The ARRIVE Trial

/

Here’s the RoshReview Question of the Week!

A 32-year-old G1P0 woman at 39 weeks gestation is admitted for induction of labor. Her induction is started with vaginal misoprostol. Cervical ripening by this method is caused by the action of which of the following substances?

Check out the links above to see if you got this week’s question correct!

Actual Title: Labor Induction vs. Expectant Management in Low-Risk Nulliparous Women 

ARRIVE = A Randomized tRial of Induction Verses Expectant Management

Background: 

  • Who did the study? 

    • As many big studies in Ob/Gyn, it was done by the MFMU and the Eunice Kennedy Shriver National Institute of Child Health and Human Development 

    • First author was Dr. William Grobman from Northwestern University (now at Ohio State!)

    • The study was done in 41 hospitals participating in the MFMU 

  • Where was the study published? 

    • Published in NEJM in August 2018 

  • Why was the study done? 

    • In previous observational trials, there was worse perinatal outcomes when delivery before 39w0d was done without medical indication than when there was delivery at full term 

    • However, there was also thought that delivery after 41 weeks can lead to increased perinatal risks (ie. increasing risk of stillbirth) 

    • There was also thought that induction of labor should be avoided if there was no reason to induce  (ie. elective induction) because induction led to increased cesarean section and possible adverse maternal outcomes 

    • There was one previous study in the UK of 619 women 35 years and older that showed increased risk of c-section 

  • What was the objective? 

    • Test if elective induction at 39 weeks would result in lower risk of composite outcome of perinatal death or severe neonatal complication than expectant management among low-risk nulliparous women 

    • So key things: 

      • Purpose of the trial was to look at NEONATAL outcomes (not mom!) 

      • Second: the population they studied was low-risk nulliparous patients, not everyone! 

Methods

  • Who was in the study? 

    • As we said above, the study was done at 41 centers in the United States that were part of the MFMU (ie. most were large academic centers) 

    • Low-risk nulliparous patients were included in the study 

      • Low risk = no maternal or fetal indication to be delivered before 40w5d (ie. hypertensive disorders, fetal growth restriction etc) 

    • They had to be 34w0d-38w6d at the time of enrollment 

      • Patient had to be certain of LMP or if dating was done with ultrasound before 21w0d 

    • Had to have live, singleton fetus in vertex presentation with no contraindication to vaginal delivery and no C/S planned 

    • Patients who were consented to participate were assessed again between 38w0d and 38w6d to ensure they did not have new indication for delivery that would make them ineligible 

      • Patients who were in labor or who had PROM or bleeding were not eligible 

  • How was the study done?

    • Patients who were eligible were randomized in 1:1 ratio to either:

      • Labor induction - assigned to undergo induction of labor at 39w0d-39w4d 

      • Expectant management - had to forego elective induction before 40w5d, and had to have delivery initiated no later than 42w2d 

      • Of note: no specific induction protocol for either group 

    • Randomization was stratified to site 

    • Participants were then followed and data was abstracted from their chart

    • Patients also had interview to rate their labor pain on Likert Scale and also rate their experience with Labor Agentry Scale 

  • What outcomes did they look for?

    • Primary outcome: composite of perinatal death or severe neonatal complications

      • Consisted of one or more of many things (don’t have to list all): perinatal death, need for respiratory support within 72 hours after birth, Apgar of 3 or less at 5 min, HIE, seizure, infection, meconium aspiration syndrome, birth trauma, intracranial or subgaleal hemorrhage, or hypotension requiring vasopressor support 

    • Main secondary outcome: cesarean section 

      • Lots of other neonatal secondary outcomes and maternal secondary outcomes that we don’t need to list 

    • Other prespecified subgroups: race, age >/= 35 or <35, BMI, modified Bishop score at time of randomization of <5 vs. 5 or more 

Results 

  • Participants 

    • Recruited from March 2014 - August 2017

    • Out of 22,533 eligible women, 6106 (27%) consented and were randomized

      • 3062 in induction and 3044 to expectant management 

      • 63% had unfavorable Bishops (<5) 

      • Both groups were similar  

    • 3 in induction group and 7 in expectant management group were lost to follow-up 

    • 6% of induction group and 4.6% of expectant management group had protocol violation 

  • Outcomes 

    • Those in induction group had shorter median time from randomization to delivery than in expectant management group (7 vs. 12 days) 

    • Women in induction group underwent delivery at a significantly earlier median gestational age (39.3 wks IQR 39.1-39.6 vs. 40.0 IQR 39.3-40.7 weeks) 

    • Primary outcome 

      • Occured in 4.3% of neonates in induction group vs. 5.4% in the expectant management group (RR 0.8, 95% CI 0.64-1.00) 

      • Did not change after adjustment for previous pregnancy loss 

      • Neonates in induction group had shorter duration of respiratory support and total hospital stay 

        • Other secondary outcomes for neonates were the same 

    • Secondary outcomes for mom 

      • Cesarean delivery was 18.6% in IOL group vs. 22.2% in expectant management group (RR 0.84, 95% CI 0.76-0.93), p<0.001 

      • HTN disorders of pregnancy was 9.1% in IOL group vs 14.1% in expectant management group (RR 0.64, 95% CI 0.56-0.74), p<0.001 

      • Of note, interestingly there were also higher scores on LAS both immediately after and 4-8 weeks after delivery in the IOL group 

      • Median labor pain was also reported as less (8 vs. 9) in IOL group vs. expectant management group 

        • Of note though, for LAS and median labor pain score, the scores were statistically significant but overall difference was small 

      • Women in the IOL group spent more time on the labor and delivery unity but their postpartum stay was shorter 

      • Subgroup analyses showed no significant difference between group differences 

Discussion 

  • What happened after the study? 

    • Don’t know about your hospitals, but we have begun offering 39 week inductions to all nulliparous patients if they desire them 

      • ACOG also made a statement that reasonable to offer 39 week induction as long as we also take patient preference into consideration 

    • It is not “recommended” but offered 

    • Why? 

      • Some people take this to mean that by having IOL at 39 weeks that we are not only not changing neonatal outcomes, we are also decreasing CS rates and HTN disorders of pregnancy per this study 

      • They also would argue that there is no difference in LAS or pain overall (and if anything, patients feel more agentry and less pain) with IOL

    • What’s the other side of the story? 

      • In 2018, the ACNM responded to the ARRIVE Trial study results 

      • Discussed that potentially by increasing IOLs, we are also increasing the use of hospital resources (ie. staff, capacity of hospital beds, etc) 

      • Also stated that the study criteria were very strict (low risk, nulliparous), and discussed that we should be careful of broadening the outcomes and applying IOL to all patients 

      • Basically: concern that we will be offering IOL to everyone without knowing the actual implications 

    • More to the story 

      • There was a lot of concern about cost and hospital resources , so in 2020 Einerson et al came out with a study looking at cost 

      • Reviewed health-system cost of elective IOL at 39 weeks vs. expectant management in Utah hospitals 

        • No cost difference between expectant vs. IOL 

          • Maternal outpatient antenatal cost were 47% lower in the induction arm, and intrapartum and delivery costs were 16.9% higher 

  • How do we practice now? 

    • One study did look at rates of IOL pre and post ARRIVE 

      • Gilroy et al looked at rates of IOL in the country in patients who were nulliparous who started prenatal care by 12 weeks and delivered at 39 weeks or later  

      • There was a significant increase in IOL after ARRIVE 

        • 36.1% vs 30.2%, OR 1.36

        • Also more likely to deliver by 39w6d (42.8% vs. 39.9%) 

        • Less likely to have a CS (27.3% vs. 27.9%) ← but that is a much higher rate than 18% in ARRIVE 

Induction & Cervical Ripening Methods

/

Background / Context for Labor Induction

  • Labor induction is becoming all the more common!

    • CDC data shows that as of 2018, over 27% of labor in the USA is induced, representing an over 2-fold increase since 1990.

    • While the effects of the ARRIVE trial and similar studies are still playing out, it’s reasonable to think that rates of induction may only continue to rise.

  • Reasons for labor induction are varied and significant. ACOG CO 818 is a great resource to review many common reasons for induction prior to 39 weeks.

Bishop Scoring

  • The Bishop score was developed by Dr. Edward Bishop, published in the Green Journal in August 1964. The score used a combination of five physical examination criteria to predict the success of induction of labor:

    • Cervical dilation

    • Cervical effacement

    • Fetal station with respect to the ischial spines

    • The position of the cervix (posterior/mid/anterior)

    • The consistency of the cervix (firm/medium/soft)

      • The first three components, dilation, effacement, and station, are known as the “modified Bishop score.” 

    • In multiparous patients, a score of 6 or greater portends favorability with labor induction with oxytocin.

    • In nulliparous patients, a score of 8 or greater portends favorability.

      • If the score is less than these, the recommendation is to pursue cervical ripening prior to augmenting labor with oxytocin. 

dGPda7beJyh4I7crKo0yvA.png

Cervical Ripening: How the Cervix Works!

  • Obviously, cervical remodeling is a HUGE part of labor. It has to completely reshape to get the baby out! This takes the form of:

    • Collagen breakdown and rearrangement

    • Changes in the glycosaminoglycan and cytokine environment

    • Infiltration of leukocytes. 

  • These changes occur with numerous local signaling pathways which cause local release of prostaglandins at the level of the cervix, as well as ultimately the central hormonal signaling pathway to begin oxytocin release from the posterior pituitary gland.

Cervical Ripening

  • When the cervix isn’t ready to dilate, as is the case with labor induction or even with procedures for pregnancy termination or demise management such as D&E, these methods improve success and reduce complications.

  • Mechanical methods use a combination of local action to physically cause cervical dilation, as well as release local endogenous prostaglandins to promote cervical dilation. 

  • Pharmacologic methods use synthetic prostaglandins or oxytocin to cause a direct pharmacologic effect on the uterus/cervix. 

Mechanical Methods of Cervical Ripening

  • Foley Balloons

    • This is probably the most common and well-tolerated form of mechanical cervical ripening. 

    • In essence, a Foley balloon can be placed into the cervix behind the internal cervical os, and filled with 20-80cc of saline.

      • This “tricks” the cervix into believing there’s a well-engaged fetal head, which promotes pure mechanical dilation just from pressure of the balloon on the cervix, as well as localized prostaglandin release.

      • Some “double balloon” devices exist, which have a second balloon acting at the external os that may help promote cervical dilation/prostaglandin release further.

    • There are relatively few contraindications to the Foley ballon.

      • Unlike pharmacologic methods, it is not associated with tachysystole or fetal heart rate abnormalities. It can also be removed easily if there is an adverse reaction.

      • An absolute contraindication might be latex allergy, if you use a balloon that contains latex.

      • Relative contraindications include: 

        • Low-lying placenta, where the balloon contacting the placenta may cause vaginal bleeding.

        • Ruptured membranes: while data is mixed on this, there is thought that placing a balloon after membrane rupture may increase risk of chorioamnionitis.

        • Variable/unstable fetal lie: putting a balloon in the cervix may displace the fetal head, so have a low threshold to re-scan for presentation if you suspect the baby may have floated away!

  • Mechanical dilators: Laminaria and Dilapan

    • These mechanical dilators could also be considered, and in philosophy are very similar to Foley balloons in how they promote cervical ripening. 

      • Laminaria, a sterilized seaweed hygroscopic dilator, has fallen out of favor for term labor induction in most centers due to studies demonstrating increased risk of infection.

        • However, laminaria is still routinely used safely for cervical ripening prior to D&E procedures.

      • Dilapan (a synthetic hygroscopic dilator) has been examined in an RCT for labor induction and has been found to be safe and acceptable for patients

        • In most places, its expense is a barrier to use versus the Foley.

  • Amniotomy & Membrane Stripping

    • Membrane stripping is a technique in which an examiner uses the gloved finger to “stir” the membranes at the internal cervical os. This promotes localized prostaglandin release and can be used to help ripen the cervix in a “natural” and low risk way.

      • Complications of this can include bleeding, contractions, and inadvertent amniotomy, but overall it’s a low risk procedure that can be considered in most low-risk women at term.

    • Amniotomy, or as it’s better known on the labor floor -- AROM / artificial rupture of membranes -- is when an examiner breaks the amniotic sac using a tool such as a plastic hook. 

      • This allows for descent of the fetal head to the cervix (engagement) to promote physical cervical dilation, as well as likely some localized prostaglandin release.

        • Amniotomy alone is likely not appropriate for ripening/labor induction.

        • Most commonly, it is used in combination with pharmacologic methods, and it seems to be very effective in this context -- most studies demonstrate a shorter intervention-to-delivery time of combination medicine/amniotomy method versus only one of these alone.

      • The most feared complication of amniotomy is cord prolapse, in which the umbilical cord prolapses in front of the fetal head into the vagina. This requires emergent cesarean delivery, as further descent of the fetal head may compress the cord and cause asphyxia.

        • Rates of cord prolapse with amniotomy are low though, with rates in the literature ranging from 0.1 - 0.7%. 

      • Other complications/contraindications relate to infection, like chorioamnionitis, or fetal heart rate abnormalities related to fluid decrease/umbilical cord compression -- these are generally variable decelerations which can be corrected with amnioinfusion.

      • Given the break in the barrier between the fetus and the vaginal environment, early amniotomy is generally not recommended in patients with HIV or hepatitis B or C. 

Pharmacologic Methods

  • Misoprostol & Other Prostaglandins

    • Misoprostol, aka PGE1, is a synthetic prostaglandin and can be administered in a variety of doses and routes - for labor induction/ripening, typically bucally, orally, or vaginally. 

      • The majority of adverse outcomes noted in studies looking at term labor has been with doses over 25 mcg.

      • It is well tolerated, effective, and generally safe! However, some complications/risks:

        • Unlike oxytocin, which has a short half-life and is given IV, when misoprostol is given, it cannot be stopped or taken away (need to use a tocolytic)!

          • Institutions providing birth services should have protocols to monitor fetal heart rate patterns and for uterine tachysystole, and have strict time intervals for dosing for this reason. Misoprostol is potent and can definitely cause tachysystole and resulting fetal heart rate abnormalities.

        • Given the potency, misoprostol is absolutely contraindicated for patients who are induced and have a prior uterine scar (i.e., TOLAC), as there is an association with its use and uterine rupture (6% rupture rate in some studies!).

        • Misoprostol should also not be administered in the context of suspicious CTG/EFM, given its potency and inability to stop the medication quickly. 

        • Additional side effects of misoprostol can include high fevers and GI upset, particularly when administered via the oral or buccal routes. This is likely due to higher absorption/systemic concentration by these routes.

    • PGE2, available as a vaginal insert containing 10mg of dinoprostone, commercially known as Cervidil. A vaginal dinoprostone gel (Prostin) was formerly in common use in the USA, but now is more commonly used internationally. 

      • There is not a significant difference in how PGE2 works versus misoprostol for cervical ripening; however, one advantage is that the vaginal insert can be removed, and the half-life is shorter -- so unlike miso, the action can be stopped relatively easily. 

      • PGE2 is likewise contraindicated in the context of TOLAC due to presumed increased uterine rupture risk. 

  • Oxytocin

    • The OG! Oxytocin is the natural hormone from the posterior pituitary that promotes uterine contractions and labor. It can be used for cervical ripening as well in patients with unfavorable cervix, particularly for patients where prostaglandins may be contraindicated. 

      • For instance with TOLACs, there is a slightly higher risk of uterine rupture with oxytocin (~2%).

        • However this is dose-dependent and lower risk compared to prostaglandins; thus some institutions will allow for oxytocin induction of TOLACs. 

      • Institutions have different protocols for “low-dose” and “high-dose” oxytocin drips; studies vary in their description of the efficacy of one over another.

    • Oxytocin has specific uterine receptors, which promote intracellular calcium release in uterine muscle and also localized prostaglandin production. It has a positive feedback mechanism with the posterior pituitary during parturition, thus more oxytocin is produced/released over the course of childbirth. 

    • Complications are fairly few with synthetic oxytocin, since it is so similar to our biologic form; however:

      • As a posterior pituitary hormone, oxytocin has similar chemical structure to anti-diuretic hormone (ADH). Thus, in large doses (particularly if infused fast and not on an IV pump), oxytocin can lead to fatal water intoxication / hyponatremia. It should always be run on a pump by specifically-trained nursing personnel! 

  • Nipple stimulation is a way to cause endogenous oxytocin release, and may be favored by some patients for home “induction start” or cervical ripening.

    • It has only been studied in low-risk pregnancies, and generally seems to work better in patients with a favorable Bishop score already.

    • Nipple stimulation has also been associated with an increased trend in perinatal death, so ACOG does not recommend its use in an unmonitored setting until there is further study. 

Which method is best?

  • That’s the million dollar question!

  • You can likely find literature to support your position.

    •  Trials comparing labor induction methods are highly variable in their populations and outcome measures. 

      • Even in outcome measures, what’s most valuable? C-section rate? Time from induction to delivery? Length of oxytocin use? Rates of infection or other complications? The literature is full of examples that have used each and every one of these, so comparisons are hard to make! 

  • There are some likely general conclusions to take away:

    • Combination of mechanical and pharmacologic methods are likely faster to achieve delivery than mechanical methods alone. 

    • If you’re concerned about fetal status or uterine tachysystole, misoprostol is probably not the best choice.

    • The patient in front of you is going to dictate what is best -- the indication for induction, the varying factors of the patient’s medical and pregnancy history, and your institution’s experience and personnel are all paramount to making induction successful!