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

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Misoprostol in combination with transcervical Foley catheter shortens the induction-delivery interval

Medical study notes

Cervical ripening using misoprostol in combination with Foley catheter accelerates the induction as compared to misoprostol alone reports the results of a randomized control trial published in forthcoming issue of Journal of Obstetrics and Gynecology.

The duration of labor was shortened on an average by 3 hours in the combined misoprostol-catheter group.

A total of 200 women from Roosevelt Hospital, New York, New York were recruited over a period of 10 months and randomized to receive either misoprostol plus Foley catheter or misoprostol alone for induction of labor (100 in each arm). Women were matched for gestational age, parity, BMI, Bishop score and reason for induction of labor.

The women in the misoprostol only group received 25mcg of misoprostol per vagina every 4hours per the standard hospital protocol. Once the cervix becomes favorable or if the patient is in active labor, or if there is no progress for 24 hours, misoprostol administration was discontinued.

Women in the combination group received vaginal misoprostol per standard protocol. In addition, a Foley bulb was inserted digitally or by direct visualization with the use of a sterile speculum. The Foley was inserted through the internal os and filled with 60cc of normal saline. The catheter was taped to the patient's inner thigh under gentle traction.

Inclusion criteria were singleton fetus, intact membranes, cephalic presentation, Bishop score 6 or less and gestational age 37 weeks or more.

Patients with previous history of uterine surgery, non-assuring fetal heart tracing, multiple fetuses, contraindication to vaginal delivery or ruptured membranes were excluded from study.

All patients were closely followed up for total time to delivery as well as time to active phase, time from active phase to delivery, cesarean delivery rate, uterine tachysystole, estimated blood loss, chorioamnionitis, cord pH, 5-minute Apgar score, and neonatal intensive care unit admission.

The combined group average induction-delivery interval was 15.00 (11.0–21.8) hours as compared to 19.00 (14.0–27.3) hours in misoprostol only group (P= .001).

There were no significant differences in both the groups in terms of rate of cesarean delivery, PPH, infection or neonatal outcome.

The authors concluded that misoprostol in combination with Foley catheter effectively shortens induction to delivery process.

Abstract

ClinicalTrials.gov Identifier: NCT02566005

Combination of labor induction agents almost halves the time to delivery.

The cascade of spontaneous events that sets the wheels of labor in motion has remained a mystery despite all the recent advances in the field of maternal and fetal medicine. Researchers hypothesize that it’s blend of physiology and magic that sets the ball rolling. Maternal and fetal signals both play a part in starting the process.

The history of labor induction dates to time of Hippocrates' when mammary stimulation and mechanical cervical dilatation was used to bring about uterine contraction.[1]

Induction of labor for singleton births has seen a slight decline from 23.8% in 2010 and 23.3% in 2012 after seeing a steady increase in past 20 years. [2]  This translate to 932,000 women undergoing induction of labor for various maternal and fetal indication.

Various mechanical and chemical methods singly or in combination have been in use since long. The choice of method depends on state of cervix, previous obstetric history, indication of induction and gestational age at induction. Foley’s balloon catheter, Prostaglandin E2 and misoprostol are common methods used for cervical ripening. Amniotomy and oxytocin are used when the cervix is already ripened.[3]

A recent paper published on November 03, 2016 in Journal of Obstetrics & Gynecology evaluated the effectiveness of the four most commonly used method. [4] The paper was also presented at the Pregnancy Meeting, the 2016 Annual Meeting of the Society for Maternal-Fetal Medicine (SMFM).

Dr. Lisa Levine, MD, University of Pennsylvania’s Perelman School of Medicine, Philadelphia, Pennsylvania, and colleagues said in their presentation “This randomized trial is one of the first of its kind to compare 4 different induction methods in a head-to-head trial. We found that combination induction methods resulted in delivery in half the amount of time as single agents with no difference in caesarean delivery rates.”

The study called as Foley or Misoprostol for the Management of Induction (FOR MOMI) trial was a 4-armed randomized trial conducted between May 2013 and June 2015. The study recruited 492 women with singleton full-term pregnancy (37 weeks of gestation or greater), vertex-presentation, with no contraindication to vaginal delivery, intact membranes, Bishop score 6 or less, and cervical dilation 2 cm or less. These women were assigned to receive either misoprostol alone; or Foley catheter alone; Foley catheter and Pitocin concurrently or misoprostol and cervical Foley catheter concurrently.

The primary outcome measured was reduction in time to delivery with a reduction of more than 4 hours considered significant. Numerous secondary outcomes like time to vaginal delivery, rate of caesarean deliveries, time in active labor, defined as cervical dilation of 5 cm or more, delivery within 12 or 24 hours, and maternal length of stay were also looked at.

The demographics and clinical characteristics of the study participants were quite similar with a mean age of 27 years, 72% being nullipara, mean gestational age at induction being 39 weeks with mean bishop score 3 and mean cervical dilatation 1.

The median time to delivery for nulliparous and multiparous women in various arms of the study are (P<.001):

misoprostol–Foley group       13.1 hours

oxytocin–Foley group            14.5 hours

misoprostol only                    17.6 hours

Foley-only group                   17.7 hours

When the data was adjusted for parity and only vaginal deliveries analyzed, women in the misoprostol-Foley group where twice as likely to deliver earlier (HR=1.92) with reference to misoprostol only or Foley-only group.

  

Women in the combination arms of the study also had the maximum chance of delivering in 24 hours. (88% of women in the misoprostol/Foley group and 84% in the oxytocin/Foley group).

Rates of cesarean section and other maternal morbidities like perineal lacerations, endometritis, wound infection and dehiscence, readmission or length of stay were comparable in all the groups. No significant difference was found in neonatal morbidities too.

The authors opined that “This study has significant clinical implications for obstetric care. The ability to shorten the length of time women spend in labor without increasing morbidity has large clinical and financial implications given the cost and known maternal–neonatal risks associated with both prolonged labor and cesarean delivery."

The only study limitation was lack of blinding, because women had to be examined for application of different methods in 4 study arms. Also, individual arm lacked the statistical power to compare the cesarean section, maternal and neonatal morbidities across different groups.

In all, the findings could help millions of women and shorten thousands of hours in labor across the world. It is estimated that nearly 20% or 932,000 women undergo induction of labor in USA. If combination method is used in all of them, then there would be more than 3 million fewer hours, or more than 125,000 fewer days that women spend in labor in the United States alone. 

This has huge financial and health care utilization implications.

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[1] www.glowm.com/section_view/heading/Induction%20of%20Labor/item/130

[2] http://www.cdc.gov/nchs/data/databriefs/db155.pdf

[3] https://sogc.org/wp-content/uploads/2013/08/September2013-CPG296-ENG-Online_REV-D.pdf

[4] http://journals.lww.com/greenjournal/Abstract/publishahead/Mechanical_and_Pharmacologic_Methods_of_Labor.98564.aspx

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.

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[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

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

 

Prior First Trimester Uterine evacuation augments the risk for preterm birth in subsequent pregnancies!

Many studies have shown that a history of evacuation in women is associated with increased risk of preterm birth in subsequent pregnancy as compared to women with  no such history. But, many studies have failed to prove a direct cause and effect relationship. Other studies have linked D&C as a cause of subsequent pre term birth (PTB), but no distinction was made between surgical and medical modality of evacuation.

2 systemic reviews and meta-analysis were recently published in 2 separate journals. The first was in January, 2016 issue of Human Reproduction published on behalf of The European Society of Human Reproduction and Embryology  and the second is still in press in the forthcoming issue of  American Journal of Obstetric and Gynecology.

The Primary source of this article is the systemic review and meta-analysis in the journal of Human Reproduction, although both the analysis has concluded that Prior surgical uterine evacuation is a risk factor for subsequent pre term birth (PTB).

This is the first systematic review and meta-analysis addressing the association between D&C and preterm birth.

Since no Randomized Control Trials (RCT) were available, only cohort and case–control studies were included. A total of 21 studies reporting on 1,853,017 women were included out of that 71,231 had a history of at least one D&C in the first trimester of pregnancy. In 66,003 women, D&C had been performed for termination of pregnancy.

The control group consisted of 1,781,786 women, out of which 24. 977 women had received a medical treatment for either miscarriage or termination of pregnancy, while 1189 had had a spontaneous miscarriage and the rest were without a history of miscarriage or termination of pregnancy.

The primary outcome was a preterm delivery subsequent to an H/O curettage. The outcome of PTB was divided into 3 categories <37 weeks, <32 weeks and <28 weeks. The study also investigated a dose –response relationship by comparing women with a history of multiple D&Cs to women without a history of D&C. Many other sub-group analysis comparing   women with a D&C for miscarriage or termination of pregnancy to women with medical treatment for miscarriage or termination of pregnancy on the risk of subsequent preterm birth <37 weeks were also performed. 

The important findings of the study were:

• It was seen that that women with a previous D&C, for miscarriage or termination of pregnancy in the first trimester, are at increased risk for preterm and especially very preterm birth, in comparison to women without a previous D&C procedure.
• The increase in risk was statistically significant when it was only run against women who had medical management of pregnancy.
• The risk of preterm birth increases with number of D&C performed, indicating a dose response relationship.
• Reasonably, these findings suggest that it is the surgical management, rather than the actual miscarriage or termination, is the deciding factor about the time of delivery in the following pregnancy.

The studies included had many limitations and bias, but the strict inclusion and exclusion criteria, sensitivity and robust analysis, multiple control groups, sub-group  analysis and including prospective cohort studies  helped to limit it to certain extent. 

The mechanism by which the surgical procedure increases the risk for preterm birth remains speculative. Multiple hypotheses have been put forward such as cervical incompetence. Another theory propose a damage to  the endometrial lining which might cause abnormal placentation in a later pregnancy, thus increasing the risk of placental abruption, pre-eclampsia, placenta praevia and intrauterine growth restriction.

It is also postulated that cervical damage might impair the anti-microbial defence mechanism thereby facilitating ascending microbial colonization, a known cause of preterm births.

The clinical implications of this study are:

Frequent follow up and increase obstetrical care for women with h/o D&C, including monitoring of early signs and symptoms of threatened preterm birth.

Avoiding unneeded D&C and going more for non-invasive management options when possible i.e. expectant management or medical management in case of miscarriage, and medical management in case of termination of pregnancy.

No data is yet available on the effect of cervical priming before the D&C and subsequent risk of preterm labor. 

References:

Wieringa-de Waard M, Vos J, Bonsel GJ, Bindels PJ, Ankum WM. Management of miscarriage: a randomized controlled trial of expectant management versus surgical evacuation. Hum Reprod 2002;17:2445–2450

M. Lemmers M, Verschoor MAC, Hooker AB, Opmeer BC, Limpens J., Huirne JAF, Ankum WM, Mol BWM. Dilatation and curettage increases the risk of subsequent preterm birth: a systematic review and meta-analysis. Hum. Reprod. (2016) 31 (1): 34-

http://www.ajog.org/article/S0002-9378%2815%2902596-X/abstract

History of induced abortion as a risk factor for preterm birth in European countries: results of the EUROPOP survey Hum. Reprod. (2004) 19 (3): 734-740 first published online January 29, 200

You JH, Chung TK. Expectant, medical or surgical treatment for spontaneous abortion in first trimester of pregnancy: a cost analysis. Hum Reprod 2005;20:2873–2878

Pregnancy loss managed by cervical dilatation and curettage increases the risk of spontaneous preterm birth Hum. Reprod. (2013) 28 (12): 3197-3206 first published online September 19, 2013 doi:10.1093/humrep/det332

Shah PS, Zao J. Induced termination of pregnancy and low birthweight and preterm birth: a systematic review and meta-analyses. BJOG 2009;116:1425–1442.