What is the most effective uterotonic agent to prevent PPH?

Postpartum hemorrhage (PPH) is responsible for more than 25% of all maternal death around the world and is the leading cause of maternal mortality in low resource settings. It affects 5% of all women during labor and leads to substantial morbidity because of compromised maternal blood volume. 

Use of uterotonics during the third stage of labor could avoid a majority of complications due to PPH. WHO recently published updated guidance on uterotonics for the prevention of PPH, after which the Cochrane Review published the results of a network meta‐analysis to identify the most effective uterotonic agent.

The network meta‐analysis included 196 trials involving 135,559 women, with the majority of women having vaginal births (71.5%, 140/196) in a hospital setting (95.4%, 187/196). 

The WHO recommendations and results of the Cochrane analysis suggest:

To effectively prevent PPH, only one of the following uterotonics should be used: Oxytocin, Carbetocin, Misoprostol, Ergometrine/methylergometrine, Oxytocin, and ergometrine fixed-dose combination.

Oxytocin (10 IU, IM/IV) is the standard recommended drug of choice for prevention of PPH in all cases. The drug has minimum side effects and is cost effective too. The main problem with Oxytocin is it requires refrigeration and rapidly loses its potency if stored at room temperature.

The use of carbetocin (100 µg, IM/IV) is also recommended for the prevention of PPH for all births if cost is not the limiting factor. It is also not readily available everywhere.

Misoprostol, injectable prostaglandins, and ergometrine have no additional benefits compared with oxytocin. Misoprostol causes more undesirable effects than oxytocin (including nausea, vomiting, shivering, fever, and diarrhea).

Combination therapy involving ergometrine plus oxytocin combination (Syntometrine ®), misoprostol plus oxytocin combination and carbetocin have the additional desirable effects compared with oxytocin and can be used if oxytocin is unavailable. However, there is always a risk of undesirable side effects as compared to oxytocin. Injectable prostaglandins (carboprost or sulprostone) are not recommended for the prevention of PPH.

Misoprostol and oxytocin are not available in fixed-dose combination and require different routes of administration so its use in routine clinical settings may not be very feasible as compared to using them alone.

If using ergometrine (alone or in combination), it is important to rule out hypertensive disorders and cardiovascular diseases.

In low resource settings and non-availability of skilled healthcare personnel, misoprostol (400 µg or 600 µg) can be administered orally by the community or lay health workers.

WHO recommendations Uterotonics for the prevention of postpartum haemorrhage

Uterotonic agents for preventing postpartum haemorrhage: a network meta‐analysis

Ob/Gyn Updated Facebook page

  

Dates fruit consumption during the last few weeks of pregnancy facilitates cervical dilatation and spontaneous labor

It is said that Mary gave birth to Jesus under a palm tree and ate date fruits to ease her labor pains. Almost 2000 years later scientist and researchers are turning towards dates to find safer alternatives for induction and augmentation of labor.

A prospective study carried out at the Jordan University of Science and Technology from 2007 to 2008 and published in 2011 in the Journal of Obstetrics and Gynaecology documented that consumption of 6 dates fruits (Phoenix dactylifera) per day for 4 weeks before the estimated due date resulted in significantly higher mean cervical dilatation at admission, intact membranes, and spontaneous labor. Spontaneous labor occurred in 96% of those who consumed dates, compared with 79% of women in the non-date fruit consumers (p = 0.024)

Results of a randomized controlled trial published in Iranian Journal of Nursing and Midwifery Research reports that consuming dates in late pregnancy shortens the labor significantly and eliminates the need of labor augmentation by oxytocin.

Another randomized trial published July 2017 in Journal of Obstetrics and Gynecology supports the findings of earlier studies and states that “dates consumption in late pregnancy is a safe supplement to be considered as it reduced the need for labor intervention without any adverse effect on the mother and child.”

Here is a very informative YouTube video about dates as the best food during late pregnancy by Dr. Michael Greger, M.D., FACLM. He is a physician, author, and internationally recognized speaker on many important public health issues and believes that food is medicine. Dr. Greger is the founder of the non-profit, science-based website NutritionFacts.org.

Abstract: Iranian Journal of Nursing and Midwifery Research
Abstract: Journal of Obstetrics and Gynaecology
Abstract: Journal of Obstetrics and Gynecology

What is the best approach for labor induction in a multiparous patient?

Simultaneous administration of oxytocin along with cervical ripening with balloon catheter minimized the time to vaginal delivery and increased the rate of delivery within 24 hours in multiparous patients with an unfavorable cervix. This has significant benefits regarding patient care and satisfaction reports the results of a randomized control trial published in September issue of the American Journal of Obstetrics and Gynecology.

The best method of induction of labor in a multiparous patient is debatable because of a paucity of data. Results available from the only previous RCT comparing the simultaneous vs. sequential use of balloon catheter and oxytocin found no difference in median time to delivery between the two groups (FIAT-M Trial).

In this RCT involving 180 patients, Bauer et al. sought to determine whether the simultaneous vs. sequential use of balloon catheter and oxytocin helps decrease the time to delivery in multiparous patients who present with an unfavorable cervix.

The study recruited multiparous women ≥18 years with prior vaginal delivery who needed induction of labor and presented with a non-anomalous, singleton fetus in cephalic presentation with intact membranes with cervical dilatation ≤2 cm on admission.

Women were randomized to receive either simultaneous (oxytocin with cervical ripening balloon) or sequential (oxytocin following cervical ripening balloon expulsion) regimen.

Investigators looked at the time from induction to delivery as the primary outcome measure while the secondary measures of interest were time to cervical ripening balloon expulsion, induction-to-delivery interval, mode of delivery and adverse maternal or neonatal outcomes.

Women who simultaneously received balloon and oxytocin were more likely to deliver within 24 hours as compared to those in whom oxytocin was started after the balloon expulsion (87.8% vs. 73.3%; P=0.02). The average induction-to-delivery interval in the simultaneous group was 12.5 h vs. 16.3 h with greater cervical dilatation when the balloon was expelled.

Both groups were comparable regarding mode of delivery, chorioamnionitis, or adverse maternal or neonatal outcomes.

The authors concluded that “The simultaneous use of oxytocin with cervical ripening balloon should be incorporated into the management for multiparous women who require cervical ripening while undergoing induction of labor.”

Presented as a poster at the 38th Annual Pregnancy Meeting of the Society for Maternal-Fetal Medicine, Dallas, TX, Jan. 29–Feb. 3, 2018.

Abstract
Ob/Gyn Updated Facebook page

Misoprostol as an add on to Oxytocin does not further reduce Postpartum hemorrhage in active management or treatment of PPH.

Clinical Pearls:

• Prophylactic misoprostol at a dose of 400 micrograms, added to oxytocin for active management of the third stage of labor, did not reduce the rate of postpartum hemorrhage, severe postpartum hemorrhage, or second-line procedures.
• Misoprostol will produce no further uterotonic effects after a prophylactic infusion of 10 international units of oxytocin.
• Findings of this trial do not support the use of misoprostol in addition to oxytocin for the prevention of postpartum hemorrhage. 
• Misoprostol may be useful in countries with poor health resources where facilities for refrigeration and skilled birth attendants are not freely available.
• Oxytocin should be used as prophylaxis and as the first line of treatment in active management of labor, especially in high income countries or countries with good healthcare facilities.

Postpartum hemorrhage remains the leading cause of maternal morbidity and mortality worldwide with a prevalence of 6% worldwide with Africa topping the list with 10.5% prevalence. It accounts for 30% of maternal deaths in Africa and Asia.[1]

Deaths due to PPH are preventable and considerable variation exist between developed and developing countries. Uterine Atony is the most common cause of PPH and active management of labor is promoted in developing countries to bring down the maternal mortality.

Oxytocin is the agent of choice because of high efficacy and low adverse effects.[2]

Misoprostol is a prostaglandin E1 analog often used off label in active management of labor because of cost, multiple route of administration and storage advantage.[3] An earlier large randomized multicentric trial compared the efficacy of oxytocin and misoprostol and showed that oxytocin was always the first agent of choice.[4]

After that another study suggested that they both could have synergist effect and reduce PPH further.

A large multicentric, double-blind, randomized, placebo-controlled trial recruited women across three French University hospitals from April 2010 to September 2013. The study subjects consist of women 18 years and older,36-42 weeks of pregnancy, in first stage of labor and under epidural anesthesia. The study was published on September 8 in Obstetrics& Gynecology.[5]

Women who met the inclusion criteria were randomized to receive two tablets of 200 micrograms misoprostol (ie, a total dose of 400 micrograms) or two tablets of placebo orally immediately after delivery of the newborn. Women in both the arm had active management of labor and received prophylactic intravenous injection of 10 international units’ oxytocin after delivery of the fetal anterior shoulder, early clamping of the umbilical cord, and controlled cord traction. 

If patient continued hemorrhaging after the treatment, they received treatment according to the standard protocol of PPH, but misoprostol was not repeated.   

There was not significant difference in both the groups in terms of primary outcome of postpartum hemorrhage greater than 500 mL within 2 hours of birth. (8.4% [68/806] in the misoprostol vs 8.3% [66/797] in the placebo group; P = .98).

After the analysis was performed on 1,721 patients enrolled in study, the trial was discontinued because the combination of misoprostol and oxytocin did nothing to reduce the PPH. Misoprostol when added to prophylactic Oxytocin did not further reduced Postpartum hemorrhage, but rather increased incidence of adverse events in mother. Misoprostol was associated with high rates of adverse effects like fever greater than 38°C (P<.001) and shivering (P<.001), diarrhea and vomiting.

"All in all, the findings of this trial do not support the use of misoprostol in addition to oxytocin for the prevention of postpartum hemorrhage," the authors write. "[D]espite misoprostol's ready availability, easy use, and utility for other pregnancy indications, oxytocin should remain the mainstay of prophylaxis of postpartum hemorrhage in high-income countries, and misoprostol should be used infrequently for this indication."

Misoprostol may be useful in countries with poor health resources where facilities for refrigeration and skilled birth attendants are not freely available.

---

[1] http://apps.who.int/rhl/archives/guideline_pphprevention_fawoleb/en/

[2] Westhoff G, Cotter AM, Tolosa JE. Prophylactic oxytocin for the third stage of labour to prevent postpartum haemorrhage

[3] Tunçalp Ö, Hofmeyr GJ, Gülmezoglu AM. Prostaglandins for preventing postpartum haemorrhage.

[4] Gülmezoglu AM, Villar J, Ngoc NT, Piaggio G, Carroli G, Adetoro L, et al. WHO multicentre randomised trial of misoprostol in the management of the third stage of labour. Lancet 2001;358:689–95.

[5] http://journals.lww.com/greenjournal/Fulltext/2016/10000/Active_Management_of_the_Third_Stage_of_Labor_With.17.aspx#P70

When to make the diagnosis of failed induction of labor after Oxytocin and Rupture of membranes?

Clinical Pearls:

• In Nulliparous women 12 hours of Oxytocin and Rupture of membranes is optimum before diagnosing an unsuccessful induction. The neonates of women who remained in latent phase past 12 hours have increased rate of NICU admissions.
• In Multiparous women 15 hours of Oxytocin and Rupture of membranes is optimum before diagnosing an unsuccessful induction. The neonates of women who remained in latent phase past 15 hours have increased rate of NICU admissions.
• The longer women remained in latent phase with Oxytocin and Rupture of Membranes, the risk of maternal and neonatal complication increased.

According to CDC between 1990 and 2011 the rate for labor induction have more than doubled rising from 9.5% to 23.2%. About 762,000 induction of labor were performed making it one of the most commonly performed obstetric procedure in US.[1]

There is no accepted definition of “failed induction of labor”, although the ACOG in its statement to bring down the cesarean section rate does quote “cesarean deliveries for failed induction of labor in the latent phase can be avoided by... requiring that oxytocin be administered for at least 12–18 hours after membrane rupture before deeming the induction a failure.”[2] However this recommendation by ACOG is based on limited studies with very small study population. [3] In the two studies on which the recommendation is based 17- 60% of the women had vaginal delivery after still being in latent phase after 12 hours. [4] [5]

A Joint statement issued by Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, and American College of Obstetricians and Gynecologists Workshop quotes that “The diagnosis of failed induction should only be made after an adequate attempt. Failed induction is defined as failure to generate regular (eg, every 3 minutes) contractions and cervical change after at least 24 hours of oxytocin administration with artificial membrane rupture if feasible.”[6] But, with the latent phase extending long, maternal and neonatal safety concerns are constantly raised.

A recent retrospective cohort study published in Journal of Obstetrics and Gynecology compared neonatal and maternal outcome in relation to oxytocin induction and rupture of membranes before the active phase of labor (Cervical dilatation > 6 cm). This large study used the data from Consortiumon Safe Labor (CSL) which is a consortium of 12 clinical institutions providing data on labor and newborn to create a perinatal database with more than 200,000 deliveries. The de-identified database is than used for secondary data analysis to answer several obstetrics questions.

The study data included 9,763 nulliparous and 8,379 multiparous women, carrying singleton term pregnancies, with unfavorable cervix. In all these women labor was induced at 2 cm dilatation or less to 6 cm dilatation with rupture of membrane.  6 cm was taken as cut-off because women entered into active phase of labor once they crossed the 6 cm dilatation. No cervical ripening agent was used in the women included in the study.

The clinical outcomes evaluated included vaginal delivery rates, maternal and neonatal morbidity including NICU admissions. Women were assessed at fixed intervals of 6, 9, 12, 15, and 18 hours post oxytocin and rupture of membranes in regards to cervical dilatation, contraction, vaginal delivery or cesarean delivery. Time was marked zero hour when oxytocin and rupture of membrane both were present.

Hypertensive disorders of pregnancy were the most common indication for induction of labor in nulliparous (21.8%) and multiparous patients (10.7%) followed by post-date pregnancy.

At the end of 12 hours most of the nulliparous women have entered the active phase or have delivered with only 6.5% still in the latent phase, while at 15 hours only .6% multiparous women were still in the latent phase.

Eventually, out of this group 36.6% of the nulliparous and 50.0% of multiparous women had vaginal birth.  Those nulliparous women who still were in latent phase of labor at the end of 12 or 15 hours had high rates of maternal and neonatal complications. For multiparous patients who were still laboring at the end of 15 hours had increased maternal complications but the rate of NICU admission were not statistically significant.

The longer the patients remained in the latent phase with rupture of membranes and oxytocin, chances of vaginal delivery decreased proportionately and maternal and neonatal complications increased as time progressed. Maternal complications include chorioamnionitis, PPH and endometritis while neonatal complications include neonatal sepsis and NICU admissions.

The large cohort of patient’s data drawn from diverse population powered the study sufficiently to study a variety of outcomes including neonatal morbidity and NICU admission associated with longer duration of oxytocin and rupture of membranes. It also increased the generalizability of the study. Labor management is not standardized across the hospitals which may have led to cesarean deliveries in latent phase without waiting longer.

It was seen that the longer women remained in latent phase with Oxytocin and Rupture of Membranes, the risk of maternal and neonatal complication increased. Because of the retrospective nature of the data, diagnosis of failed induction cannot be made but 12 hours of Oxytocin and rupture of membranes in Nulliparous and 15 hours in Multiparous patient is a reasonable cutoff, because neonatal morbidity rises after that.

---

[1] http://www.cdc.gov/nchs/fastats/obstetrical-procedures.htm

[2] Safe prevention of the primary cesarean delivery. Obstetric Care Consensus No. 1. American College of Obstetricians and Gynecologists. Obstet Gynecol 2014;123:693–711

[3] http://www.acog.org/Resources-And-Publications/Obstetric-Care-Consensus-Series/Safe-Prevention-of-the-Primary-Cesarean-Delivery

[4] Rouse DJ, Owen J, Hauth JC. Criteria for failed labor induction: prospective evaluation of a standard protocol. Obstet Gynecol 2000;96:671–7

[5] Simon CE, Grobman WA. When has an induction failed? Obstet Gynecol 2005;105:705–9

[6] http://journals.lww.com/greenjournal/Fulltext/2012/11000/Preventing_the_First_Cesarean_Delivery__Summary_of.26.aspx

When and How to Induce Labor in Nulliparous Women-- News from ACOG Annual Clinical and Scientific Meeting 2016.

Induction of labor is a major component of obstetrics practice with nearly one third of multiparous women   and 43 percent of nulliparous women undergoing induction.

Mary Catherine Tolcher, MD, MS, assistant professor of obstetrics, Mayo Clinic Rochester said “Induction of labor is likely to become more common with increasing maternal age, hypertensive disorders and obesity,” at Saturday afternoon Clinical Seminar at the conference.

The leading indications for induction of labor at the Mayo Clinic are late-term pregnancy, fetal indications, PROM, gestational hypertension and diabetes.

She further added that benefits of induced labor are clear, Induced labor avoids maternal and fetal risks of continuing pregnancy, avoids risks of late-term pregnancy, allows the timing of labor to be controlled in cases where delivery in a particular facility is appropriate and may be an alternative to cesarean delivery.

The risks are equally clear too, which means prolonged hospitalization before delivery, increased likelihood of more intrusive interventions, increased risk of postpartum hemorrhage and increased likelihood of cesarean delivery.

Answering the key question of whether induction increases the risks of cesarean section she said that it is like a lot of other things in medicine, and depends on your comparison group. 

Results based on retrospective cohort data show the following conclusions.

Depending upon studies the odds ratio for undergoing a cesarean delivery was somewhere between 1.9 and 3.5 when comparing spontaneous labor and induction. 

But compared to expectant management, induction does not seem to be associated with an increased risk of cesarean delivery. 

The first randomized control trial of induction vs expectant (ARRIVE TRIAL) management is currently recruiting participants and will be completing the data collection at the end of 2016.

Since the inception of induction of labor, many methods have been in use like mechanical ripening by Foleys catheter, pharmacological use of prostaglandins and oxytocin. These are either used alone or in combination with or without amniotomy.    

According to Dr. Tolcher, clinical trials have shown all of them to be effective. Cervical ripening is definitely more effective than oxytocin alone, while prostaglandins and Foleys catheter seems to have the same outcome.  Recent data reported at annual meeting of Society for Maternal-Fetal Medicine in 2016, concluded that time to delivery is shortened by using combination methods than using each of the method alone with no increase in cesarean section rates.

Amniotomy is also effective in augmenting the labor, but when early amniotomy (Cervix < 5 cm dilated) was compared to late amniotomy (Cervix > 5 cm dilated), the latter seemed more appropriate. Early amniotomy does results in shorter labor time but it comes with higher incidences of chorioamnionitis and increased fetal cord compression.

Dr. Tolcher also said that Mayo clinic has its own protocols for induction and the cases scheduled for induction in the coming week are reviewed in a staff meeting on Friday and Labor and Delivery nurse also has a significant say to put a stop to non-indicated cases.

Current indication for inductions include advanced maternal age, cholestasis, diabetes, fetal issues, hypertensive disorders, obesity, preterm premature rupture of membranes, prolonged pregnancy, prior stillbirth and unstable presentation. Depending on the indication, the pregnancy must be in week 37 and later.

Cervical ripening is the initial step, followed by oxytocin as needed and amniotomy at the discretion of physician. A failed induction is 24 hours of oxytocin or 18 hours of oxytocin plus rupture of membranes.

Before the decision for induction is taken, the physician should have a very good discussion with patient about the procedure, the expected time to delivery and slightly higher odds of having a cesarean delivery.

References:

http://www.acogdailynews.com/when-and-how-to-induce-labor-in-nulliparous-women/

http://www.acog.org/Womens-Health/Labor-Induction