Espresso: Update to the Mifespristone REMS Requirements

Reading: ACOG Practice Advisory: Updated Mifepristone REMS Requirements

Background 

• What is mifepristone? 

• As you probably know, mife is used in combination with misoprostol as part of medication abortion 

• This method is safe, effective, and FDA-approved 

• Can also be used for early pregnancy loss 

• Check out our medication abortion and telehealth abortion episodes! 

• However: 

• Starting in 2011, the FDA implemented the Mifepristone REMS (risk evaluation and mitigation strategy) Program placed several restrictions on mifepristone distribution 

• There needed to be an in-person dispensing requirement 

• Needed to be dispensed in a clinic, medical office, or hospital by or under direct supervision of a certified clinician 

• So patients could not get the mifepristone in a retail pharmacy or by mail 

• ACOG has long advocated for removal of this restriction 

• Doesn’t make care safer 

• Not based on medical evidence 

• Creates barriers to clinician and patient access to medication abortion and medical management of early pregnancy loss 

• Disproportionately burdens communities already facing structural barriers to care 

Why are we making this episode? 

• Timeline 

• During COVID-19, with advocacy, the FDA halted enforcement of the REMS in-person dispensing requirement due to public health emergency

• This allowed telehealth provision of mifepristone and also by mail in some states  

• December 2021 - FDA completed a review of the Mifepristone REMS Program and determined that modifications were warranted to reflect long-standing safety data, improve patient access, and reduce burden on health care delivery 

• January 3, 2023 - Drug manufacturer’s submission of updated prescribing information, etc. and was approved by FDA 

• Updates 

• Permanent removal of in-person dispensing requirement 

• So in addition to clinics, medical offices, hospital: certified pharmacies can now dispense mifepristone to patients with prescription from certified prescriber 

• Mifepristone can be dispensed in-person or by mail 

• Addition of a pharmacy certification requirement 

• Retail pharmacies that meet certain requirements and complete a Pharmacy Agreement Form can now dispense mifepristone to patients to patients who have a prescription from a certified prescriber 

• Find the documents can be found on the FDA website.

What does this mean for us and for our patients? 

• Increase access to medication abortion 

• Maybe – can still be dependent on state-specific laws and ability and willingness of retail pharmacies to achieve REMS certification 

• Some states restrict abortion

• Some states restrict telehealth access, may still require in-person dispensing of mifepristone, and regulation of medications by mail 

• So… the REMS requirements still remain as a medically unnecessary barrier to obtaining this medication 

Espresso: The Emergency Department Consult

Why do patients come to the ER with GYN complaints?

• A whole host of reasons! But some of the most common:

  • Bleeding irregularities – heavy bleeds, mistimed bleeds, unusual bleeding

  • Pain – PID, ovarian cysts, ectopic pregnancy, ovarian torsion, endo, non GYN pain issues

  • Infections – Bartholin’s and other cysts, UTIs, PID

  • Urinary complaints – most often retention or incomplete voiding

  • OB - patients who haven’t established prenatal care, or otherwise sick OB patients (trauma, medical issues) may be first evaluated in the ED

  • Sexual assault and injuries, such as lacerations

Before the Consult: What the EM Clinician Should Do

• Normal EM things – obtaining your acute history and HPI, vital signs, physical exam, and getting the “sick vs not sick” intuition.

  • Consider pregnancy test and pelvic exam as part of your basics.

    • Pregnancy tests should mostly be protocolized for appropriate patients in EDs, but also frequently missed in the evaluation of reproductive-aged patients.

      • If positive – be sure that your labs include a type-and-screen for Rh status, and likely plan on an ultrasound (especially if the diagnosis of pregnancy is new).

    • Pelvic exams are controversial, and we see the argument:

      • OBs are specialized in performing the exam, and we’re likely to repeat it.

      • However, particularly with bleeding – having a sense of whether the bleeding is light, moderate, or heavy/rapid helps us triage the consult urgency and a differential! 

        • Contraindications to digital pelvic exam –

          • Suspected rupture of membranes at 34 weeks or less (unless laboring);

          • Bleeding in pregnancy without confirmation of placental location.

        • OB residents – this is a long-standing controversial issue and training / advice will differ based on region and one’s own biases.

          • If it hasn’t been done and you can’t go to evaluate immediately, ask kindly for it to be performed and for a call back if the bleeding is concerning. 

      • EMs, consider bouncing back with your OB/GYN colleagues when they do a pelvic exam!

        • Getting to do these exams and then comparing your findings will help you to gain comfort with making calls when you’re in the community on your own!

What constitutes an emergency consult?

• Sometimes, things can’t wait!

  • If you have clinical suspicion of ovarian torsion or ruptured ectopic pregnancy, those are surgical emergencies and so merit a rapid response from your GYN colleagues.

  • Heavy vaginal bleeding (>1 maxipad per hour) and/or hemodynamically unstable patient – can range from ectopic pregnancies to gynecologic cancers - need an expert in exam present to help triage.

  • Major OB traumas – ideally, this should prompt OB to be present at the time of patient arrival or rapidly.

  • The “sick” OB patient – this should also prompt OB to be present rapidly, especially if the patient is “viable” or the uterus is at/above umbilicus. Considerations for delivery might need to be made.

    • Common reasons for this could be DKA in pregnancy, sepsis in pregnancy or septic abortion, or other decompensated illness.

Framing the ED Consult

• For our EM colleagues, we love the mnemonic BLUF: bottom line, up front.

  • “This is a consult for possible ectopic and hemodynamic instability” immediately grabs our attention.

  • Follow with that history though so we can help:

    • Gs and Ps – even we mess these up, so just sharing some important pregnancy history can be more helpful (i.e., G3P0020 is less helpful than “two prior ectopics.”)

    • Nature of presenting complaint: as you normally would

    • Vitals / hemodynamic status

    • Laboratory and imaging evaluation done or ongoing

  • In the less-emergent patient, lead off with your BLUF by starting with the specific question or ask:

    • I.e., “This is a consult for a pregnancy of unknown location, and we need your assistance in confirming the findings and coordinating follow up.”

• For our OB colleagues, help facilitate this conversation:

  • Ask for the BLUF – “before we get to her history, can you tell me what your primary clinical concern or question is? That just helps me to triage more appropriately.” 

  • Recognize you’re not going to always get a history or question on a silver platter.

  • Formulate your differential even if it seems like a slam dunk – and make sure you’re asking the right questions to get there

    • For instance, common misses include pregnancy tests, Rh status.

  • When in doubt, go see the patient faster! You’re the expert here and your expertise is being requested. 

  • Follow up with colleagues after you see the patient, or even better as you are getting ready to see them – particularly at training facilities, your EM resident colleagues may want to go see the patient again with you to get confirmatory findings, pearls of wisdom for their independent practice, and help with counseling.

Espresso: Acute Uterine Bleeding

What causes bleeding?

Remember - PALM-COEIN! We talked about this way back in episode 47. As a quick refresher:

PALM - the structural causes:

• P - polyp

• A - adenomyosis

• L - leiomyoma (fibroids)

• M - malignancy

COEIN - the non-structural causes

• C - coagulopathy

• O - ovulation (i.e., anovulatory)

• E - endometrial (local endometrial factors)

• I - iatrogenic 

• N - not otherwise specified

Your EM colleagues call you STAT! It’s really bad! What should you do?

• Start ABCs! 

  • Get your vital signs - assess for signs of hemorrhagic shock

  • IV access - 2 large-bore if possible

  • Resuscitate - balanced crystalloid is a good place to start if relatively stable; blood if appearing unstable 

• Laboratories:

  • Pregnancy test

    • Remember, pregnancy heavy bleeding opens up a whole new can of differential diagnosis and management -- from miscarriages to retained placental fragments.

      • We’ll set that aside for today.

  • CBC - know where you’re starting from. 

    • Note that with an acute bleeding episode, H/H may not accurately reflect actual RBC status as there hasn’t been time to equilibrate.

    • CBC may also clue you into rarer disorders -- i.e., thrombocytopenia due to TTP-HUS or leukemia -- that may result in vaginal bleeding.

  • Coag panel - do you suspect coagulopathy?

    • In the adolescent patient, this may be sign of underlying bleeding disorder like von Willebrand’s disease or hemophilia. 

    • In an older patient without history of bleeding, abnormal coags may point to evolving DIC from very significant bleeding, or acquired coagulopathy (i.e., overdose with warfarin).

  • Type and screen/crossmatch - get blood ready! 

    • A type and screen is always a good place to start, and will be the test that takes the longest.

      • Assuming no antibodies to screen against, a crossmatch can then be had relatively quickly in most large medical centers.

• History & Exam:

  • History should be directed towards understanding how much, how long, and how frequently.

    • How much - get a sense for the amount of acute blood loss, and whether this is life threatening.

    • How long - understand timing of the bleeding as another marker of amount of blood loss, and how long the episodes have lasted if they have happened in the past.

    • How frequently - understand if this is a one-off acute event versus a recurrent issue.

      • Frequent heavy bleeding events may be suggestive of underlying bleeding disorder in younger patients, versus structural causes of heavy bleeding (i.e., fibroids) in older patients. 

    • Examination may help point towards cause immediately - trauma, prolapsing fibroid/polyp. 

      • Also, exam should help increase or ease your suspicion for life-threatening hemorrhage based on what you find!

    • Imaging and other testing may be warranted:

      • Imaging if patient is stable, and suspect but need to diagnose underlying cause (i.e., pelvic ultrasound)

      • Consider endometrial biopsy in those under age 45 with risk factors (unopposed estrogen).

How do I stop the bleeding?!?!

Medical therapy is most ideal in the moment, though surgical therapy is occasionally required! 

Meds to remember:

• Conjugated equine estrogen (IV estrogen). 

  • Source: equine (horses)

  • Dose: 25mg IV, every 4-6 hours for 24 hours

  • Avoid in patients with breast cancers, history or risk of thromboembolic disease,

  • Efficacy: excellent

    • Small RCT demonstrated stoppage of bleeding in 72% of women with exposure to IV estrogen over 8 hours (vs 38% with placebo).

  • Requires observation/inpatient administration as IV only, and will ultimately need to transition to a PO medication (can’t use unopposed estrogen forever!)

• Combined oral contraceptives

  • Suggested dose: 35mcg monophasic combined pill, TID x 7 days.

    • Many alternative regimens that are discussed, likely one exists that is a favorite at your hospital.

  • Avoid in patients who are smokers age 35+, history of or current VTE, migraine with aura, or other major risk factors for VTE (diabetes with vascular complications, recent surgery with immobility, etc).

  • Easy to administer, and patients are generally familiar with OCPs.

  • Side effects generally include nausea from high amount of estrogen - consider coprescription with antiemetic.

  • High efficacy -- 88% stop bleeding within 3 days.

• Medroxyprogesterone acetate (Provera)

  • Suggested dose: 20mg PO, TID x 7 days

    • Like COCs, many alternative regimens exist, and likely one is a favorite at your hospital.

  • Similar contraindications: avoid in those with past/current history of DVT/PE, breast cancer, or liver disease.

  • High efficacy -- 76% stop bleeding within 3 days.

  • May have improved side effect profile over COCs (less nausea)

• Tranexemic acid

  • Dose: 1300mg PO TID x 5 days; alternatively, can use IV formulation at max 600mg q8h.

  • Uncertain thromboembolic risk, but follows again that may increase this risk so use with caution in those with significant risk factors.

  • Reduces bleeding in those with chronic AUB 30-55%.

Bleeding disorder suspected?

Get hematology involved! Resuscitation / treatment may be influenced by particular factor deficiencies.

Surgical management

• D&C, hysteroscopy, etc.

  • May be helpful for known causes (i.e., polyp, submucosal fibroid) but are often just temporizing measures otherwise.

  • Unless cause is truly identified, will not necessarily impact bleeding beyond the current cycle.

• Balloon tamponade

  • On the small, nonpregnant uterus, use a 26F Foley catheter with 30cc saline in the balloon.

• Interventional radiology for uterine artery embolization; hysterectomy

  • These can be considered as options, though ideally not in the mega-acute situation. More ideal to have some planning involved first!

Perinatal Depression

Depression is a major health disorder affecting around 10% of women, particularly in the perinatal and postpartum periods. Depression is twice as common in women as in men, and OB/GYNs should be familiar with its diagnosis and management, particularly in the perinatal period. You can read more with ACOG CO 757.

There are many different types of depression diagnoses, including: major depressive disorder, persistent depressive disorder, seasonal affective disorder, perinatal (postpartum) depression, premenstrual dysphoric disorder (PMDD), etc. According to the DSM-V, a major depressive episode is diagnosed when one has: 

• Five (or more) of the following symptoms have been present for a 2-week period and represent a change from previous functioning; at least one of the symptoms is either depressed mood or loss of interest/pleasure. 

• Symptoms cannot be explained by medications or another medical illness (i.e., hypothyroidism).

• The remaining (need 4+ from this list):

  • Depressed most of the day, nearly every day as indicated by subjective report or observation made by others;

  • Diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day;

  • Significant weight loss when not dieting or weight gain, or increase/decrease in appetite nearly every day;

  • Insomnia or hypersomnia;

  • Psychomotor agitation or retardation; 

  • Fatigue or loss of energy;

  • Feelings of worthlessness or inappropriate guilt;

  • Decreased ability to think/concentrate;

  • Recurrent thoughts of death/suicidal ideation.

Perinatal depression is defined separately as major and minor depressive episodes that occur during pregnancy or in the first 12 months after delivery. This is one of the most common medical complications during pregnancy and the postpartum period, affecting 1/7 women. 

Depression and other mood disorders can have devastating effects on women and their families: maternal suicide exceeds hemorrhage and hypertensive disorders as a cause of maternal mortality 

SO how do we screen for perinatal depression? ACOG recommends that obstetric care providers screen patients at least once during the perinatal period for depression and anxiety symptoms using a standardized tool, and again in the postpartum period during a comprehensive postpartum visit. There is evidence that screening alone can have clinical benefits for patients suffering with depression.

One of the most commonly used is the Edinburgh Postnatal Depression Screen, which is a 10 item survey that takes less than 5 minutes to complete. The sensitivity is estimated between: 59-100%, and specificity: 49-100%. A Spanish version is available.

The Patient Health Questionnaire 9 (PHQ-9) is another acceptable tool. Other items like the Postpartum Depression Screening Scale (PDSS) is more sensitive (91-94%) and specific (72-98%), but it is a 35 item survey and thus more time intensive.

Management of perinatal depression is a team sport, requiring multiple additional support members and medical team members. Medication prescription will vary for OB/GYNs and their comfort with this. In brief:

• Women with current depression/anxiety or a history of perinatal mood disorder should have close monitoring, evaluation, and assessment.

• Some OB/GYNs are comfortable starting antidepressant medication and following their patients, most commonly an SSRI. Psychiatry referral is also acceptable.

• Referral to social work and behavioral health - possibly for psychotherapy, which alone is a reasonable alternative to antidepressants if needed.

• For those with severe postpartum depression, another possibility is brexanolone.

  • Limited clinical experience and restricted availability 

  • Usually restricted to patients who do not improve with antidepressants 

Espresso: Umbilical Cord Gas Interpretation

Building somewhat on our fetal circulation episode from last week, today we’ll talk about umbilical cord gases. From an obstetrics perspective, these can be challenging to really interpret, but the simple interpretation is often worth some CREOG points if you can analyze these systematically.

Remember, the umbilical vein is carrying oxygenated blood, and the umbilical arteries are carrying deoxygenated blood. This can help you remember the normal values, as they’ll be opposite those for an ABG versus VBG on an adult. Additionally, the umbilical vein is originating at the site of the placental interface with the mother -- so venous pHs will give a sense of maternal acid-base status, or the acid-base status at this interface. For this reason, the arterial pH is more helpful to truly measure fetal acid-base status.

The components of the blood gas are:

• pH: represents the inverse log of the concentration of hydrogen ions in the circulating blood, or how acidic the blood is. In essence, more acid represents a lower pH, which represents more compromise. 

  • Normal value for a venous pH is around 7.35 (as it is in adult blood).

  • Normal value for an arterial pH is around 7.28.

• pO2: the pressure of oxygen (in essence its concentration) in fetal blood.

• pCO2: similarly, the pressure/concentration of CO2 in fetal blood.

  • The pO2 and pCO2 can given additional clues to help with non-straightforward (i.e., mixed) acidosis.

• Base Excess/Deficit: in blood, acid is buffered by bicarbonate ions. The base excess or deficit represents how much difference there is between those bicarbonate ions and hydrogen ions in order to return to a normal pH value of 7.35 in the umbilical vein. An excess is more bicarb; a deficit is less bicarb. However, these tend to get used interchangeably, and in these acid-base status questions, you’ll see the “excess” written as a negative number — implying what is actually a deficit.

  • Normal values for base excess are around 4 mmol/L in both the umbilical artery and vein.

  • A more significant base deficit signifies a metabolic acidosis -- i.e., the process causing insult has been longstanding, and there has been time to utilize bicarbonate to buffer the acid. 

  • A lower base deficit signifies a respiratory acidosis -- i.e., the process has been acute, so there has been no buffering of the hydrogen ions. 

    • A base deficit of 12 mmol/L has been suggested as severe, and more suggestive of metabolic acidosis. 

(c) MDEdge

What about administering more O2 to the mother? Won’t that help things and reduce the fetal risk of acidosis?

If only it were that simple! Sadly, the answer is no. In most cases, maternal hemoglobin is fully saturated on room air. Fetal hemoglobin has a greater O2 avidity, and will pull O2 across the placental circulation. But when maternal blood is already saturated, the fetus won’t get any more O2 even if you pump it up to 4000L a minute by mega face mask! Some studies have suggested the additional free O2 in maternal serum may actually lead to vasospasm and cause harm! 

The exception to this certainly is a change in maternal oxygenation or an indication for maternal O2 use -- but these indications suggest that maternal Hb is less than 100% saturated. 

When should I get a cord gas?

It’s a good idea to practice the technique for cord gas collection, which requires collecting a 10-20cm doubly-clamped (i.e., proximally and distally) cord segment. Even on routine, vigorous deliveries, getting into this habit as part of your deliveries will help you be prepared. 

Cord gases are not recommended to be sent with delayed cord clamping, so don’t send these if DCC is part of your practice! However, collecting the cord segment can be good practice for those learning proper technique.

There are no consensus rules about when to send a cord gas sample. At our institution, the general thought is “if you think you need one, send one.” However, common scenarios where cord gas sampling can be helpful to at least set aside on a “just in case basis”  include:

• Nonvigorous infant at delivery (i.e., Apgars at 5 mins less than 7)

• Category III or “bad category II” tracings

• Operative deliveries performed for NRFHT

• Multiple gestation

• Premature infants

• Meconium stained fluid

• Growth restriction

• Breech deliveries

• Shoulder dystocia

• Intrapartum fevers or chorioamnionitis

Obviously this list is non-exhaustive, but goes to show there are a lot of indications! Some literature has suggested even universal arterial blood sampling at delivery may be cost-effective. 

The best way to learn this is to do some practice cases. Check out the below resources for some practice questions and further explanations.

• https://www.texaschildrens.org/sites/default/files/uploads/documents/health_professionals/kaleidoscope/Day%201%20Fetal%20Monitoring%20and%20Umbilical%20Cord%20Gases.pdf

• https://www.mdedge.com/obgyn/article/132375/obstetrics/how-and-when-umbilical-cord-gas-analysis-can-justify-your-obstetric/page/0/1

• https://www.uptodate.com/contents/umbilical-cord-blood-acid-base-analysis-at-delivery#H2