Transabdominal Cerclage

To follow along, we suggest reading SMFM Consult Series #65: Transabdominal Cerclage 

• What is the background to cerclages? 

• Preterm birth is still the leading cause of neonatal morbidity and mortality 

• Cervical insufficiency (inability of cervix to retain a pregnancy, characterized by painless cervical dilation usually in middle of second trimester) is an important cause of preterm birth 

• Diagnosis of cervical insufficiency: 

• History of one or more second-trimester losses after painless cervical dilation in absence of labor or abruption 

• Cervical cerclages are indicated for those with cervical insufficiency – most are done transvaginally 

• McDonald or Shirodkar method 

• Other indications = history of PTB <34 weeks, cervical length <25 mm before 24 weeks 

• Advanced cervical dilation before 24 weeks 

• Transabdominal cerclage (TAC) are also an option - first described by Benson and Durfee in 1965 

• Advantages: can be placed higher, in the cervicoisthmic junction, so may provide greater structural support  

• Avoids presence of foreign body in vagina, so may decrease risk of PPROM or IAI 

• Disadvantages: more morbid and more complicated surgery because need abdominal access and dissection, necessitates cesarean delivery 

• So when is a TAC indicated? 

• TACs are usually not offered as first line treatment for cervical insufficiency 

• Due to increased morbidity of placement and need for CS 

• Exception is for those where transvaginal cerclage would be very difficult to place 

• Ie. Those with history of multiple LEEPs or trachelectomy 

• More often, TAC is used for patients with unsuccessful transvaginal cerclage 

• Previous unsuccessful TV cerclage = spontaneous delivery before 28 weeks of gestation 

• TAC reduced risk of recurrent preterm birth compared with repeat transvaginal cerclage in patient with a previous delivery <33-34 weeks gestation 

• Multicentre Abdominal vs. Vaginal Randomized Intervention of Cerclage (MAVRIC) study 

• Randomized controlled trial 

• Compared use of a TAC, high vaginal cerclage, and low vaginal cerclage among patients with previous miscarriage or preterm birth between 14-28 weeks of gestation with transvaginal cerclage in situ in previous pregnancy 

• TACs were performed as an open procedure either before pregnancy or up to 14 weeks 

• Vaginal cerclages done between 10-16 weeks gestation 

• Findings: preterm birth rates <32 weeks were significantly lower with TAC compared with both low vaginal cerclage (8% vs. 33%%, RR 0.23, 95% CI 0.07-0.76), and high vaginal cerclage (8% vs. 38%, RR 0.2, 95% CI 0.06-0.64) 

• NNT to prevent 1 preterm birth when TAC was compared with low vaginal cerclage was 3.9, and compared with high vaginal cerclage was 3.2 

• How is a TAC placed?

  • We won’t go into full detail, since that’s a little beyond the scope of a podcast! 

• Open technique 

• Typically done via spinal or regional anesthesia 

• Pfannenstiel incision 

• Uterus is exteriorized and surgeon identifies and palpates the uterine vessels bilaterally 

• Uterine vessels are retracted laterally → create an avascular space between the uterus and the vessels in the broad ligament at the level of the internal os of the cervix 

• Non-absorbable thick braided 5mm suture (ie. Mersilene tape) guided through space with right-angle clamp 

• Suture is tied anteriorly or posteriorly and left in place 

• Minimally invasive technique 

• Many different techniques have been described, using both traditional laparoscopy and robotic surgery

• Most will use 3-port laparoscopic approach, some with fourth suprapubic assistant port 

• Some will use a uterine manipulator (usually done prior to pregnancy) 

• Can dissect the uterovesical and paravesical spaces and make a window in the broad ligament through which the suture is placed 

• Suture used can be same nonabsorbable thick braided 5-mm suture (Mersilene tape), and some places have described using mono-filament, non-braided polypropylene suture 

• Suture is tied anteriorly or posterior and left in-situ 

• Is laparoscopic or open better? 

• Studies show that laparoscopic TACs are associated with less risk of blood loss and shorter hospital stays 

• However, laparoscopic procedures take longer 

• Other studies show no difference in blood loss, operative time, or hospital stay between the two 

• Overall, similar rates of pregnancy and miscarriage rates after laparoscopic and open TAC placement 

• Many studies have also shown similar preterm birth rates <34 weeks with both approaches, but overall, no RCTs as of yet 

• Therefore, both laparoscopic and open TAC are acceptable 

• Should I tocolyze? 

• No evidence to suggest that tocolysis is helpful 

• Ideal time for placement 

• Can be placed before pregnancy or in the first trimester 

• However, if there is an indication for TAC after first trimester, placement up to 22 weeks can be considered 

• Management of a pregnancy after TAC? 

• Management antepartum 

• MFM consultation should be obtained before TAC placement is done 

• Can continue with MFM consultation if questions arise 

• Should we continue to measure transvaginal cervical lengths? 

• Several studies show that although cervical shortening after cerclage may increase the risk of preterm birth, cervical length does not directly correlate with outcomes 

• Rescue cerclage does not improve outcomes in the setting of a short cervix after cerclage 

• Therefore, SMFM does NOT recommend routine transvaginal cervical length screening for patients with TACs 

• Should we use progesterone? 

• In the MAVRIC trial, 27% of patients used progesterone (17% in TAC, 28% in high vaginal cerclage and 48% in low vaginal cerclage) 

• However, since this trial, the FDA has withdrawn approval of IM progesterone 

• Benefit of adding vaginal progesterone to treatment regimen of patients with cerclage is unknown

• SMFM recommend having a risk-benefit discussion of supplemental vaginal progesterone be undertaken and shared decision making take place

• What we did at Penn: If they were already on progesterone, we didn’t take it away. If they weren’t on progesterone already, we don’t recommend 

• What did they do in UW? - same

• What to do in setting of pregnancy loss 

• If needed, D&E can be done with a TAC in situ 

• Large retrospective study of 142 patients with TAC found that 14 patients underwent 19 D&E procedures, with 15 of those occurring at <12 weeks 

• Osmotic dilators and standard surgical techniques were used 

• No major complications noted 

• SMFM recommends that pregnancy loss be managed with D&C or D&E with TAC in situ or with obstetrical management after laparoscopic removal of TAC depending on gestational age 

• Timing of delivery 

• Cesarean delivery is recommended, as TACs are not removed 

• There have been case reports of uterine dehiscence or uterine rupture when patients with TAC labor 

• Therefore, recommendation is delivery timing similar to previous myomectomy (37w0d-39w0d) 

• Leave TAC in situ for future pregnancies 

Surgery: The McDonald Cerclage

What is a McDonald cerclage? 

• Definition: a suture placed around the cervix in a purse-string fashion and tied anteriorly 

• Purpose: to decrease the risk of preterm birth in patients with

• History of preterm birth and short cervix 

• Second trimester with open cervix <24 weeks 

• For more indications, please see our prevention of preterm birth episode! 

UPTODATE

Today we will focus on the surgical steps:

• For pictures, we still like Atlas of Pelvic Surgery: 

  Pre-operative 

• Surgical consent 

• Review the way the procedure is done 

• Discuss risks, benefits, and alternatives

• Risks: injury to organs around the cervix (ie. bowel, bladder, vagina), small risk of breaking the bag of water and losing the pregnancy, infection, bleeding, etc.  

• Benefits: could decrease preterm birth before 37 and 34 weeks compared to women who did not get cerclage (RR 0.77, 95% CI 0.66 to 0.89 based on a Cochrane review) 

• Alternatives: doing nothing, using vaginal progesterone, etc. 

• Preoperative work up 

• Most providers will not need a CBC or other additional work up in young, healthy patients 

• Some hospitals may require a type and screen for all patients going to the operating room, and most hospitals nowadays may also require a COVID swab 

• Patients who are Rh negative: typically do NOT give Rhogam just for cerclage, given that any bleeding caused is presumably only cervical bleeding and we are not traumatizing the pregnancy.

• Ultrasound, genetic screening 

• General practice is to perform genetic screening if a patient desires it (ie. we don’t want to put a cerclage into a pregnancy that is affected by aneuploidy in a patient who may desire termination) 

• Ultrasound - make sure there are not obvious fetal malformations early on (ie. anencephaly), make sure there is a fetal heartbeat before the procedure.

• Anesthesia 

• Most procedures are done with neuraxial anesthesia (ie. Spinal) 

• Expectations 

• Patients will go home same day 

• Some can have some cramping and spotting, but if more than cramping, should come in for evaluation 

• During the surgery 

• Patient should have adequate anesthesia in the operating room and be prepped and draped 

• Positioning: 

• Dorsal lithotomy - yellowfins vs candy canes 

• Tip: make sure patient’s bottom is slightly hanging off of the bed; put patients in slight Trendelenburg for visualization  

• Empty bladder - usually helpful to be able to visualize cervix 

• Surgical steps

• Evaluate the cervix after adequate anesthesia has been achieved even if you examined them before anesthesia

• After anesthesia and relaxation, the cervix can appear different or even more open! 

• Evaluation should be done visually first in case there are exposed membranes 

• Achieve visualization 

• Can place a weighted speculum into the posterior vagina, or can also place 3 Bryskie retractors to visualize the cervix 

• Place two ringed forceps onto the anterior and posterior lip of the cervix - this allows for maneuverability of the cervix 

• Visualize the reflection of the bladder on the anterior cervix 

• Place the suture

• Permanent suture is used 

• Types: Mersilene tape or a 0- or 1- Ti-Cron (coated braided polyester suture) - usually will use a large caliber suture

• If using Ti-Cron, will usually use a mayo needle given large size of the needle that comes with the Ti-Cron 

•  Usually the suture is placed with 4 or 5 bites 

• Start at 12 or 1 o’clock on the cervix, as far back as possible without getting into the bladder 

• The next bites should avoid 3 and 9 o’clock where the vessels are 

• Assistants should use Bryskie retractors to hold back the vaginal walls, and the surgeon should use the two ringed forceps to maneuver the cervix 

• Tying the suture 

• Tighten the suture on both sides and recheck the cervix to make sure the suture is tight and the cervix is closed 

• Tying: Fei ties 6 knots for Ti-Cron, and 4 for Mersilene tape. Then, for ease of removal later, I will tie an airknot and then tie down four more knots. You can also tag Mersilene tape with another soft non-absorbable suture (i.e., silk).

• Post-operative 

• In the hospital, the patient needs to have their spinal/epidural anesthesia wear off before they can go home 

• Should be able to walk 

• Should be able to urinate 

• Check fetal heart tones 

• Indocin and antibiotics or no? 

• Er… it depends and there is a lot of conflicting data 

• There is a randomized controlled trial of only 53 patients in 2014 looking at antibiotics and indocin for exam-indicated cerclages 

  • This showed that there was increased time to delivery for those that received Indomethacin and antibiotics, but gestational age at delivery and neonatal outcomes were the same in both groups 

  • Then a repeat study was done in 2020 that showed similar results (increase in latency):

  • So… I think many people would do Indocin and antibiotics for exam-indicated cerclages 

• A retrospective study for all cerclages showed that there was no increase in gestational age or neonatal outcomes 

  • So, maybe not use indocin in history-indicated cerclages.

• Follow-up 

• Usually 1-2 week follow up for cerclage check in office.

The PROLONG Trial (Progesterone for Preterm Birth, Part II)

Last week, we introduced our major progesterone trial series with a discussion of the Meis trial. We finish up this week talking about the follow up trial: the PROLONG study.

The PROLONG Trial 

Methods

• Location

  • 93 total centers across 9 countries  

• Eligibility criteria and exclusion criteria: pretty much the same as the earlier trial 

• Randomization and treatment 

  • Randomized 2:1 to receive 17OHP weekly, to start between 16-20w6d 

  • Placebo was benzyl benzoate, caster oil, benzyl alcohol 

• Outcomes 

  • Measured preterm birth <35 weeks 

  • Composite neonatal morbidity and mortality index 

  • Secondary outcomes: 

    • Neonatal death, PTB <32 weeks, PTB <37 weeks and also medical indicated preterm births 

  • Primary safety outcome: fetal/early infant death 

• Stats 

  • Unlike previous trial, wanted it to have adequate power to identify both the primary efficacy and the primary safety analyses 

  • Therefore, needed 1665 liveborn infants to detect a reduction of 35% in the rate of the composite index 

  • Needed 1707 patients to provide 98% power to detect a reduction of approximately 30% in the rate of PTB <35w0d

Results 

• Timeline: November 12, 2009 - October 8, 2018 

• Total of 1740 women were consented and agreed to study 

  • 1130 allocated to 17OHP, 578 allocated to placebo 

  • 390 were randomized in the US, 1317 randomized in non-US 

• Demographics were similar between groups 

  • 88.8% vs. 87.2% Caucasion in 17OHP vs. placebo groups 

  • Prepregnancy BMI 23 

  • Almost 90% were married, living with partner compared to just about 50% in the other study 

  • Only 7-8% smoked in pregnancy compared 20-22% in other study 

• So… similar for each arm of this study, but very different demographic compared to the Meis trial.

• Primary Outcome 

  • Preterm birth prior to 35 weeks: 11.0% in 17OHP vs. 11.5%

    • Spontaneous was 8.4 vs 8.9%, RR 0.93, 95% CI 0.67-1.30

  • Not a primary outcome, but PTB <37 weeks: 23.1% vs 21.9% RR 1.06, 95% CI 0.88-1.28! 

    • So different from 36 vs. 50% in Meis study 

  • Neonatal outcomes: 

    • Unsurprisingly, given no diff in preterm labor, no diff in composite neonatal morbidity and mortality 

• Secondary Outcome 

  • Preterm birth <32 weeks - also not different 

  • Other things: cerclage, preterm labor eval, tocolysis, corticosteroids, maternal GDM, preeclampsia, chorio, abruption, CS all not different 

  • Neonatal: no difference in anything, including neonatal death, RDS, NEC, IVH, NICU admission, birth weight, TTN, PDA, ROP

Conclusions

• Study was done in consultation with the FDA as part of approval for use of 17OHP 

• Unlike the findings in the MFMU trial, this study had much lower event rate of PTB and did not confirm treatment efficacy 

Discussion points

• While the Meis study was conducted in the USA, the PROLONG study was mostly not, and that was because the findings from the Meis study had changed practice 

• Most places in the US were already prescribed 17OHP and likey didn’t want to change their practice 

• Also, the Meis showed a large predominance of black women (60%), while there were very few in the PROLONG study 

• Finally, there was a huge discrepancy in baseline preterm labor rates between the two studies, with the rates in PROLONG about ½ has much as that of the Meis study 

• Why castor oil? 

  • Not that it has shown to cause preterm labor, but castor oil can cause contractions, usually due to GI distress when ingested 

• Consequences of the Studies 

  • After Meis, everyone started doing 17OHP 

  • After PROLONG, an FDA advisory committee proposed to take Makena (17OHP) off the market in 2019 (9 to 7 vote) 

    • https://www.nytimes.com/2022/03/25/health/fda-drug-approvals-makena.html ← NY times article about all this 

  • Plan: Oct 17-19 the FDA’s advisory committee will meet to discuss the medicine and hear arguments if it should stay on the market 

• Follow up to the study 

  • EPPPIC - Evaluating Progesterone for Preventing Preterm birth International Collaborative - meta-analysis of individual participant data from randomized controlled trials 

    • Published in the Lancet in 2021 

    • Basically: 31 trials were included with individual participant data

      • From these studies, it seems that vaginal progesterone and 17OHP both reduce birth before 34 weeks gestation in high risk singleton pregnancies 

      • Absolute risk reduction is greater for women with short cervices 

      • The data seems a little better for vaginal progesterone in consistently decreasing preterm birth <37 weeks and <34 weeks

      • For 17OHP the data just crosses the line of no effect at <34 weeks 

The Meis Trial (Progesterone for Preterm Birth, Part I)

One of the hottest controversies in OB in the last several years has been about the role of progesterone for treating preterm birth. We covered these trials very briefly in our episode on preterm birth prevention. Today, let’s dive deeper and start with part I - talking through the Meis Trial.

Next week, we’ll talk in depth about the PROLONG trial and some takeaways for your practice.

Background: 

• Titles 

  • The Meis Trial - Prevention of Recurrent Preterm Delivery by 17 Alpha-Hydroxyprogesterone Caproate 

  • The PROLONG Trial - 17-OHPC to Prevent Recurrent Preterm Birth in Singleton Gestations (PROLONG Study): A multicenter, International, Randomized Double-Blind Trial 

• Who wrote the papers and where were they published? 

  • Meis: Dr. Paul Meis!  - Done with the NICHHD as part of the MFMU 

    • Published in the NEJM! Very fancy - published 2003 

  • PROLONG: Done by Dr. Sean Blackwell (was a president of SMFM!) and a bunch of people who are active in SMFM like Dr. Cynthia Gyamfi-Bannerman, Dr. Brenna Hughes, Dr. Judette Louis 

    • Published in American Journal Perinatology in 2020; which is a good journal but… nowhere near the impact factor of NEJM lol 

• Who funded the studies? 

  • Meis: NICHD

  • PROLONG: AMAG Pharmaceuticals (those that make Makena) 

• Why were the studies done? 

  • The initial study (Meis) was done to try and decrease preterm delivery (leading cause of infant mortality and morbidity in the US!). There had been small trials with prophylactic treatment with progestational compounds that had shown promise, but not all of them had positive results 

    • Had been a meta-analysis restricted to 17-OHP that showed a reduction in preterm delivery 

  • The second study was done after the first study was stopped early because it was thought to be unethical to continue recruitment given the robustness of evidence (spoilers, sorry) 

    • The FDA granted conditional approval for 17-OHP for commercial use in 2011 under the provision that another well-conducted randomized controlled trial was done 

    • This was a confirmatory trial for 17-OHP, and the FDA also required a long-term infant follow-up study 

• Question to answer: Does the use of weekly 17-OHP in pregnancy decrease the risk of preterm birth? 

The MEIS Trial

Methods

• Done at 19 participating centers, primary USA based 

• Eligibility criteria

  • History of spontaneous preterm delivery in previous pregnancy between 20w-36w6d 

  • Current pregnancy between 15w0d-20w3d gestation 

  • Ultrasound between 14w0d-20w6d to confirm duration of gestation and to identify any major fetal anomalies 

• Exclusion criteria 

  • Multifetal gestation

  • Known fetal anomaly 

  • Progesterone or heparin treatment during current pregnancy 

  • Current or planned cerclage 

  • Hypertension requiring medication

  • Seizure disorder 

  • Plan to deliver somewhere other than the 19 participating center 

• Intervention 

  • Patients that consented were randomized to either IM study drug (17 OHP) or castor oil (omg - need to talk about this after!)

    • Had to be given first dose between 16w0d-20w6d; if they did not return before 20w6d, could not participate

    •  Weekly injections until 36 weeks 

• Outcomes 

  • Date of delivery, birth weight, neonatal course - to assess for preterm delivery!  

• Statistics 

  • Power calculation: 

    • Estimated 37% of patients in placebo group would have a preterm delivery 

    • Sample size calculation of 500 women, with 334 in progesterone group and 166 in placebo to find a reduction of 33% in rate of preterm delivery 

  • At second interim analysis, when 463 patients had undergone randomization, outcome data was available for 351 patients

    • The boundary (p=0.015) for test of significance had been crossed for preterm delivery, and enrollment was halted 

Results

• Timeline: 

  • Started in April 1998, but ultimately stopped in February 1999 because the FDA ordered the company that supplied to the active drug to shut down and mandated a total recall of the company’s drugs because of poor quality control and documentation 

    • 150 patients had been enrolled 

  • The study was then restarted with a new drug company. The 150 women previously with other med were not included in the study data analyses 

  • New Timeline: 

    • September 1999 - February 2002 

• Patient Demographics 

  • 1039 eligible, 463 eligible women gave their consent  

    • 310 in progesterone group 

    • 153 in placebo group 

  • Patients were similar in mean duration of previous gestational age (that qualified them for the study), mean gestational age at time of randomization, race, marital status, BMI, smoking, education level, etc. 

    • Of note, interestingly, approximately 60% of those in the study identified as non-Hispanic black (compare to PROLONG, which has very different demographics) 

    • Prepregnancy BMI 26 

  • But, women in the placebo group had more previous preterm deliveries (1.6 vs. 1.4, p=0.007) 

  • 91.5% of women were compliant with their injections (meaning they didn’t go more than 10 days without an injection) 

  • 50% reported at least one adverse effect 

    • Most common: 34.2% reported soreness at sight of injection; 14% reported swelling, 11% itching, 6.7% bruising 

    • More women with progesterone had swelling or a lump at injection sight 

• Primary outcome 

  • Preterm delivery

    • Data was available for 459/463 women

    • Delivery before 37 weeks was reduced, 36.3% for 17-OHP group, 54.9% for placebo group (wtf, that’s super high) RR 0.66, 95% CI 0.54-0.81 

      • Spontaneous PTL was 29.4% vs. 45.1% respectively 

    • Findings were similar for black vs nonblack women 

    • Even more interesting, significant for delivery before 35 and 32 weeks gestation

      • Delivery before 35 weeks: 20.6% vs. 30.7%, RR 0.67, 95% CI 0.48-0.93 

      • Delivery before 32 weeks: 11.4% vs 19.6%, RR 0.58, 95% CI 0.37-0.91

  • Other things were not different: hospital visit for PTL, tocolytic therapy, corticosteroid use, CS, chorio 

• Secondary outcome 

  • Fetal and neonatal outcomes 

    • No difference in fetal death, antepartum or intrapartum 

    • There was a significant difference in birthweight

      • <2500g was 27.2% vs. 41.1%, RR 0.66 (95% CI 0.51-0.87)  

    • Also difference in supplemental oxygen use (14.9% in 17OHP vs. 23.8% in placebo) 

    • And lastly, difference in IVH (1.3% vs 5.2%) 

  • No difference in neonatal death, TTN, RDS, bronchopulmonary dysplasia, vent support, NEC, retinopathy, etc. 

Conclusions 

• Authors concluded: treatment with 17OHP weekly from 16-20 weeks to 36 weeks of gestation reduced preterm delivery at 37, 35, and 32 weeks in patients with history of sPTB

  • But … they also did say that there was an overall very high rate of preterm delivery (50% in placebo vs. 36% for 17OHP)

  • Next week, we’ll contrast with PROLONG!

The ALPS Trial

The #OBGynInternChallenge is back! Enrollment will open Monday 4/18. Check out www.obgyninternchallenge.com/enroll.

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Here’s the RoshReview Question of the Week:

A 21-year-old G1P0 woman at 36w2d gestation presents to L&D with preterm contractions. Which of the following is an indication for giving antenatal corticosteroids?

• Intrauterine fetal demise

• Patient who hasn’t yet received antenatal corticosteroids

• Patient who received antenatal corticosteroids 10 days ago

• Patient who received antenatal corticosteroids previously at 24 weeks

Check out the links above for the correct answer, and get more details on the group discount deal with RoshReview QBanks for CREOG and ABOG exam studying!

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THE ALPS Study

Actual Title: Antenatal Betamethasone for Women at Risk for Late Preterm Delivery 

ALPS = Antenatal Late Preterm Steroids 

Some general background information 

• Who did the study and who published it? 

  • Another study done by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, MFMU 

  • Published in the NEJM in 2016 

• Why was the study done? 

  • Antenatal corticosteroids were widely used up to 34 weeks prior to this study 

  • Decided after consensus conference held by the National Institutes of Health in 1994 - strong evidence that corticosteroids reduce adverse neonatal outcomes (death, RDS, and other morbidities) 

  • Recommendation not given after 34 weeks because it was thought that babies usually do well after 34 weeks 

    • However, it became clear later that infants born in the late preterm period still have increased neonatal and childhood risks compared to term infants 

    • 8% of all deliveries occur in the late preterm time period 

• Question we want answered: 

  • Does administration of betamethasone to women likely to deliver in the late preterm period (defined as 34w0d - 36w6d) decrease respiratory and other neonatal morbidities?

Methods 

• Who participated and when? 

  • Done at 17 university-based clinical centers participating in the MFMU Network

  • Recruitment began in October 2010 - February 2015  

  • Eligibility criteria:

    • Live singleton pregnancy 34w0d- 36w5d 

    • High probability of delivery in the late preterm period

      • Preterm labor with intact membranes, at least 3 cm dilated or 75% effaced or

      • Spontaneous rupture of membranes 

      • If neither applied, expected preterm delivery for any other indication via IOL or CS between 24h - 7 days after planned randomization  

  •  Ineligible if: 

    • Expected to deliver in <12 hours for any reason

      • ROM with more than 6 contractions/hour or cervical dilation of 3 cm or more unless pit was withheld for at least 12 hours (but other induction agents were allowed) 

      • Chorioamnionitis 

      • Cervical dilation 8 cm or more 

      • Evidence of non-reassuring fetal status requiring immediate delivery  

    • Previously received steroids for fetal lung maturity in pregnancy  

    • Candidate for stress dose steroids 

    • Contraindication to betamethasone 

    • Pre-gestational diabetes 

    • Known major fetal anomaly 

• How was the study done? 

  • After subjects were consented, they were allocated in 1:1 ratio to either course of 12 mg of BMZ (2 doses 24 hours apart) or placebo 

  • Stratified by clinical site and gestational age categories (34-35 weeks vs. 36 weeks) 

  • Double-blind (neither study participant nor investigator knew if BMZ or placebo)

  • Rest of labor/delivery managed per indication  

• What outcomes did they look for?

  • Primary outcome 

    • Composite endpoint for need for respiratory support by 72 hours of age consisting of:

      • CPAP or HFNC for at least 2 consecutive hours 

      • O2 requirement with FiO2 of at least 30% for at least 4 continuous hours

      • ECMO or mechanical ventilation  

    •  Stillbirth and neonatal death before 72 hours were also included in both composite outcomes as they could be competing events 

    • Subgroup analysis for primary outcome and severe respiratory morbidity  for 34-35 vs 36 weeks gestation, indication for trial entry, planned CS vs planned VD, sex, and race/ethnicity 

  • Secondary outcomes 

    • Neonatal: many, but included severe respiratory morbidity; TTN, apnea, bronchopulmonary dysplasia, need for surfacntat, hypoglycemia, resuscitation, feeding difficulty, IVH, sepsis, death before discharge, etc.  

What were the results 

• Who did they recruit?

  • Out of 24,538 screening, 2831 eligible were consented and randomized

    • 1429 got betamethasone 

      • Only 860 (60%) got both doses 

    • 1402 got placebo  - only 826 (59%) got both doses 

    • Reason those did not get a second dose: 95% delivered before 24 hours

• What were their outcomes?

  • No stillbirths or neonatal deaths within 72 hours

  • 4 women lost to follow up (0.14%) 

  • Primary outcome: 

    • Occurred less frequently in the BMZ group than placebo 

      • 11.6% vs. 14.4% RR 0.8, 95% CI 0.66-0.97, p = 0.02 

      • Number needed treat to prevent one case was 35 

    • Unchanged in post-hoc analyses 

    • None of the subgroup analysis were significant 

  •   Secondary outcome 

    • Severe respiratory morbidity composite outcome also significantly reduced in BMZ compared to placebo

      • 8.1 vs. 12.1%, RR 0.67, 95% CI 0.53-0.84, P<0.001 

      • NNT 25 

      • Rate of TTN, need for resuscitation, and BPD were significantly less frequent in BMZ group  

    • No significant difference in chorio or endometritis 

  • Other findings of note: 

    • Significant difference in hypoglycemia of glucose <40

      • 343 (24.0%) vs 209 (14.9%) -  those that got BMZ more likely to have hypoglycemia, P<0.001 

What was the impact? 

• Found that BMZ even up to 36w5d for initial can decrease respiratory morbidity 

• Consistent with previous data from the ASTECs trial (Antenatal STeroids for Term Cesarean Section)

  • This did find dec NICU admission for respiratory distress

  • So babies in the UK do get steroids at term for CS not in labor!  

• There is a recommendation from ACOG now to give single course of steroids to pregnant patients between 34w0d-36w6d at risk of preterm delivery within 7 days who have not previously received steroids