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

Induction of labor in older mothers does not hike the Caesarean section rate! The 35/39 Trial.

Since last 30 years, we have seen a trend of increasing number of women delaying childbirth till later in life, especially in industrialized nation . In a span of 10 years, births to women 35 years and older increased from 12% to 20% in UK.

Women 35 years and  older are at increased risk of antepartum, intrapartum and postnatal complications  like hypertensive disease, gestational diabetes mellitus, placenta previa, and placental abruption and perinatal deaths. They are also at risk of delivering macrosomic or low birth weight infants.

The rate of obstetrical intervention and caesearean deliveries also rises with maternal age, being 38% in nulliparous women over 35 and nearly 50% in those over 40 years of age.

According to Smith GCS et al the gestational week of delivery associated with the lowest cumulative risk of perinatal death was 38 weeks' gestation and the risk of death increased more sharply among primigravid women after 38 weeks' gestation because of a greater risk of antepartum stillbirth.

Currently, in the absence of maternal and fetal complication, routine induction is available to all women in U.K at 41-42 weeks when the risk of still birth is 2-3/1000 live births. However, based on many observational studies, it is a general consensus among obstetrician that induction leads to increased rate of caesarean deliveries and increased perinatal complications.

Trials of induction of labour at term are mostly in women with complications like hypertension, prelabor rupture of membranes, fetal growth restriction, diabetes, or fetal macrosomia. Only few trials involving women with no complications are found in literature, but lack power and are in 1970s. Trials of induction of labour due to advanced maternal age are lacking 

This 35/39 trial was designed to test the hypothesis that induction of labour at 39 weeks in older nulliparous women reduces the risk of operative delivery. The results of the trial was published in March 3, 2016 issue of New England Journal of medicine.

The investigators performed a multicenter, randomized, controlled trial to compare the rate of cesarean section between  women who were induced at 39 weeks and 0 days – 39 weeks and 6 days ( n= 304) with  those who were managed expectantly(n=314). Inclusion criteria were nulliparity, age 35 years or older and carrying a single fetus in cephalic presentation.

The primary outcome was cesarean section and the secondary outcome being other form of vaginal deliveries, onset of labour, augmentation of labour , intrapartum , postpartum and neonatal complications.

The induction of labour was done according to the protocols of the units, but most used prostaglandin ripening followed, if necessary, by amniotomy and oxytocin infusion.

It was seen that there was no significant difference in the rate of cesarean sections between the induction group (98 of 304 women [32%]) vs. (103 of 314 women [33%]) in the expectant group. Also a total of 115 of 304 women (38%) in the induction group delivered vaginally as compared with 104 of 314 women (33%) in the expectant-management group.

The results were also comparable across different maternal age group according to a sub group analysis.

The authors acknowledge the limitations of the trials "the results may not be generalizable to older multiparous women and may not apply to all nulliparous pregnant women who are 35 years of age or older."

The authors further say that “Our trial did not address whether induction of labor at 39 weeks of gestation can prevent stillbirths. It does, however, provide support for the safety of performing a larger trial to test the effects of induction on stillbirth and uncommon adverse neonatal outcomes in women 35 years of age or older, although such a trial would need to be extremely large.”

The journal article was also accompanied by an editorial by William A. Grobman, M.D, from the Northwestern University Feinberg School of Medicine in Chicago, Illinois,  he emphasized that “it would be premature to alter recommendations regarding the timing of delivery in uncomplicated pregnancies. Although the study did not show evidence of harm from induction at 39 weeks of gestation, it also did not show evidence of benefit, and one could argue that medical interventions in general, and intervention in the natural progress of gestation specifically, should be performed only when benefit has been shown.”

He also stressed that the study lacked sufficient power to analyze differences in perinatal outcomes, whether labor induction at 39 weeks of gestation affects these outcomes remains unknown!

He further added “The trial makes an important contribution to medical knowledge. It is the largest trial of its type to be completed, and it suggests that a belief that guides decisions about the timing of delivery — namely, that induction of labor at term increases the risk of cesarean delivery — may not be true after all.”

In summary,the authors concluded “ in women of advanced maternal age, induction of labor at 39 weeks of gestation, as compared with expectant management, had no significant effect on the rate of cesarean section and was not associated with adverse short-term effects on maternal or neonatal outcomes.”

Currently Dr. Groban is the principal investigator for a larger trial to test the effects of induction on stillbirth and uncommon adverse neonatal outcomes. The trial is currently under way within the Maternal–Fetal Medicine Units Network of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. This trial, which has a targeted enrollment of 6000 women, is designed to identify differences in perinatal outcomes among nulliparous women with uncomplicated singleton pregnancies who are randomly assigned to induction between 39 weeks 0 days and 39 weeks 4 days of gestation or to expectant management.

References:

Walker KF, Bugg GJ, Macpherson M, et al. Randomized trial of labor induction in women 35 years of age or older. N Engl J Med 2016;374:813-822

Smith GCS. Life-table analysis of the risk of perinatal death at term and post term in singleton pregnancies. Am J Obstet Gynecol 2001;184:489-496

The dilemma of cervical ripening --Should it be oral or vaginal; should it be misoprostol or dinoprostone? A systemic review and network meta-analysis.

Induction of labor is considered  when the benefit of the procedure is surpasses the benefit of continuation of pregnancy. The rate of induction of singleton pregnancies in US in 2012 was 23.3%, almost more than double a decade ago. 

A primed and favorable cervix is a prerequisite for successful induction of labour.

Numerous methods are in use for cervical ripening to induce labour, that includes Foley’s catheter( Mechanical Method) to pharmacological methods including  the use of prostaglandins, oxytocin, and mifepristone.  Prostaglandin E₂, also known as dinoprostone, is the only prostaglandin that has been approved by the US Food and Drug Administration (FDA) for cervical ripening in labour induction.

Misoprostol, a prostaglandin E₁ analogue is often used as an off-label drug for inducing labour. Its use is fraught with many complications from uterine hyper stimulation, rupture and adverse FHR.

Many studies and reviews comparing the safety and efficacy of different methods have been conducted but the best agent and route is still unanswered.

The three most common agents widely in use are dinoprostone, Foley catheter and misoprostol (oral and vaginal). There are many RCTs comparing these different modalities but no large single trial has compared them all  head to head.

The study conducted by W Chen et al. is a systemic review and network meta-analysis of all the available RCTs comparing the five most commonly used methods,  published in the February issue of  BJOG: An International Journal of Obstetrics & Gynaecology .

The study aims at providing a comprehensive summary of the existing evidence to further inform clinical practice and aid in the design of future trials.

Network meta-analysis, in the context of a systematic review, is a meta-analysis in which multiple treatments (that is, three or more) are being compared using both direct comparisons of interventions within randomized controlled trials and indirect comparisons across trials based on a common comparator.

The selection criteria was including all the (RCTs) of cervical ripening during the induction of labour, evaluating rates of failure to achieve vaginal delivery within 24 hours, incidence of uterine hyperstimulation with fetal heart rate (FHR) changes, and rates of caesarean section. Studies including women with prelabour rupture of membranes were excluded.

Trials were excluded if they included the following cases: women with pregnancies less than  28 weeks of gestational age; non-cephalic presentations; multiple pregnancies; and women with previous caesarean sections, combination interventions, non-relevant outlook and conference papers, posters  and abstracts.

A total of 96 RCTs met the selection criteria resulting it a total of 17387 study subjects.

The interventions included in this review were Foley catheter, vaginal misoprostol, oral misoprostol, vaginal dinoprostone, and intracervical dinoprostone.

The primary outcome chosen for network metaanalysis were vaginal delivery not achieved in 24 hours; uterine hyperstimulation with FHR changes; and caesarean section.

The meta-analysis compared five different modalities of cervical ripening for induction of labour. It was seen that:

The rank probabilities of reducing the number of vaginal delivery not achieved in 24 hours according to different interventions from best to worst are vaginal misoprostol (100%), vaginal dinoprostone (95%), Foley catheter (59%), oral misoprostol and intracervical dinoprostone

The rank probabilities of not causing hyper stimulation with FHR changes from best to worst are Foleys catheter (90%), intracervical dinoprostone, oral misoprostol, vaginal dinoprostone, and vaginal misoprostol (99%).

The rank probabilities of different intervention in decreasing the rate of caesarean sections, from best to worst are oral misoprostol (83%), vaginal misoprostol (80%), vaginal dinoprostone, intracervical dinoprostone and Foley’s catheter.

Thus it was seen that although vaginal misoprostol was the most effective intervention for achieving vaginal delivery within 24 hours, but it came at the cost of highest rate of uterine hyperstimulation with FHR changes. Vaginal dinoprostone was second best vaginal delivery withi 24 hours.

Foley catheter was found to be the least likely to cause hyperstimulation, but is worse than both vaginal misoprostol and vaginal dinoprostone in achieving vaginal delivery within 24 hours.

Compared to Vaginal misoprostol, oral misoprostol had lesser incidences of uterine hyperstimulation but at the expense of slightly decreased number of vaginal deliveries in 24 hours, but this difference was not statistically significant.

In most countries misoprostol is not legalized to be used for induction of labor, because of the concerns of hyperstimulation. The study shows that oral misoprostol is safe in comparison to vaginal misoprostol and it also performed better than vaginal dinoprostone.The other advantage of misoprostol is it is effective, cheap, does not requires cold storage; the dose can be measured and precise as compared to vaginal route. It is the first drug of choice in developing countries.

Foley catheter has similar effect as oral misoprostol in achieving vaginal delivery.  It is inferior to prostaglandins in decreasing the C section rates but superior to use of Oxytocin alone. It may be highly indicated in women with high risk of Fetal hypoxaemia like postdate pregnancies, sickle-cell disease, pre-eclampsia, or intrauterine growth restriction, due to it’s least effect on hyperstimulation . It also has advantages in terms of cost and storage conditions, less stringent monitoring of uterine contraction and no medical intervention until it is expelled in labor.The drawback is high rate of chorioamnionitis, but metaanalysis was not performed due to lack of reporting of this data in most trials.  

Conclusion:

 

Vaginal misoprostol followed by vaginal dinoprostone are most effective methods for induction of labor beyond 28 weeks of gestation with intact membranes, in terms of achieving vaginal delivery. However they are also associated with  uterine hyper stimulation and adverse FHR requiring close monitoring.

Mechanical stimulation by Foley catheter was least effective method for vaginal delivery, along with oral misoprostol and intracervical dinoprostone, but caused the least uterine hyper stimulation and adverse FHR.

Oral misoprostol was the best method in terms of overall safety, least likelihood of uterine hyperstimulation and adverse FHR and reducing the likelihood of cesarean section than vaginal misoprostol. 

References:

 

Chen W, Xue J, Peprah MK, Wen SW, Walker M, Gao Y, Tang Y. A systematic review and network meta-analysis comparing the use of Foley catheters, misoprostol, and dinoprostone for cervical ripening in the induction of labour. BJOG 2016;123:346–354.

Hemming, K. and Price, M. (2016), Is it oral or vaginal; and should it be misoprostol or dinoprostone for cervical ripening? How to interpret a network meta-analysis. BJOG: An International Journal of Obstetrics & Gynaecology, 123: 355. doi: 10.1111/1471-0528.13533

http://www.improvingmedicalstatistics.com/meta_network.htm