Viral Hepatitis in Pregnancy, with Dr. Brenna Hughes

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We were lucky enough to get a sneak peak at ACOG’s newest Clinical Practice Guideline #6 on Viral Hepatitis in Pregnancy. We sat down with co-author Dr. Brenna Hughes, professor of obstetrics and gynecology and Vice Chair of Obstetrics and Quality at Duke University, to get highlights of the newest updates and changes concerning hepatitis in pregnancy.

Background

  • There are five types of viral hepatitis: A, B, C, D, E

    • A and B are preventable through vaccination

    • B and C are recommended for screening in pregnancy.

  • Screening and vaccination is important, as these infections cause morbidity for pregnant folks.

  • Hepatitis A — small case-fatality and rare complications

    • Associated with food-borne outbreaks

    • Fecal-oral contamination or foodborne outbreaks related to contaminated food/water

  • Hepatitis B — highly pathogenic and infectious

    • Perinatal transmission is single largest cause of chronic infection worldwide.

    • Also associated with sexual contact, IV drug use, contaminated blood product.

    • Mortality 1%

      • 85-90% of adults will experience resolution of physical findings and develop antibody.

      • 10-15% will develop chronic infection, with a minority of those continuing with viral replication and active viral DNA synthesis.

  • Hepatitis C

    • Most commonly reported bloodborne infection in the US

      • Principal risk factor: IV drug use

    • 75% of individuals are asymptomatic with infection

    • Can be concomitantly spread with HIV

  • Hepatitis D

    • Incomplete viral particle that exists only in presence of hepatitis B

    • Transmission primarily blood borne

    • Produces more severe disease than other forms of chronic hepatitis

      • 70-80% develop cirrhosis and portal hypertension, 15% within 2 years of initial onset of acute illness

        • This is compared to just 15-30% of patients with Hep B alone who develop cirrhosis and portal hypertension over time.

  • Hepatitis E

    • Similarly to hepatitis A, associated with fecal-oral transmission

    • Generally self-limited viral illness

      • In pregnant persons, higher risk of fulminant hepatitis E with 20-35% fetal mortality and significant maternal morbidity (including need for transplant).

      • Rare in US

New Updates in Screening for Hepatitis B

  • ACOG recommends triple panel screening for all pregnant patients without documented negative triple screen after age 18, or haven't completed HepB vaccine series, or who have ongoing risk for HepB infection regardless of prior vaccination / testing.

    • This encompasses obtaining a:

      • HepB surface antigen (Hep B sAg)

      • HepB anti-surface antibody (anti-HBs)

      • HepB total core antibody (total anti-HBc)

    • A triple panel provides opportunity to inform decisions regarding treatment (if needed) or vaccination.

    • If positive surface antigen — additional testing will help determine type of infection and chronicity.

  • ACOG still recommends early universal prenatal screening for HepB sAg in all pregnancies regardless of testing and vaccination status.

    • 12-18% of patients still don’t receive even this baseline level of screening.

ACOG CPG 6

Managing Hepatitis B in Pregnancy

  • Pregnancy is well tolerated in those with hepatitis B infection without advanced liver disease.

    • There is a risk of hepatitis flare, particularly postpartum.

  • Those with chronic hepB and a viral load of > 200,000 IU/mL should be on antiviral therapy in the third trimester to reduce risk of perinatal transmission.

    • Some patients with lower VL may also be on antivirals if indicated for their own risk/health.

  • Vertical transmission is low with amniocentesis and shared-decision making can be employed when making decisions on this.

  • There is insufficient evidence to suggest invasive obstetric procedures (FSE, episiotomy, operative delivery) increase transmission risk, but there are some reports of increased risk with neonate coming to contact with infected blood.

  • All neonates of individuals with HBsAg-positive status or unknown status should receive HBIG and hepatitis B vaccine within 12 hours of birth.

  • Breastfeeding can proceed unless there are other contraindications.

    • Tenofovir can be continued during breastfeeding.

Hepatitis C: Screening, Treatment, and Pregnancy Pearls

  • ACOG recommends pre-pregnancy screening for hepatitis C virus infection and treatment.

    • Ideally, pregnant folks will get screened for hepatitis C antibody at the first prenatal visit of each pregnancy.

      • If positive —> assess hepatitis C viral PCR testing to confirm active infection vs cleared infection or false positive.

    • There are no treatment options for hepatitis C diagnosed in pregnancy — but there are really successful treatment options outside of pregnancy.

      • OB/GYNs can help get these patients to successful treatment in the postpartum period with prenatal screening.

    • Ribavirin achieves virology cure in large proportion of patients.

      • If patients are taking prior to pregnancy, couples should wait 6 months after completion of therapy due to possible teratogenic effects.

  • In pregnancy, there are no known preventive measures to reduce risk of vertical transmission.

    • Risk is generally low for amniocentesis and CVS: use shared decision making in decision to proceed.

    • There is insufficient evidence to suggest routine invasive obstetric procedures should be avoided (internal monitoring, episiotomy, operative delivery) but can be considered/minimized when possible.

      • No evidence pre labor cesarean decreases transmission risk.

    • Breastfeeding is not discouraged in patients with active hepatitis C.

      • Not enough data on cracked/bleeding nipples.

Immunization in Pregnancy

  • Both hepatitis A and hepatitis B vaccination are safe in pregnancy!

    • Newer hepatitis B vaccines do not have sufficient data (HepBZ-CpG and Hepb Vaccine Recombinant) — so need to know your manufacturer.

    • There is a combination vaccination for adults that can be used in pregnancy as well!

Surgical Injury Part II: Ureters and Bowels

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Bowel Injuries - Enterotomies and Colotomies

  • Tips for Prevention

    • Surgical technique is crucial in preventing bowel injury.

    • Adhesions can hide the bowel quite well!

      • Entering peritoneum – bowel loop adhered to anterior abdominal wall – very common scenario for injury.

      • Endometriosis – leads to scarring and adhesions, or bowel may be directly impacted and injury may occur with excision.

    • When breaking down adhesions:

      • Gentle, controlled traction and countertraction on bowel loops.

      • Sharp, cold dissection is preferred – typically Metzenbaum scissors or scalpel.

        • Blunt dissection may cause the bowel to tear.

        • Gentle, blunt dissection may be useful for some translucent adhesions – rub your thumb and index finger back and forth over the tissue to loosen it up, then switch back to sharp dissection once the adhesion “window” can be seen.

      • This can be a long process in some surgeries! Patience is key. Don’t be afraid to move to another area if you’re not making progress in one spot.

  • “Running the Bowel”

    • You’ve probably heard of this before… but how do you do it, exactly?

    • Most of the time, we’re talking about small intestine:

      • Start at the Ligament of Treitz. 

        • This band of tissue extends from the diaphragm to the duodenojejunal flexure - so up high (close to T12) and posteriorly (remember the duodenum is largely retroperitoneal).

      • Hand over hand, move down the bowel, inspecting for injury or perforation.

        • You’ll start in the jejunum, and move to the ileum of small intestine.

          • There’s no landmark to distinguish these two, but the ileum feels thinner and the lumen is somewhat smaller.

      • For small intestine, you end your run at the ileocolic junction.

        • This is denoted by the appendix! 

      • Large intestine is distinguished by epiploic appendages, outpouchings of the colonic wall (haustrae), and three large muscular bands (taenia coli). 

        • Should also be inspected for injury if suspected!

  • Site and extent of injury

    • Technique

      • Critically important – repair to bowel injuries are done perpendicular to the long axis of the bowel.

        • I.e., if you are looking at bowel in your hand going right-to-left, your repair is up-and-down.

          • If you repair parallel to the long axis of the bowel, the bowel lumen will narrow and potentially cause obstruction.

Operative obstetrics and gynecology - Correct technique for bowel repair

    • Serosal injuries: 

      • If underlying muscle and mucosa are intact and the serosal injury is small, then this can be left unrepaired – stitching may just increase complications.

      • If muscle is torn as well, then repair should be performed as the muscle provides integrity – the bowel wall may perforate without overlying muscle.

        • Small, tapered needle with 3-0 or 4-0 silk.

        • Avoid placing the stitch through the mucosa and into bowel lumen!

    • Perforating injuries:

      • Ideally they are repaired immediately to limit contamination of the peritoneal cavity!  

      • Antibiotics should be given to cover anaerobic intestinal flora, if they haven’t already:

        • Typically a dose of metronidazole

      • Smaller perforations can typically be closed in a two-layer fashion:

        • Inner layer of absorbable, braided suture (i.e., 3-0 Vicryl or Polysorb) that goes through the full thickness of the bowel.

          • Need to ensure mucosal approximation for a water tight seal!

        • Outer layer is the seromuscular repair as we described before, with 3-0 or 4-0 silk. 

      • Larger perforations may require bowel resection and reanastamsois.

        • Should be considered if perforation:

          • Involves more than 50% of bowel wall circumference

          • There are multiple perforations within a short segment of bowel

          • There is vascular compromise to a segment of bowel

            • If you see the serosa appears dark and dusky and fails to pink up after a few minutes… likely needs resection.

        • This is generally beyond the skillset of a generalist OB/GYN - so call your general surgery or colorectal surgery friends to help with these.

      • Regardless of size, irrigation should be performed copiously to clear out intestinal spillage, particularly if there was a colotomy.

        • Surgery may advise placement of a Jackson-Pratt (JP) drain with spillage occurring, to monitor for leaks at site of bowel reanastamosis – this is less and less common as better evidence has emerged that drains don’t alter outcomes.

        • We are definitely not the experts here – defer to surgical colleagues on indications and necessity of drains!

    • Management after Injury/Repair

      • Timing of feeding after bowel injury and repair is also controversial.

        • However, most recent evidence in colorectal surgery suggests that early enteral (PO) feeding is feasible and safe, with early frequently defined as within 24 hours of surgery. 

          • Small injuries that are within the purview of OB/GYNs to repair do not need to have feeding restrictions.

          • Larger injuries where you’re obtaining consultation for sure – defer to your surgical colleagues.

      • Ongoing antibiotic therapy and postoperative imaging studies are generally not warranted.



Ureteral Injuries

  • Prevention

    • Knowing your anatomy is really important, as the ureter runs in some high-risk areas:

      • At the pelvic brim, where it crosses the bifurcation of the common iliac artery – injury can occur with hypogastric artery ligation.

      • In the pelvis, just below the infundibulopelvic ligament – can be injured with oophorectomy.

      • Beneath the uterine artery – often coursing laterally within 1.5 - 2cm – site of injury often in cesarean, if it occurs, and of course at hysterectomy.

      • From there it courses medially and ventrally, around the cardinal ligaments to enter the trigone – also a high risk point of injury at hysterectomy, as well as in urogynecologic surgeries like anterior colporrhaphy and uterosacral ligament suspension.

    • Risk goes up with more complex surgeries – be particularly aware with:

      • Malignancy

      • Large fibroids

      • Adhesive disease and PID

      • Placenta accreta and cesarean hysterectomy generally

      • Vaginal hysterectomy with significant prolapse

      • Congenital anomalies

    • Do preoperative stents help?

      • They may be helpful for identification of ureters and dissecting around them, however, there’s no evidence to say they reduce the risk of injury.

        • They may help you identify it once it happened, though!

      • Consider them on a case-by-case basis with high risk procedures.

  • Detection

    • Intraoperative detection is so much better than delayed injury.

      • Injuries can cause transection which is easily detected, but also be aware that injuries may be delayed particularly with thermal injury, crush injuries, or overly aggressive dissection leading to devascularization.

    • Dye solutions (indigo carmine, methylene blue, fluorescein) provided intraoperatively can allow you to see:

      • Extravasation of dye in the surgical field – an abdominal transection injury

      • Failure to see ureteral efflux on cystoscopy – more likely a crush injury, or a kink from a suture.

    • Cystoscopy is very helpful:

      • You want to see brisk efflux – wisps of dye passage may suggest partial occlusion or kinking.

      • Stents can be passed if you’re qualified, or by urologic consult. 

        • If stents pass easily and dyed urine drips from a stent, it’s likely that ureter of concern is kinked somewhere – review, release suture, and cystoscope again to see if that causes improvement.

        • If stents cannot pass more than a few centimeters, ligation or transection likely occurred.

          • Dye can be passed through a stent retrograde as well to aid in visualization in the abdomen of an injury site.

    • Unfortunately, 50-70% of ureteral injuries are not diagnosed in the acute setting.

      • Delayed recognition of injury manifests as flank / abdominal pain, anuria, urinary ascites, and concern of course for fistula development (copious discharge from wound and/or vagina). 

      • If suspected postop, workup is usually through CT scan (IV pyelogram - preferred) or a retrograde pyelogram.

  • Repair techniques (a brief review, as if an injury occurs this will be done by consultant, typically):

    • Depends largely on the site and mechanism of injury.

    • Stents: may be needed alone for some crush injuries or other ‘minor’ damage.

      • Some small laceration injuries (<50% diameter of the ureter) can be primarily sewn over a stent.

      • If over 50%, requires anastomosis or reimplantation. 

    • Ureteroneocystotomy: the ureter is reimplanted into a deliberate cystotomy site. 

      • Typically for distal injuries.

      • Modifications if additional mobilization is needed include:

        • Elongation of the bladder

        • Psoas hitch: a technique where the bladder is hitched up onto the psoas muscle to bring it closer to the ureter.

    • Ureteroureterostomy: can be:

      • Ipsilateral – the two cut ends are brought back together. Most common.

      • Transureteroureterostomy (contralateral) - essentially connecting the ureter to the other side, creating a “Y-shaped” drainage. For more complex repairs that are more proximal. Not common.

    • Boari flap: similar in principle to a psoas hitch, but a lot more extensive – the bladder is essentially turned into a tube to allow for greater reach for more proximal injuries.

  • Postoperative management:

    • Guided by urology – stent needs to be left in place for healing for a while, usually 2-6 weeks.

      • If cystotomy as well, a Foley catheter would also be left.

    • Retrograde pyelogram can be performed at time of stent removal to demonstrate healed tissue without leaking or stenosis, and patients should be followed by urology postoperatively.  

Surgical Injury, Part I: Bladder Injuries

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Oh no…

  • Surgical injuries happen in OB/GYN. As you’ve probably shared in your surgical informed consent discussion previously, we often talk about risks like:

    • Bleeding

    • Infection

    • Damage to surrounding structures.

  • The “surrounding structures” are typically:

    • Bladder

      • Most common injury

      • ~0.3% of cesarean deliveries; ~1% of major GYN surgery

    • Bowel

      • Less than 1% of GYN surgeries

    • Ureters

      • About 0.5% of GYN surgeries

  • The best prevention for injury is preparation - know your anatomy!

What are risk factors to intraoperative injury?

  • Anything that increases surgical complexity, essentially!

    • More extensive “bigger” surgeries - hysterectomy in particular

    • Obesity

    • Age or chronic medical conditions that might limit exposure

      • Particularly in laparoscopy (i.e., less distension ability)

    • Emergent surgeries - more frequent bladder injuries in STAT cesareans, 2nd stage arrests

    • Adhesive disease from prior surgeries, infections, trauma, etc.

    • Patients with congenital or acquired anatomic differences

    • Oncology - invasive disease and altered vasculature/structures 

What should I do when I identify something that is / may be injured?

  • If safe to do so: pause and evaluate

  • Call for assistance: senior colleagues, consultants as needed

  • If awaiting assistance but need to move on (i.e., bleeding accreta case) – can use “tagging suture” to mark area of concern

    • Bladder / bowel: place a small, brightly-colored suture (i.e., dyed 2-0 or 3-0 Polysorb/Vicryl) and leave a long tail at the suspected site of injury, so it’s easy to find later on.

  • Try to identify the mechanism and extent of an injury:

    • Is it just a serosal tear, or was mucosa exposed?

    • Were any contaminated (i.e., gastric / intestinal) contents spilled?

    • Cold cut, or is there potential for thermal (and thus more expansive) injury?

Do I have to deal with this? Can’t I just leave some things unrepaired, and it’ll heal on its own?

  • In some cases of bladder and bowel injury, very small, non-thermal injuries can be left unrepaired:

    • Verees needle “clean poke” of small intestine or bladder

  • However, failure to recognize injury or leaving an injury that is too large or going to expand due to thermal damage unrepaired risks complications:

    • Early

      • Copious wound drainage

      • Abdominal pain - urinary ascites

      • Fever

      • Ileus

      • Peritonitis

        • Have a high index of suspicion in the postoperative period for a patient having an unrecognized injury, especially if they’re having lots of drainage from the incision or a lot of unexpected pain!

    • Delayed

      • Recurrent urinary tract infection

      • Urinary incontinence 

      • Pelvic pain

      • Fistula formation

        • This is of course a major dreaded complication of unrecognized injury.

        • Quick detour – why can cystotomies occurring in TVT procedures stay unrepaired?

          • These injuries occur extraperitoneally in the retropubic space. 

            • Simple extraperitoneal injuries almost always heal on their own and can usually just be managed with catheter drainage & won’t form fistula

          • Injury occurring intraperitoneally should be repaired and are at risk for fistula formation.

            • We’ve provided the two “windows” of injury for fistulas to form at the time of a hysterectomy with the opening to the vagina:

              • Vesico-vaginal (bladder-to-vagina, at hysterectomy)

              • Uretero-vaginal (ureter-to-vagina, at hysterectomy)

              • Entero-vaginal (bowel-to-vagina)

Bladder Injuries

  • Site and extent of injury

    • Most commonly, injuries occur to the dome of the bladder - makes sense anatomically.

    • Rarely, injuries can occur lower, into the trigone or base of the bladder - this is a danger zone for ureteral injury as well.

      • Always evaluate the extent of the injury - if limited to the dome, repair is usually possible without consultative assistance. If more extensive or unsure, urology should be notified.

    • You can use your cystotomy to look into the bladder and see relative anatomy – 

      • ie, visualize the foley, visualize the ureteral openings from above.

      • If you’re within the dome vs the trigone

        • If you’re within just a few centimeters of the ureteral openings… may be worth having a consult come by for repair assistance!

  • Technique of repair for dome injuries

    • Two layers with absorbable suture – typically use a 2-0 or 3-0.

      • Don’t use non-absorbable or very delayed absorbable – there will be suture material in the bladder, which acts as a nidus for infection.

      • First layer: mucosal closure, in a simple running fashion (but not locking).

      • Second layer: imbricating layer over serosa/muscularis, not entering mucosa (to limit amount of material in bladder).

    • After repair, check integrity of the bladder repair while you still have access to the abdomen:

      • A variety of materials can be used to backfill, but generally you want something that is going to have color so you can see a leak, if it’s present.

        • Sterile milk/formula – works! Though can make your cystoscopy quite cloudy later.

        • Crystalloid with methylene blue/indigo carmine/fluorescein added.

    • Many folks may choose to perform cystoscopy at the same time or after backfilling.

      • The cystoscopy is more for checking your ureteral patency – you’ll have a hard time determining bladder repair integrity from a cystoscopy view unless there’s a large defect.

        • That said, if your injury was in the dome and far away from ureters, and you could see the ureters from above, cystoscopy may not totally be necessary - as they’re unlikely to get kinked in your repair. 

    • Postop, the Foley needs to stay in place usually 7-14 days.

      • A void trial and a voiding cystogram should be performed to again demonstrate bladder repair integrity.

  • Technique of repair for trigone injuries

    • You should call urology / urogynecology for these.

    • You will need to assess the status of the ureters, as the ureteral orifices coming into the trigone may be damaged.

      • IV methylene blue, indigo carmine, or fluorescein along with small dose of furosemide.

        • If you see dye entering the bladder but not entering the retroperitoneal or intraabdominal space - likely no ureter injury.

      • Urologists on consultation with a trigone injury may go ahead and place stents to evaluate the ureters.

        • Placing the stents (and the relative ease or not of doing so) may help them to triage where a ureteral injury is at, and then with repairing the injury ensure the ureter is not incorporated.

        • Stents may remain in place postoperatively to keep ureters patent, as nearby tissue may swell and obstruct them otherwise.

Transabdominal Cerclage

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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 


The CLASP Trial

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CLASP: A randomized trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women 

Background: 

  • Who did the study and who published it? 

    • CLASP: Collaborative Low-dose Aspirin Study in Pregnancy Collaborative Group 

      • Coordinating center in Oxford, UK but multiple centers in the UK participated 

      • Published in the Lancet in 1994.

  • Why was the study done? 

    • Preeclampsia is a serious condition that can lead to both maternal and fetal morbidity and mortality 

    • Specifically, it can cause fetal growth restriction and neonatal demise due to prematurity

    • Those that did the study hypothesized that preeclampsia is due to structure and occlusive changes in the spiral arteries that can affect uteroplacental circulation

      • Thought that this contributed to FGR as well 

    • Therefore, if there is some way to prevent preeclampsia, it might also prevent some cases of FGR without preeclampsia 

    • PEC associated with deficient intravascular production of prostacyclin and excessive production of thromboxane → aspirin can modify these pathways, so low-dose aspirin might help by blocking thromboxane 

  • What was the research question?

    • Can use of low-dose aspirin in pregnancy decrease fetal/neonatal morbidity and mortality in those at high risk of developing severe preeclampsia or fetal growth restriction? 

Methods: 

  • Who participated in the study? 

    • Conducted in 213 centers in 16 countries over 5 years (from January 1988 to December 1992) 

    • Inclusion criteria 

      • Between 12-32 weeks of gestation 

      • If there was sufficient risk of preeclampsia or IUGR as deemed by the opinion of the responsible clinician, but no clear indication for or against low-dose aspirin otherwise. Divided into two groups  

        • Prophylactic entry - women with history of PEC or IUGR in previous pregnancy, chronic hypertension, renal disease, or other risk factors (maternal age, family history, multiple pregnancy) 

        • Therapeutic entry - women with signs or symptoms of preeclampsia or IUGR in current pregnancy 

    • Exclusion criteria 

      • Increased risk of bleeding 

      • Asthma 

      • Allergy to aspirin 

      • High likelihood of imminent delivery 

  • How was the study done? 

    • Randomized controlled trial 

    • Staff would call a central 24-hour service at Clinical Trial Service Unit at Oxford —> randomized by computer to get a specific trial treatment pack containing aspirin or placebo tablets 

      • Minimization algorithm was used to limit differences between treatment groups for certain prognostic baseline variables 

    • Treatment was either 60 mg aspirin daily or matching placebo tablet 

      • Sign of the times: currently, we use 81 mg here in the US and the current low dose aspirin in the EU is 150 mg 

    • Follow-up 

      • Single page follow-up form completed after hospital discharge of both mother and baby (or 6 weeks postpartum if either had not been discharged) 

      • Compliance with study treatment 

      • Use of antihypertensives or anticonvulsant drugs (remember this was before magnesium!) 

      • Major events that occurred after randomization (esp. Preeclampsia, fetal loss, maternal or neonatal bleeding) 

      • Birthweight, vital status of baby, and neonatal complications 

  • What outcomes were they looking for? 

    • Main outcomes: 

      • Development of proteinuric pre-eclampsia 

      • Estimated duration of pregnancy 

      • Crude birthweight, birthweight <3rd%ile for sex and gestational age 

      • Stillbirth/neonatal death due to preeclampsia or maternal hypertension or associated with IUGR, or ascribed to maternal or neonatal bleeding 

      • Death of baby at any time attributed to preeclampsia, maternal hypertension, or IUGR 

    • A word on definitions 

      • This was 1994, so the definition of preeclampsia was very different 

      • Defined proteinuric preeclampsia as:  

        • For those with baseline diastolic pressure <90 mmHg, hypertension defined as rise of at least 25 mmHg to 90 mmHg or higher 

        • For those with initial diastolic pressure of 90mmHg or higher, increment of at least 15 mmHg was required 

        • Proteinuria was defined as appearance after randomization of at least 1+ on protein stick-testing during pregnancy w/o UTI evidence 

      • Defined IUGR as: 

        • Birthweight <3rd%ile for sex and estimated gestational maturity 

      • Preterm delivery: before 37 weeks 

    • Other outcomes 

      • Also looked at comparisons regarding parity, prophylactic use according to time of entry (<20 weeks or >20 weeks), and therapeutic use according to time of entry (<28 weeks or > 28 weeks) 

    • Statistics 

      • Wanted to be able to detect a decrease of a quarter in incidence of proteinuric preeclampsia, increase of 100g in mean birthweight, and increase of 1 day of mean duration of gestation 

      • Initially wanted 4000 women, but because this size could not detect differences in rate of stillbirth and neonatal death ascribed to preeclampsia, ultimately decided to include 10,000 women 

Results:

  • Who did they recruit? 

    • 9364 women randomized (4683 in aspirin arm and 4681 in placebo arm) 

      • 74% in prophylaxis for preeclampsia, 12% for prophylaxis of IUGR alone 

      • 11% for treatment of preeclampsia, 3% for treatment of IUGR alone 

    • Some other interesting characteristics: 

      • 62% of women were enrolled at 20 weeks gestation or earlier 

      • 2% had already developed preeclampsia 

      • 28% were primigravidas 

    • Post delivery follow up forms were obtained for 9309 patients (99.4%) 

    • Compliance 

      • Of the 8915 randomized patience where compliance information as gathered, 96% started the medication, 66% continued treatment for 95% of the time, and 88% continued for 80% of the time between randomization and delivery 

  • Outcomes - note, there are a TON of findings in the results section, but for time purposes, here are the main ones 

    • Preeclampsia 

      • 6.7% of women on aspirin had preeclampsia compared to 7.6% of those with placebo 

        • 12% reduction, but not statistically significant 

        • No difference when looking specifically at women who entered for prophylaxis vs. therapeutic reasons 

      • Effect was greater among women who entered for prophylaxis at 20 weeks gestation or earlier (22% reduction) p =0.02) 

      • Interestingly, when looking at those that delivered earlier, there was a progressively greater reduction in preeclampsia with aspirin use 

  • Duration of pregnancy 

    • Average duration of pregnancy was 1 day longer among aspirin allocated patients than placebo allocated women (38.15 vs. 37.99 weeks), p=0.05 

    • Aspirin did reduce likelihood of delivery before 37 weeks 

      • 19.7% vs. 22.2%, p=0.003 

    • Seemed to be in prophylactic group 2 fewer preterm deliveries/100 women allocated to aspirin 

    • In therapeutic group, benefit was about 5 fewer preterm deliveries/100 women allocated to aspirin  

  • Birthweight 

    • Aspirin group had babies that were on average 32 g greater (p=0.05) 

    • Slightly smaller proportion of babies with IUGR, but not statistically significantly different 

    • Interestingly, among women entered for therapeutic reasons, aspirin seemed to have discrepant effects, with increased incidence of IUGR among those entered at 28 weeks or earlier and decreased incidence among those entered later 

  • Stillbirth

    • 129 (2.7%) stillbirths/neonatal deaths in the aspirin group vs. 136 (2.8%) in the placebo group 

    • Not statistically significantly different 

  • Safety 

    • Intraventricular hemorrhage rates were not different in the two groups 

    • No significant differences in fetal or neonatal deaths attributed to hemorrhage 

Impact 

  • Conclusions from this study: 

    • Impact of aspirin on preeclampsia and fetal sequelae were smaller than previously thought 

    • POtentially important effect of aspirin could be discerned on prevention or delay of delivery with early-onset preeclampsia 

  • How do we practice now and why? 

    • So… why are we using aspirin for everything nowadays? 

      • It’s important to realize that this study, while groundbreaking, was almost 30 years ago 

    • Aspirin does have a good mechanism to potentially decrease preeclampsia development, but may need to be used earlier in pregnancy 

      • Hypothesis as stated before is that preeclampsia might be associated wit vascular disturbances and coagulation defects resulting from an imbalance in prostacyclin and TXA2 

    • Until recently, this has not borne out in the data 

    • Another study in 2017 - Aspirin for Evidence-Based Preeclampsia Prevention Trial 

      • Randomized 1776 women and was based on first trimester screening algorithms 

      • Used 150 mg aspirin vs. placebo 

      • Found significant decrease rate of preterm preeclampsia (4.3% vs. 1.6%, OR 0.38, 95% CI 0.2-0.74) 

    • Meta Analysis in 2014 from the USPSTF guideline pooled data from 15 high-quality RCTs, and showed a 24% reduction in preeclampsia (RR0.76, CI 0.62-0.95) with low dose aspirin prophylaxis (60 - 150 mg/day) 

  • So what are the actual recommendations, and what are the lingering questions? 

    • Basically, based on the data from the USPSTF guidelines, in low risk groups (where disease prevalence is 2%), the number needed to treat to prevent preeclampsia is 500

      • Compared to those in a high risk group with disease prevalence of 20%, the number needed to treat is only 50 

      • USPSTF guideline recommends giving low-dose aspirin after 12 weeks of gestation to women with absolute risk of preeclampsia of at least 8% (optimally before 16 weeks) 

      • ACOG has a list of guidelines regarding who meets criteria for aspirin prophylaxis  - can post on website

    • Lingering questions 

      • What is the best dose? 

        • Is it 60? 81? 150? - we don’t know as there hasn’t been a head to head comparison between these doses 

      • What about other things like stillbirth and fetal growth restriction?

        • Insufficient evidence, as few studies have solely looked only at stillbirth or only at FGR  

      • Preterm birth? 

        • Maybe! 

        • There is some good data coming out, so stay tuned