum dose of 42 mU/min, and was used in the subsequent 1537 pregnancies. Labor augmentation was > 3 h shorter in the high-dose group compared with that of the low-dose group. High-dose augmentation resulted in fewer cesarean deliveries for labor dystocia and fewer failed inductions when compared with the low-dose regimen, although cesarean deliveries for fetal distress were performed more frequently. A literature review of randomized clinical trials of high versus low-dose oxytocin regimens published from 1966 to 2003 concluded high-dose oxytocin decreased the time from admission to vaginal delivery, but did not decrease the incidence of cesarean delivery compared with low-dose therapy. Only one double-blinded randomized trial has been published, and had the same findings [35]. High-dose regimens are associated with a higher rate of tachysystole than


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low-dose regimes, and in some studies this has resulted in a higher rate of cesarean delivery for fetal distress [35], but no significant difference in neonatal outcomes. The dose is typically increased until there is normal progression of labor, or strong contractions occurring at 2 -- 3-min intervals, or uterine activity reaches 200 -- 250 Montevideo units (the peak strength of contractions in mmHg measured by an internal monitor in 10 min). There are limited data on which to support maintenance of oxytocin infusion once an adequate contraction pattern has been achieved. The evidence-base includes a noninferiority study involving 138 subjects, two parallel groups were compared: continuation of oxytocin until delivery versus discontinuation of oxytocin at onset of active labor, they found that discontinuation prolongs labor [36]. The authors of a meta-analysis assessed the effect of discontinuation of oxytocin after active phase of labor is established on maternal and neonatal outcomes. Eight studies were included and involved 1232 subjects. They observed decreased cesarean delivery in subjects that discontinued oxytocin (OR 0.51, 95% CI 0.35, 0.74). Similarly, cases of non-reassuring fetal heart rates were fewer among women that did not receive oxytocin after the establishment of the active phase of labor (OR 0.63, 95% CI 0.41, 0.97) [37]. Some contraindications to use of oxytocin include significant cephalopelvic disproportion, fetal malpresentations that are undeliverable vaginally such as transverse lie, in obstetrical emergencies where surgical intervention is warranted, in uterine tachysystole with fetal distress, or hypersensitivity to the drug. Additionally, oxytocin would be contraindicated in situations where there is contraindication to induction of labor such as complete placenta or vasa previa, prior classical uterine incision, prior uterine rupture, or active genital herpes infection. Some experts have suggested use of a standardized protocol of oxytocin to minimize errors in administration [38--40]. In one of the studies Clark et al. implemented a checklist-based protocol, and found that in the checklist-managed group the maximum dose of oxytocin used to achieve delivery was significantly lower [40]. No differences were noted in the length of labor, total time of oxytocin administration, or rate of operative vaginal delivery or cesarean delivery. However, there is not one protocol that has demonstrated its superiority in efficacy and safety over another. There is new information emerging on the contribution of genetics on progress of labor. Recently, some investigators have shown that polymorphisms in the oxytocin receptor (OXTR) gene have been tied to variations in labor progress. OXTR genotype may join other genes as a candidate gene to contribute to a haplotype for labor progress. Although checklists and formulaic administration of oxytocin are important for safety reasons, the emerging information of pharmacogenomics and individual variations in the OXTR and gene may demonstrate that the one-regimen-fits-all approach may be flawed. 1662

In a study in 2012, Terwaki et al. aimed to identify the genetic factors that influence the first stage of labor. They found that women who were homozygous for ‘G’ at OXTR gene rs53576 transitioned to active labor later and thus had slower labor. Although there is no literature to date on the genetic variation in response to oxytocin, this information as well as other studies of OXTR gene polymorphisms may lead to advancements in the prescription of this commonly used adjunct in labor management [41]. 4.

Complications and side effects

Side effects of oxytocin Oxytocin is similar to antidiuretic hormone and can crossreact with vasopressor receptor. If high doses of oxytocin are used in large quantities of hypotonic solution for prolonged period of time excessive water retention and subsequent hyponatremia can occur [42,43]. This can be manifested as headache, nausea, vomiting, pain, lethargy and rarely irreversible neurologic injury. Some researchers have suggested that a 10-IU bolus of oxytocin given in the third stage of labor was not associated with adverse hemodynamic responses compared with oxytocin given as an infusion [44]. However, other investigators have found that an intravenous bolus was associated with ST depression [45]. Given the potential hemodynamic adverse consequences of boluses, this form of administration is not recommended. An epidemiological study suggested an association between induced or augmented labor with oxytocin and the risk of autism [46]. However, analysis of this data with diagnostic criteria for autism indicates that there was no increase in autism from baseline. Additionally, these authors were careful to point out the limitations of this study and to advise against changing clinical practice based on their results. Caution should be used in interpreting these findings; studies that test this association are limited. Given that oxytocin has been implicated in the etiology of autism, future studies are needed to investigate the effect of oxytocin on infant development. There is some information suggesting that autism may be associated with an aberrant methylation of OXTR [47]. 4.1

Side effects of prostaglandins Some potential side effects of prostaglandins include fever, chills, vomiting and diarrhea. The frequency of these depends on the route, dose and type of prostaglandin administered. These systemic side effects occur in up to 5% of cases and the treatment of maternal discomfort is supportive. 4.2

Side effects of both oxytocin and prostaglandins Tachysystole is the most frequently encountered complication of these agents. Contractions cause intermittent interruption in blood flow to the intervillous space, excessive activity of the uterus will result in fetal hypoxemia; this can be seen as 4.3



Table 4. Medical methods of cervical ripening.

than did placebo. However, further studies are required to confirm the role of mifepristone as a labor-inducing agent.

Medical methods


nonreassuring fetal heart rate. Tachysystole is most common when higher doses of oxytocin and prostaglandins are used [48--50] especially with the concurrent use of oxytocin and prostaglandins, thus this combination is not recommended. In one study, the frequency of tachysystole with both dinoprostone and oxytocin was 14 vs 5% with oxytocin alone [51]. If this complication is encountered removing the PGE2 vaginal insert will reverse the effects, however, if prostaglandin gel is applied unable to reverse the effect of the drug as rapidly. If oxytocin is being infused, it should be discontinued if the tachysystole is accompanied by fetal heart rate changes; this usually results in resolution of such uterine overactivity. 5.

Alternative methods

Researchers have evaluated several other pharmacological alternatives for cervical ripening and labor induction in term pregnancies (Table 4). Some of the advantages of these techniques include low cost, low risk of tachysystole, and few systemic side effects. All of these methods likely work, at least in part, by causing the release of prostaglandin F2-alpha from the decidua and adjacent membranes or prostaglandin E2 from the cervix. There is limited data on the safety and efficacy of glucocorticoids, castor oil, hyaluronidase, estrogen, relaxin, evening primrose oil, or herbal preparations for induction. Mifepristone The role of mifepristone (RU-486), a progesterone antagonist, in labor induction is not well established as it is for therapeutic abortion. A randomized double-blind trial using 200 mg of mifepristone daily for 2 days resulted in a shorter interval to the onset of labor, and less oxytocin was required for those achieving vaginal delivery [52,53]. In the mifepristone group, 58% went into spontaneous labor, compared with 22.6% in the placebo group. More recently, Elliot et al. [54] compared the effects of 50 and 200 mg of oral mifepristone with placebo on labor induction in primigravid women with unfavorable cervixes. At a dose of 200 mg, mifepristone resulted in a favorable cervix or spontaneous labor more often 5.1

Nitric oxide This agent acts by increase the expression of COX-2 in the cervix, thus improving cervical distensibility without causing uterine contractions. Some of the benefits include use in outpatient setting, low cost and ease of administration. Women reported headaches and palpitations as the most common side effects of intravaginal administration of isosorbide mononitrate. A trial comparing isosorbide mononitrate with placebo results in no difference in admission to delivery interval despite a clinical effect on cervical ripening [55]. More research is needed for isosorbide mononitrate use as a cervical ripening agent before it is accepted [56]. 5.2

Oxytocin Prostaglandins E2 (dinoprostone) E1 (misoprostol) Progesterone receptor antagonist (mifepristone) Nitric oxide Estrogen Relaxin Hyaluronic acid

Labor induction in women with prior cesarean

6.

In women with prior cesarean delivery, the risk of failed induction and uterine rupture are a major concern. The best agent for induction in this population has not been well established [57]. Most of the literature in this group is from retrospective studies and poor quality. Most of the available studies in outcome of induction in women with prior cesarean delivery use those undergoing induction and compare to undergoing spontaneous labor. These studies show that induction results in lower vaginal delivery rate. However, there is new information that those with prior cesarean in spontaneous labor are not the most appropriate control group. The new thought is to compare women with a similar group who are managed expectantly. In a recent study of over 12,000 women with singleton gestational age ‡ 39 weeks and one previous low transverse cesarean delivery, women undergoing induction of labor at 39 0/7 -- 39 3/7 weeks without an acute indication were more likely to delivery vaginally than those managed expectantly (73.8 vs 61.3%; OR 1.31, 95% CI 1.03 -- 1.67). This study supports the finding of relatively high probability of vaginal delivery with induction of labor after a previous cesarean [58]. Investigations have shed light on the question of labor induction for women attempting trials of labor after previous cesarean deliveries (TOLAC). While randomized trials currently do not exist, a large prospective investigation evaluated > 17,000 women attempting TOLAC [59]. The incidence of uterine rupture was 0.4% for those subjects who spontaneously labored versus 0.9% for those who received augmentation and 1.0% for subjects undergoing induction. The highest risk of rupture was in those patients who received a combination of prostaglandins and oxytocin. ACOG currently recommends the use of oxytocin in augmentation and induction of women undergoing a TOLAC, although caution is encouraged in women with unfavorable cervixes [60]. However, with the recent study


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showing that more women are likely to delivery vaginally if induced than expectantly managed, it may be that many of the historical studies used a control group of spontaneous labor, perhaps not the most appropriate for comparison. Risk of induction in women with prior cesarean delivery


6.1

In women with a prior cesarean delivery, uterine rupture is a concern. Several factors affect the risk of rupture in this group of women. In a nested case--control study, women induced with a favorable cervix had a similar risk of rupture as those who entered labor spontaneously (HR 1.5, 95% CI 0.97 -- 2.36), whereas an unfavorable cervix increased the risk of rupture (HR 4.09, 95% CI 1.82 -- 9.17 [61]. In addition, women with a prior vaginal delivery were at no increased risk of rupture with induction of labor (HR 0.78, 95% 0.42 -- 1.37). There are no large randomized trials and limited good quality studies on which to base a recommendation on use of prostaglandins alone or with other agents for cervical ripening or induction in TOLAC. Most data are from observational studies. The concern raised after a population-based cohort study found the rate of uterine rupture was significantly higher if labor was induced with prostaglandins as opposed to elective repeat [62]. Given the lack of data from large randomized trials and the paucity of good controlled studies, ACOG advises that misoprostol (prostaglandin E1) not be used for cervical ripening or labor induction in women in the third trimester with prior uterine incisions [60]. Oxytocin induction A systematic review of retrospectively collected data on women with prior cesarean births did not find that the rate of uterine scar disruption was significantly higher for women who received oxytocin for induction of labor compared to women who begin labor spontaneously (pooled OR 2.10, 95% CI 0.76 -- 5.78) [63]. However, this should be interpreted with caution as there is no data from large trials and there is a lack of good quality-controlled studies. Maximal oxytocin infusion rates administered were rarely reported, thus a cut-off above which the risk of uterine rupture is increased cannot be determined from the existing data. This is important because a dose--response relationship appears to exist between maximum oxytocin dose and uterine rupture [64,65]. Doses exceeding 20 mU/min increased the risk for uterine rupture at least fourfold, and should only be used in cases where the risk--benefit ratio favors their use. At this time, however, there are no high-quality data for the optimal maximum dose of oxytocin to be used during labor in women with prior cesarean deliveries. We suggest a cautious approach that adheres to the institution’s policy on use of oxytocin. A low-dose infusion typically consists of an initial dose between 0.5 and 2.0 mU/ml, with incremental increases of 1 -- 2 mU/ml at 15 -- 40 min intervals [66]. 6.2

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The largest prospective study to evaluate the risk of rupture by labor status in women with one or more cesarean deliveries (n = 17,898 trials of labor and 15,801 repeat cesarean deliveries) was not included in the pooled analysis cited above [59]. In this series, women who underwent induction with oxytocin alone had a significantly higher risk of uterine rupture than those in spontaneous labor (OR 3.01, 95% CI 1.66 -- 5.46). These data do not allow a definitive conclusion as to whether use of oxytocin for induction of labor in women attempting vaginal birth after a previous cesarean delivery is associated with an increased risk of uterine rupture. The decision to administer oxytocin to women with prior uterine surgery is influenced by some factors, including presence or absence of uterine activity, cervical ripeness, gestational age, past history of vaginal delivery and the indication for induction of labor. Given the lack of definitive data showing a high risk of rupture, oxytocin for induction of labor in TOLAC candidates is an appropriate option when done so for standard obstetrical indications. ACOG acknowledges that induction of labor may be necessary for women with previous cesarean deliveries [59]. They advise counseling patients as to the risks and benefits of oxytocin induction in women with prior cesarean and selecting patients who are most likely to give birth vaginally. Prostaglandins for induction As with oxytocin, there are no data from large randomized trials and limited data from good quality-controlled studies to base a recommendation on use of prostaglandins for induction of labor in TOLAC. Most data on use of prostaglandins in women with a prior cesarean delivery were derived from observational studies in which misoprostol was used. Reports on use of other prostaglandins are limited by their small size, the co-administration of oxytocin, and stratification by prior vaginal delivery. In 2001, Lydon-Rochelle et al. raised concern over the use of prostaglandins with a publication of a population-based cohort study that analyzed data from ~ 20,000 primiparous women who gave birth to live singleton infants by quently delivered a second singleton child [62]. The rates of uterine rupture in women with spontaneous labor and women in whom labor was induced without prostaglandins were not significantly different, but both were higher than the rate of uterine rupture for repeat cesarean delivery without labor. The highest risk of uterine rupture occurred in the prostaglandin-induced group. Compared to repeat cesarean, the relative risk of rupture with use of prostaglandins was RR 15.6 (95% CI 8.1 -- 30.0). Unfortunately, this study was performed using hospital discharge coding and therefore likely contained missing and inaccurate data regarding uterine ruptures or medications [67]. There are few studies that look at outcome for labors induced by prostaglandins alone. In one study prostaglandins alone were not associated with uterine rupture, but the 6.3




sequential use of prostaglandin and oxytocin was associated with uterine rupture (OR 3.07, 95% CI 0.98 -- 9.88) [68]. In another small study, the rate of rupture was similar for women who received a single daily application of prostaglandin E2, only oxytocin or combination of prostaglandin E2 with oxytocin [32]. A randomized trial on use of misoprostol for cervical ripening or labor induction in women with previous cesarean births was stopped early because of safety concerns [69]. This trial and some smaller studies have led to the conclusion that misoprostol may be associated with higher risk of uterine rupture than other prostaglandins and should not be used in women attempting TOLAC. ACOG advises against the use of misoprostol for cervical ripening or labor induction in the third trimester in women with prior uterine incision [60]. For women with unfavorable cervix who choose to be induced, risks and benefits of mechanical and pharmacologic options of cervical ripening, as well as labor induction and augmentation should be discussed. In general, misoprostol is not recommended in women with prior cesarean deliveries. Other prostaglandins may be considered after extensive counseling of the patient, however, sequential prostaglandin followed by oxytocin may increase risk of uterine rupture and should be avoided. 7.

Conclusion

In the last 20 years, the rate of induction of labor has increased significantly. In women with a low modified Bishop score a ripening process is recommended and prostaglandins for cervical ripening are useful. Regardless of the method employed, the patient should be counseled on the rationale for inducing labor, the risks of the method chosen and the alternatives available. Current practice is to limit elective induction to at or above 39 weeks gestational age. Although many of the used agents have been well studied, there continues to be a need for rapid, safe and effective agents for induction of labor. When the cervix is unfavorable prostaglandins can increase the probability of successful labor induction. Misoprostol and dinoprostone have similar safety profiles and outcomes. Oxytocin is considered an agent for induction of labor as opposed to cervical ripening. Prostaglandins increase the risk of uterine rupture in women with prior cesarean or uterine surgery. 8.

Expert opinion

Induction of labor is indicated when continuing the pregnancy is thought to be associated with greater maternal or fetal risk than delivery. Elective induction of labor before 39 weeks should be avoided as it has the potential to increase cesarean delivery and increase iatrogenic prematurity. For those undergoing induction of labor with a favorable cervix, oxytocin is the preferred agent, while prostaglandins are reserved for cervical ripening. Either dinoprostone or

misoprostol are superior to oxytocin alone for cervical ripening. Prostaglandins, especially misoprostol are contraindicated for cervical ripening in women with a prior uterine scare. ACOG advises that misoprostol not be used for cervical ripening or labor induction in women in the third trimester with prior uterine incisions [60]. The obstetric benefits and dangers of oxytocin in promoting uterine activity have long been appreciated. Over the years, recognition of the pharmacokinetics of oxytocin has led to modifications in how it is administered. Most agree that it should be used in the lowest possible dose that will provide a safe and efficacious progress of labor. In many hospitals across the US, there has been a push for improving the safety of oxytocin administration. As discussed earlier, implementing a checklist has been found to decrease the total amount of oxytocin administered. It is important to note that individual patient response to oxytocin may vary considerably and using a ‘one regimen for all’ approach is impractical and could be dangerous. Using these formulaic approaches to oxytocin administration discounts the varied responses women may have to the agent. The sensitivity of the uterus to oxytocin likely varies not only with gestational age but also from individual to individual. Although there is limited information on the pharmacogenomics of oxytocin as it relates to induction of labor, this is an emerging area of research. It is unclear if a high dose is better than the standard dose for labor induction and the answer in this debate may lie in what is yet to be discovered regarding the variations in OXTR gene that may make some women more susceptible to lower doses of the drug. There is, however, information on genetic variation within the oxytocin gene that is thought to explain variability in dopamine-related stress response. Love et al. studied concluded that the variability in the OXTR gene could explain the interindividual variability in dopaminergic responses to stress. While data emerging from animal models has illustrated interactions between the oxytocinergic and dopaminergic systems, this relationship is only beginning to be explored in humans [70]. Response to oxytocin and labor progress is likely another area that is affected by this genetic variation. Pharmacogenomic research related to oxytocin is likely to change our understanding of the drug and will allow tailormade dosing regimes possible. Similar to oxytocin, for many years, prostaglandins have also played a significant role in obstetrics. The available evidence for the use of the most optimal induction agent continues to expand with ongoing research studies. Although the use of misoprostol for induction of labor is off-label from FDA recommendations it continues to be used in the US and all over the world. Given the popularity of this agent there continue to be studies involving differing doses and methods of administration. The research in this field is aimed at finding an agent that combines the ideal route of administration, safety, and minimal dosing. The problem encountered with many of the available studies is that they


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are simply underpowered for the rare outcomes, yet there is sufficient evidence that these agents are effective in ripening the cervix and labor induction. As labor induction continues to be a common procedure, it is important to improve on available agents that are both safe and effective. The ideal agent is one that decreases the time to delivery without compromising maternal or fetal safety. Clinicians must balance the advantage of shortening the time to delivery with potential complications. The choice of agent for cervical ripening and induction depends on the clinician preference and the presence of contraindications. Caution should be taken with induction involving nulliparous and parous patients with previous cesarean delivery. This careful decision on which agent to use contributes to the successful and safe induction of labor. Because of the rapidly declining cost of obtaining genetic information, the application of pharmacogenomics studies Bibliography

of oxytocin and prostaglandins should translate into improvements in cervical ripening and labor induction. The impact of human genetic variation on drug response should ultimately result in administration of the safest and most efficacious dosing regimes of either of these induction agents on an individualized basis.

Declaration of interest DA Wing is a consultant for Ferring pharmaceuticals and has served as a PI for the clinical trials of misoprostol vaginal insert. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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Affiliation

Deborah A Wing† & Lili Sheibani † Author for correspondence University of California Irvine School of Medicine - Obstetrics & Gynecology, 101 The City Drive Building 56 800, Orange, CA 92868, USA Tel: +1 714 456 5967; Fax: +1 714 456 8383; E-mail: [email protected]

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