Menstrual Suppression

Read the new ACOG Clinical Consensus! – General Approaches to Medical Management of Menstrual Suppression

Why menstrual suppression?

• As an OB/GYN that might sound like a silly question – but for our patients, this is a serious concern!

  • A holdover of understanding (even with the design of OCPs) that a “natural cycle” is necessary for health – it’s not. 

• Goal overall is to:

  • Reduce menstrual flow, by amount and total days while

  • Find a strategy based on patients preferences and goals, balancing any risk factors.

Which method is best?

• Combined Hormonal Contraception

  • Can achieve menstrual suppression by skipping the placebo week.

    • Some packs designed for this - 84/7 regimens, 24/4 regimens.

    • This can be done indefinitely!

      • Studies have found these extended cycle and continuous use regimens to be safe and effective

  • Patients should be counseled that over time, breakthrough bleeding is more likely to occur. In a recent RCT comparing OCPs to an LNG-IUD for menstrual suppression, folks in the OCP group had BTB:

    • 50% at pill pack 3;

    • 69% at pill pack 7;

    • 79% at pill pack 13.

  • Bleeding overall tends to decrease with successive cycles.

  • Breakthrough happens less with higher doses of estrogen (i.e., more bleeding on a 20mcg pill than a 30mcg pill).

  • BTB will decrease with each successive cycle – so it’s not unreasonable to consider monthly cycles for 3-6 months, then transition to more extended cycles. 

    • Intermittent estrogen can also be used to help prevent BTB.

  • The patch and vaginal ring can also be used for menstrual suppression, and have advantage of not requiring daily medication.

    • Patch has no difference in frequency of BTB compared to pills.

    • Ring is well tolerated for extended cycles and seems to be effective in reducing/minimizing bleeding.

• Progestin-Only Methods

  • These can be of particular importance to patients where estrogen is contraindicated (cardiovascular disease, migraine with aura, hypertension, hypercoagulability) or undesired (trans-men, patient preference).

• POPs

  • The mini-pill (norethindrone 0.35mg) has to be taken in a tight window, and has low rates of amenorrhea, so is generally not a great choice for menstrual suppression.

  • Norethindrone acetate 5mg can be used for menstrual suppression with better success compared to the minipill, with amenorrhea rates of up to 76% at 2 years of use.

    • However, this formulation is not approved as a contraceptive so can’t be used for this.

  • Drosperinone 4mg is a new progestin only pill on the market; data is limited, but it is likely more promising than the minipill for menstrual suppression and also has contraceptive effect. 

    • That said, likely not a first line choice for this indication specifically.

• DMPA (depot medroxyprogesterone acetate)

  • The DMPA shot is given roughly every 3 months.

  • Amenorrhea rates are good, especially with more prolonged use – 68-71% at 2 years.

    • However, unscheduled bleeding is a common side effect.

    • Loss of bone mineral density and weight gain are other common concerns; the loss of BMD is reversible with discontinuation. 

• LNG-IUD

  • Excellent at amenorrhea - 50% at 1 year, 60% at 5 years; highest with the 52mg varieties.

  • BTB can be managed by offering a trial of NSAIDs, POPs/OCPs, or doxycycline before discontinuing the IUD.

  • Not a good choice for patients where ovulation suppression is also desired (ie, PCOS) – the IUD has unclear/unpredictable effects on ovulation suppression.

• Etonogestrel implant (nexplanon)

  • Can be continued up to 5 years for contraception, FDA approved for 3 years.

  • For menstrual suppression, use past 3 years may not be effective. 

  • 22% achieve amenorrhea, but breakthrough bleeding and spotting are common, especially shortly after insertion.

    • BTB can be managed with OCPs or norethindrone.

• The ACOG document contains a very helpful but large table on the different types of hormonal contraception and their relative success, advantages, and disadvantages with menstrual suppression. Definitely worth keeping a bookmark on or a snapshot on your phone!

How do I go about selecting a method?

• Counsel your patient with shared-decision making in mind:

  • Be aware of inequities in provision of menstrual suppression methods and your own biases

  • Share with patients realistic expectations of what each method might offer in the way of menstrual suppression

    • No method can guarantee amenorrhea

  • Take into account patient’s preferences and values

  • Be aware of medical history / medical eligibility criteria that might contraindicate certain methods

    • CDC Contraception App – super helpful to have the MEC handy!

By patient population:

• Adolescents:

  • Hormone therapies are safe for adolescents

  • Initiation of menstrual suppression is safe anytime after menarche!

    • Need to have at least one menstrual period to be certain of normal pubertal development.

  • Pelvic exam is not needed for routine prescription of contraception, unless needed for the actual insertion (i.e., IUD)

    • IUD insertion has been shown to not be any more difficult in adolescents compared to older individuals, nor more difficult in nulliparas compared to parous patients.

  • Other tenets of adolescent reproductive healthcare counseling should be applied:

    • Discuss concerns about any side effects that are common / common concerns - fertility, weight, development, bone health, STIs

    • Use the opportunity to establish healthy alignment with adolescent at the OB/GYN office to establish as a safe place for current & future care

• Transgender / Gender Diverse Patients

  • Menstrual suppression can help reduce feelings of gender dysphoria associated with menstruation

  • Testosterone use for gender-affirming care is associated with amenorrhea, often within a few months of starting therapy.

  • GnRH is also capable of pubertal blockade and suppression of menses for gender-affirming therapy, with amenorrhea rates nearing 100%.

    • Testosterone and GnRH are not contraceptives, though - so if they are at risk of pregnancy, contraception should be discussed

    • GnRH also cannot be used long term given concerns for bone density effects.

• Patients with physical or cognitive disabilities, or both

  • Particularly for patients with cognitive disability, menstruation is a significant source of anxiety for caregivers and is a common reason for visit for pediatric gynecology clinics, even among premenarchal patients

  • Adolescents and adults with disabilities are also often assumed (erroneously) to be asexual and do not receive sexuality and contraceptive counseling on par with their peers

    • These individuals are also at increased risk of sexual abuse and unintended pregnancy

  • Assist families with developmentally-appropriate education and family assistance with hygiene concerns, contraception, STIs, and abuse prevention

  • Menstrual suppression methods can follow the patient’s needs, preferences, and values. 

    • Consider in these patients their mobility and presence of contractures; swallowing ability for pills; and presence of other interacting drugs (i.e., antiepileptics).

    • If plan for LARC and anesthesia required, it can be considered to “bundle” together services like dental work to minimize patient exposures to anesthetics

  • If patient doesn’t have capacity to make independent decision, menstrual suppression discussions should be made with the caregiver in patient’s best insterest.

    • Ethical and prudent choice is reversible and low-risk options.

• Populations with challenges affecting hygiene/privacy

  • Military deployment

  • Incarceration

  • Houselessness

  • Patients in war zones or difficulty with care access

  • Athletes

    • Obviously hard to think about all of the potentials here, but consider patient access to medical services, sanitary products, restrooms or private areas, in making shared-decision making on menstrual suppression

How do I manage breakthrough bleeding?

• One of the most common challenges in menstrual suppression

• Anticipatory counseling that this is common is helpful in reducing method discontinuation rates and improving method satisfaction, as well as reassuring that BTB is benign and common.

  • Reassure that with some methods BTB decreases or ceases after some time period of initial use

Updates in Pap Screening Part II: High Grade Lesions

Here’s the RoshReview Question of the Week:

A 45-year-old woman presents to your office for follow-up. She has a history of postpartum tubal ligation. She had a colposcopy for high-grade squamous intraepithelial neoplasia. The procedure was performed at the office and revealed one white lesion after acetic acid application. Biopsy results reveal cervical intraepithelial neoplasia grade 1. The borders of this lesion were not entirely identified. Which of the following is the best next step in management?

• Colposcopy and human papillomavirus-based testing in 1 year

• Cryotherapy

• Laser ablation therapy

• Loop electrosurgical excision procedure

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We’re back this week with Part II on Pap smears! Let’s cover high grade lesions.

First, the easy part: any ASC-H result merits colposcopy, regardless of HPV status! The down-the-line management will vary by age. 

• In patients aged 21-24, ASC-H and HSIL get treated the same - colposcopy.

• In patients 25 and older, ASC-H goes to colposcopy, but HSIL can proceed immediately to excision, or perform colposcopy first prior to excision.

• Why is there an option to go straight to excision?

  • The overall 5 year CIN2+ risk for HSIL above age 25 is 77%, and for CIN3+ its 49%. Given those high risks, it is acceptable to proceed directly to excision without colposcopy.

  • Most women with HSIL will have HPV+ testing. 

    • But even with negative HPV results, an HSIL test carries a 5-year risk of CIN3 of 25% and an invasive cancer risk of 7%. Thus, it’s still acceptable to proceed straight to excision in this scenario. 

      • One way to think about this is the number needed to treat, which is super impressive. For HSIL HPV+, the NNT is 1.7 – that is, 1.7 excisional procedures for every CIN3+ treated – a very low rate of overtreatment!

        • For HSIL HPV-, the NNT is still very low at 2.8.

So we do a colpo and get biopsies… now what?

Your biopsy result will be a histology result – so CIN1, CIN2, CIN3, AIS, or invasive cancer. Let’s review the non-invasive management strategies for post-colposcopic biopsy.

CIN1 - this depends on the preceding Pap cytology, and the patient’s age:

• HSIL cytology: many strategies are acceptable:

  • Observation, which entails colposcopy and cytology in patients under 25, or HPV-based testing with colposcopy in patients 25 and older, at one year.

  • An excisional procedure (not recommended in patients under 25)

  • Or a pathology review to determine if there is a discrepancy in the previous interpretation of cytology or histology.  

  • With observation being most typical in younger patients:

    • Colposcopy and cytology/HPV testing should occur again in one year. 

      • If these are negative, age specific retesting should happen again in an additional year, followed by HPV-based testing every 3 years for at least 25 years.

      • If there’s any abnormality, then manage that using the ASCCP guideline for the specific abnormality; though specifically, if HSIL again, excision is recommended.

        • Unless the patient is still under age 25, then observation can be continued for up to 2 years prior to recommendation for excision. 

• ASC-H cytology: observation is the most typical strategy:

  • Perform cytology if under 25, or HPV-based testing if > 25, in one year.

    • If negative, HPV-based testing can resume in 3 years from that.

    • If abnormal - you manage according to the ASCCP guideline.

      • Specifically, if progresses to HSIL – excision is recommended if over age 25.

      • If persistent ASC-H, can repeat again in 1 year, but excision is recommended if over age 25 and ASC-H persists for 2 years. 

      • For those under age 25, HSIL or ASC-H should persist for two years before excision is recommended.

• Lower grade cytology (ASC-US or LSIL):

  • Repeat co-testing at 12 months and 24 months.

    • If normal, then can have repeat testing in 3 years before resuming normal age-appropriate intervals.

    • If there is an abnormality in this 2 year window, then management should be performed according to cytology – though if there’s progression to HSIL, colposcopy and/or excision is recommended using the same guidelines as we stated for ASC-H.

CIN 2 or 3 on colposcopic biopsy - this will warrant an excisional procedure, typically.

• For CIN2, observation is considered acceptable in patients under 25, or those over 25 if there are concerns about future pregnancy that, for the patient, outweigh their concerns about cervical cancer.

  • If that’s the case, colposcopy and HPV-based testing should occur at 6 and 12 months. 

    • If two consecutive evaluations have less than ASC-H cytology and less than CIN2 histology, then testing can space to annually for 3 total years.

    • If the tests are abnormal, q6 month testing can continue for up to 2 years.

    • If CIN3 develops at any point, or the abnormalities persist for more than 2 years, excision becomes recommended.

• For CIN3, observation is not advised – these should proceed to excision.

• If you proceed with excision, the management is based on your excisional margins:

  • If margins are negative, then cotesting at 12 and 24 months is subsequently recommended, with repeat colposcopy needed for any abnormal result.

  • If margins are positive, then you have three choices:

    • Repeat cytology with endocervical curettage q4-6 months.

    • Repeat excision, if feasible.

    • Hysterectomy.

      • Notably, hysterectomy should only be considered if repeat excision is not feasible, or if high grade abnormalities are persistent after attempted repeat excision. 

Adenocarcinoma In Situ (AIS)

• If AIS is identified, excision is needed to rule out invasive cancer.

  • If margins are positive, reexcision is recommended to try to achieve negative margins.

  • If margins are negative, hysterectomy is generally preferred after the excision.

    • The excision is mandatory! You can’t proceed straight to hysterectomy – because if invasive cervical cancer is advanced enough, then hysterectomy may not be the recommended treatment.

  • If margins are negative, and the patient desires fertility, then reevaluation with HPV-based testing every 6 months for 3 years, then annually for two years, is acceptable. 

    • Hysterectomy is recommended following childbearing, though! 

Other Uncommon Pap Results

Unsatisfactory Cytology

• Super frustrating! Your Pap didn’t have enough to evaluate!

• Recommendations:

  • Follow your HPV result if you got it!

    • If HPV positive (especially 16/18), colposcopy is warranted.

    • If HPV is negative in someone 25 years or older, or if no HPV result, or unknown HPV result, then repeat the Pap in 2-4 months.

      • If the Pap is again unsatisfactory, colposcopy is recommended – good idea to take a look and figure out what you’re missing if two in a row are not satisfactory.

Negative for Intraepithelial Lesion, but Absent transformation zone or endocervical cells

• This is also usually an insufficient Pap that didn’t sample that transformation area from glandular to squamous cell. This is the area where most HPV-associated disease is located, so effectively this is an insufficient Pap.

  • If Age 21-24, routine screening can continue.

  • If age 25+, HPV screening can triage:

    • If negative, routine screening can continue.

    • If unknown, repeat cytology in 3 years is acceptable, or get HPV testing (preferred).

    • If positive, then you follow the HPV-positive management guideline – which as a reminder for 16/18 is colposcopy, and for other types of HPV in this case would be to repeat the HPV-based test in one year.

Atypical Glandular Cells (AGC) and Atypical Endometrial Cells (AEC)

• For these pathologies, a number of tests are recommended:

  • If atypical glandular cells or other subcategories, 

    • Colposcopy with endocervical sampling is recommended. 

    • Endometrial sampling should also be performed if the patient is 35 or older, or under 35 with risk factors such as AUB, chronic anovulation, or obesity.

  • If atypical endometrial cells

    • Endometrial and endocervical sampling are recommended, and colposcopy can also be performed – 

      • and generally colposcopy should be performed, as if the other samplings are negative, colposcopy would then be warranted at that point. 

• Management would then proceed on the basis of these findings.

  • If no CIN2+, AIS, or cancer, then cotesting is recommended at 1 and 2 years, and can be spaced to every 3 years after that if remains negative.

  • If CIN2+ is identified, or if the initial cytology was concerning for neoplasia, then excisional procedure is typically recommended.

Updates in Pap Screening and Management, Part I

Here’s the RoshReview Question of the Week:

A 26-year-old woman presents to the office to review her Pap smear results. Her Pap smear showed atypical squamous cells of undetermined significance with positive human papillomavirus testing. Her previous Pap results are unknown. What is the best next step in management, given this result?

• Colposcopy

• Proceed with loop electrical excision procedure

• Repeat cotesting with cervical cytology and human papillomavirus testing in 3 years

• Repeat Pap smear in 12 months

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We talked about Pap screening last in July 2019 and managing an abnormal Pap in January 2020.

Shortly after, the ASCCP published its updated screening and management guidelines!

And they updated their awesome Pap management app – if you have $10 to spare, you’ll definitely get value out of it in residency and likely beyond.

What’s new with Pap screening?

• Short answer – not a lot, but there is controversy!

  • In July 2020, the American Cancer Society published new recommended screening guidelines for individuals at average risk, with three major changes:

    • Recommendation of primary HPV testing every 5 years as the screening strategy, rather than co-testing.

    • Beginning Pap screening at age 25, rather than age 21.

    • Co-testing and/or cytology are acceptable per old guidelines, but ultimately the guidelines are meant to be transitory until facility/area has accessible primary HPV testing.

  • The USPSTF guidelines overall remain unchanged (for now!), but do include the option for primary HPV testing. Highlights:

    • Screening with cytology alone starting at age 21, q3 years.

    • Co-testing acceptable at age 25, and can space with cotesting to q5 years, HPV primary screening q5 years, or cytology alone q3 years. 

    • Ending screening after benign hysterectomy with no prior high risk dysplasia, or 25+ years after high-grade dysplasia, presuming adequate negative screening previously.

  • How does ASCCP feel?

    • July 2021 Statement

    • They note that evidence does exist that primary HPV screening is safe and effective as a cancer screening strategy, and in increasingly-immunized populations appears to be more effective than cytology-based screening.

      • One referenced study noted 5-fold higher detection rates in patients with CIN2+ based on HPV screening versus cytology beginning at age 21. 

    • However, uptake has been slow and implementation has been challenging, and thus they do endorse the USPSTF guidelines that suggest greater flexibility. 

      • They offer a more qualified statement of support for the ACS  guidelines in locations that can equitably and effectively implement primary HPV screening. 

    • They also recognize that HPV self-collection may help increase access and availability to patients, and hope to identify more evidence of comparative efficacy to provider-collected specimens. 

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Comparison of USPSTF 2018 and ACS 2020 screening guidelines (ASCCP statement).

Managing Abnormal Pap Smears

• In our last episode, we gave a framework that first separated Paps into “high grade” and “low grade,” age, and HPV status. We’ll apply that again and re-review the management.

• Ultimately, the guidelines are framed around the question of what CIN3+ risk exists:

  • The first question: is the immediate risk greater than/equal to 4%?

    • If yes → how high is that risk? 

      • If 60+%, then expedited treatment is preferred

      • If 4-24%, then colposcopy is preferred

      • If in between, either is acceptable.

    • If immediate risk of CIN3+ is less than 4%:

      • What is the risk of CIN3+ within 5 years?

        • If > 0.55%, then return in 1 year for screening.

        • If between 0.15 and 0.54%, then return in 3 years.

        • If < 0.15%, then return in 5 years.

    • “Equal management for equal risk” is the underlying principle.

• ASCCP also adjusts risk given the clinical situation, such as a routine screen; a patient who is rarely screened; management of results during post-colposcopy surveillance; or follow ups after excision/treatment. 

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ASCCP

So let’s go through possible results on Pap smears at this point. 

We’ll presume that you are either performing co-testing, or HPV-primary screening with reflex to cytology.

We’ll also presume that the patients we mention here are undergoing “routine screening” – meaning that they’ve had prior screening, or it is their first screen in their lifetime if they are under age 30. 

Finally, given the additional nuances with screening, we strongly recommend reviewing management steps using the ASCCP app for guidance.

We will just review the first steps in management plans; follow ups get very much into the weeds and are individualized – a huge plus for patients, but much more challenging for memorization!

HPV Primary Screening Management

• HPV 16/18+ – colposcopy (and obtain reflex cytology).

• HPV other + – reflex cytology, then follow the appropriate cytology guidelines! 

Cytology/Cotesting Guidelines

Normal Cytology. 

The only potential abnormal in this category for someone 25 years or older is HPV positive. The risk of CIN 2 or greater in this population is approximately 2-6%. It increases if HPV is persistently positive over time, or is type 16/18.

• If typed and result is HPV-16 or HPV-18, colposcopy is recommended.

• If untyped or not 16/18, repeat cotesting in 1 year.

 Low Grade Cytology (ASC-US, LSIL)

• Age 21-24, ASC-US and LSIL get treated the same, with the recommendation for repeat cytology in 12 months. 

  • This is because the clearance of HPV-caused ASC-US and LSIL is overall high in this group, and colposcopy may lead to overly aggressive management. 

  • As long as there’s no progression to high-grade, there is no indication for colposcopy.

• In patients aged 25-29 and 30-64, the management of LSIL and ASC-US are similar.

  • Age 30-64, ideally HPV testing is always available by cotesting or primary screening!

  • The USPSTF guidelines in 25-29 year olds though do call for cytology q3 years as the primary screening strategy.

    • LSIL or ASC-US, HPV negative: overall low risk of malignant transformation.

      • Thus, with LSIL, can repeat cotesting in 1 year.

      • With ASCUS, repeat in 3 years.

    • LSIL, HPV unknown: get colposcopy given unknown HPV status.

    • ASC-US, HPV unknown: repeat cytology in 3 years if 25-29, and 1 year if 30-64

      • Ideally both would have co-testing on the repeat evaluation!

    • LSIL or ASC-US, HPV positive: colposcopy should be performed.

    • The 5-year CIN3+ risk for both HPV+ ASCUS and LSIL are very similar, approximately 7%.

• Finally in patients aged 65+, Pap smears are likely only continuing at this point if there have been previous abnormalities, or a lack of screening. Thus, ASC-US or LSIL with negative HPV should be treated as abnormal, and thus merit repeat cytology in 1 year. All other abnormalities (i.e., HPV positive) in this age group should receive colposcopy!

Note that we didn’t talk excisional procedures at all; low grade lesions (ASC-US, LSIL) should generally proceed to colposcopy before considering excision. 

Part II will encompass high grade lesions, so stay tuned!

Hysteroscopy II: Complications and Troubleshooting

Here’s the RoshReview Question of the Week!

A 45-year-old woman in the postoperative recovery unit develops dyspnea. Her serum sodium is 130 mEq/L. Which of the following was the most likely distending medium used during her hysteroscopic monopolar fibroid resection?

• 1.5% glycine

• 5% mannitol

• Lactated Ringer solution

• Normal saline

Check out the answer and enter the QE QBank Giveaway at the links above!

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Why do we do hysteroscopy?

• Diagnostic

  • AUB

  • Infertility

  • Structural anomalies

• Operative

  • IUD removal

  • Polyps

  • Fibroids

  • Septums

  • Intrauterine adhesions and Ashermans

  • Endometrial ablation

  • C/section scar (isthmocele) excision

  • C/section scar or cervical ectopics

  • Tubal cannulation

Complications of Hysteroscopy -check out ACOG CO 800!

• Perforation

  • Most common complication - range 0.12-1.61%

  • Risk factors

    • Blind insertion of instruments

    • Cervical stenosis

    • Anatomic distortion - fibroids, adhesions, myometrial thinning, extreme anteversion or retroversion)

  • High index of suspicion

  • Decrease risk by using ultrasound or laparoscopic guidance

  • With dilation or with scope (unlikely)

    • Low risk of subsequent complications

  • During instrumentation

    • Increased risk of injury to extra-uterine structures

    • Requires evaluation - laparoscopy +/- laparotomy 

• Fluid Overload

  • Rare - 0.2%

  • Risk factors - resection of large or deep lesions, high pressure setting

  • As reviewed in prior episode

    • Limit fluid deficit to 1000mL for electrolyte-free hypotonic media, 2500mL for electrolyte-rich isotonic media

    • Use fluid management systems, Designated individual to monitor fluid deficit, decreased deficit limits for patients with comorbidities

    • Other preventive measures

      • GnRH agonists (pre-op)

      • Intracervical vasopressin injection

      • Planning for staged procedures

  • Management

    • Stop procedure

    • Assess hemodynamic, neurologic, respiratory, CV status

    • Check labs - serum electrolytes, osmolality

    • Consider loop diuretic (Furosemide)

    • Consider hypertonic saline

• Hemorrhage

  • 0.03-0.61%

  • Risk factors - cervical laceration, uterine perforation, cavitary lesion resections

  • Management will depend on site and severity of bleeding

    • Suture, electrocautery, intrauterine foley balloon, UAE, hysterectomy

  • Prevention

    • Dilute vasopression injection

• Cervical laceration

  • Prevention

    • Ensure good bite with tenaculum

• Air embolism

  • 0.03-0.09%

  • Risk factors - repetitive reintroduction of instruments through the cervix, not purging air from tubing

  • Signs/symptoms

    • If awake - chest pain, SOB 

    • If under anesthesia - decreased end-tidal CO2, hypotension, tachycardia

    • Mill-wheel murmur on physical exam

  • Management

    • Terminate procedure - deflate cavity

    • Place patient in left lateral decubitus and trendelenburg to move air bubble away from RV outflow tract

• Infection

  • 0.01-1.42% (includes intrauterine infection (endometritis) and UTIs)

  • Risk is low enough that antibiotic prophylaxis not routinely warranted

• Vasovagal reaction

  • Typically due to cervical dilation

  • Stop procedure, assess ABCs, raise legs/Trendelenburg

  • Can consider atropine if needed for bradycardia

Troubleshooting Hystersocopy

• Cervical stenosis

  • Misoprostol (200-400mcg vaginally 12-24 hrs pre-procedure)

  • Vasopressin

  • Small dilators (lacrimal duct dilators), ultrasound guidance

• Sudden increase in fluid deficit

  • Consider perforation

  • Ensure all outflow is being collected appropriately

• Reaching fluid deficit limit

  • Staged procedures (particularly Type 2 fibroids)

Tubal Ectopic Pregnancy Management

Here’s the RoshReview Question of the Week!

A 24-year-old G2P1 woman presents to the emergency department with right-sided pelvic pain and vaginal spotting. She has been trying to conceive and her last menstrual period was 8 weeks ago. The patient reports her left fallopian tube was removed 3 years ago due to hydrosalpinx. Her beta-human chorionic gonadotropin is 6,700 mIU/mL. On ultrasound, there is no intrauterine pregnancy identified. Fetal heart tones are detected in the right fallopian tube. There is a minimal amount of free fluid noted in the posterior cul-de-sac. What is the most indicated intervention at this time?

• Methotrexate

• Salpingectomy

• Salpingostomy

• Surveillance

Check to see if you got it right at the links above!

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While we have reviewed the workup of the early unlocated pregnancy and diagnosis of ectopic pregnancy previously with Dr. Cleary, and talked about the unusual problem of cesarean ectopic pregnancy before on the show, somehow we missed the management of the regular tubal ectopic! 

ACOG PB 191 is a great resource for all things ectopic pregnancy and important companion reading for the podcast today.

Background Info

• Ectopic pregnancy represents about 2% of reported pregnancies, but this is likely an undercall as not all ectopic pregnancies are reported.

• Ruptured ectopic accounts for a significant cause of maternal morbidity and mortality - 2.7% of maternal deaths in 2011-2013 were attributable to ruptured ectopics. 

• Fallopian tube is the most common location for an ectopic (90%), but as we’ve talked about before, these can be anywhere – abdomen (1%), cervix (1%), ovary (1-3%), and cesarean scar (1-3%). 

  • Can also co-occur with an intrauterine pregnancy – heterotopic pregnancy.

    • Naturally conceived: 1 in 4,000 to 1 in 30,000

    • IVF: as high as 1 in 100

Risk Factors for Ectopic Pregnancy

• 50% of those who receive a diagnosis don’t have any known risk factor. 

• Risk factors that can be present include:

  • Prior ectopic - recurrence risk is about 10% after 1 prior, 25% after 2 prior

  • Prior fallopian tube surgery / damage

  • History of PID or ascending pelvic infection

  • ART - tubal infertility, multiple embryo transfer, infertility in general

  • Cigarette smoking

  • AMA > 35yo

• Contraception and ectopic risk:

  • Those using IUDs are at lower risk overall of ectopic because IUDs are highly effective at preventing pregnancy in general.

    • However, in those who do become pregnant with an IUD in place, up to 53% of these pregnancies are ectopic.

  • OCP use, emergency contraceptive failure, previous pregnancy termination, pregnancy loss, and cesarean delivery have not been associated with increased risk of ectopic pregnancy. 

Confirming a Diagnosis of Ectopic Pregnancy

• We covered this pretty extensively in our episode with Dr. Cleary - there we do a great job of talking you through the “pregnancy of unknown location” workup, especially when you see a patient in ED/triage with bleeding/pain and early pregnancy. 

• We won’t go through it all again today, as we want to focus primarily on management, but a few big points:

  • Trending bHCG every 48 hours helps to determine if the pregnancy is normal or abnormal.

    • If a bHCG is higher than the DZ and you don’t see anything - that’s a good indicator of an abnormal pregnancy, with 50-70% being ectopic. 

  • Transvaginal ultrasound to assess the uterus and adnexae will help you identify any unusual mass that might be an ectopic.

• So let’s start from the point of abnormally rising bHCG, so we know our suspicion is for an abnormal IUP versus ectopic. What options are available?

  • Expectant Management

    • We can continue to trend bHCG in a stable patient, particularly in the case of highly desired pregnancy or low bHCG values that may need more time to declare itself.

    • These patients should be counseled strongly about presenting for care should they experience significant bleeding, severe pain, or other symptoms worrisome for ectopic rupture. 

  • Uterine Aspiration

    • If we are reasonably certain the pregnancy is abnormal, a uterine aspiration can be done to determine if the pregnancy is intrauterine or not.

      • The aspirate can be sent to pathology or floated to quickly identify chorionic villi – if found, then you know it was an IUP.

      • If villi are not found, then hCG should be measured again at 12-24 hours after aspiration.

        • If the hCG drops at least 10-15%, it was likely successful aspiration of a failed IUP; however, drops of 50% or greater are more indicative. 

          • Serial hCG should be followed to zero in these patients since no pathology was identified.

        • If the hCG is plateaued or rising, then the pregnancy is ectopic, and the patient will need additional treatment. 

  • Proceeding Directly to Treatment

    • The PB mentions there is debate whether aspiration is necessary before treating an abnormal pregnancy with methotrexate.

      • On one hand, confirmation of the diagnosis with the procedure helps avoid unnecessary exposure to MTX.

      • On the other hand though, the procedure adds at least 12-24 hours of additional time (and potential ectopic rupture) before giving treatment.

    • ACOG notes that the risk of rupture during this time period overall is low, and that presumptive treatment with MTX doesn’t confer cost savings

      • However, it reserves the choice for patients and their physicians after discussion of risks and benefits.

Medical Treatment of Ectopic Pregnancy

• The standard, as we’ve mentioned, is methotrexate.

  • Folate antagonist binding to catalytic site of dihydrofolate reductase → inhibits synthesis of nucleotides and amino acids, thus inhibiting DNA synthesis, cell repair, and cell replication.

  • MTX affects all rapidly-proliferating cells because of it – marrow, mucosa, cancers, and trophoblasts. 

    • This is helpful to keep in mind to thinking about side effects of MTX:

      • Nausea, vomiting

      • Stomatitis 

      • Abdominal pain

      • Alopecia (rare)

      • Pneumonitis (rare)

    • There are no recommended alternatives to MTX for medical therapy.

• Contraindications to MTX:

  • Absolute:

    • Intrauterine pregnancy

    • Chronic liver or kidney disease

    • Bone marrow dysfunction (anemia, blood dyscrasia, thrombocytopenia, leukopenia).

    • Active GI disease (i.e., PUD) or respiratory disease.

    • Breastfeeding

    • Hemodynamically unstable patient.

    • Inability to participate in follow up. 

  • Relative:

    • Cardiac activity in the ectopic pregnancy

    • High hCG concentration (>5000 mIU/mL)

      • Reviews demonstrate a failure rate of 14.3% or higher at this concentration (vs 3.7% when under 5000 mIU/mL)

    • Ectopic size greater than 4cm on TVUS

    • Refusal to accept blood transfusion

• MTX Regimens:

  • ACOG in the PB 191 mentions three primary regimens: single-dose, two-dose, and fixed multi-dose.

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• Single-dose is the simplest but may require additional dose in up to 25% of patients.

• Two-dose has high success rate with similar monitoring to single-dose regimen.

  • A recent review article suggested the two-dose protocol was more successful while also exposing patients to only minimal, transient side effects versus single dose, and has higher success rates with higher hCG levels.

• Multi-dose fixed regimen requires up to 8 days of treatment with alternating MTX and folinic acid for rescue and minimization of MTX side effects.

• What about surveillance / labs for MTX?

  • Before administration (day 1), you should obtain:

    • bHCG

    • CBC

    • CMP

  • Patients should be counseled about side effects of MTX, and should avoid medications, foods, and supplements that may worsen efficacy

    • Have them stop prenatal vitamins at this time, so the folate doesn’t counteract the MTX!

      • Folate-rich foods and NSAIDs may also decrease the efficacy of MTX.

      • Narcotics, alcohol, and gas-producing foods should also be avoided so as not to mask or be confused with signs of rupture.

      • Patients should also avoid vigorous activity and sex until confirmation of resolution so as not to induce ectopic rupture. 

  • With single and two-dose protocols, you’ll evaluate bHCG again on days 4 and day 7.

    • Success in these protocols is noted with a 15% or more decline between days 4 and 7. 

      • If the decline is less than that, or bHCG increases, then an additional dose of MTX should be administered on day 7. 

      • With repeat doses of MTX, it’s reasonable to consider repeat laboratories to evaluate for any toxicity. 

    • bHCG should continue to decline to zero, and should be followed at least weekly once the initial 15% decline is noted.

      • Resolution can take up to 8 weeks, though average:

        • Two dose: 25.7 +/- 13.6 days

        • One dose: 31.9 +/- 14.1 days

  • Finally, patients should consider avoiding pregnancy for at least 3 months after the last dose of MTX.

    • Studies have found MTX still detectable in cells up to 116 days past exposure. 

    • However, limited evidence also suggests that anomalies and pregnancy loss is not elevated in those who become pregnant shortly after MTX exposure.

  • MTX does not have a measurable effect on fertility.

Surgical Therapy

• For patients who do not desire MTX or are not candidates, surgical therapy is the other option. Surgical therapy is also needed for the patient with hemodynamic instability or symptoms of rupture/intraperitoneal bleeding. 

  • Can also be reasonably considered in stable patients with an indication for another procedure, like salpingectomy for sterilization or hydrosalpinx removal. 

• Surgeries available include salpingectomy (removal of the tube) or salpingostomy (opening the tube).

  • These are generally accomplished laparoscopically – laparotomy is reserved for unstable patients or patients with large bleeding and compromised laparoscopic visualization. 

• Surgery may be more effective than medical therapy and requires less follow up, but does expose patient to surgical risk. 

• Salpingectomy is technically easier to perform, and that’s likely how most of us have trained.

  • Salpingostomy can be considered in patients with desired fertility and damage to the contralateral fallopian tube, and would require ART for future pregnancy.

  • To perform, typically you make an incision along the long axis of the tube over the ectopic, and resect the pregnancy tissue. 

    • Achieving hemostasis is rather tricky in these cases, and may additionally cause damage to the tube. The tube is usually left to heal on its own and not sutured as this may crimp the tube and cause further damage. 

    • Because you may not resect all of the pregnancy tissue at salpingostomy, bHCG monitoring after salpingostomy is needed to ensure complete resolution.

    • MTX may also be given prophylactically if incomplete resection is considered. 

Expectant Management

• We bet you weren’t expecting this one… but ACOG does mention there may be a role for expectant management of ectopic.

• They note that candidates for EM should be:

  • Asymptomatic

  • Objective evidence of resolution (i.e., plateau or decreasing bHCG)

  • Accepting of potential risks after counseling, including tubal rupture, hemorrhage, emergent surgery.

    • EM should be abandoned if hCG insufficiently decreases or begins to rise or with any suspicion for tubal rupture. 

• If initial hCG is under 200 mIU/mL, 88% of patients will have spontaneous resolution.

• In a single small RCT of patients with hCG < 2000 mIU/mL, EM was not associated with lower treatment success than single dose MTX (59% vs 76%).