Updates in Pap Screening Part II: High Grade Lesions

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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?

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

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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?

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. 

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. 

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!

Managing Abnormal Pap Smears

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When you look at the American Society for Colposcopy and Cervical Pathology (ASCCP) guideline flowsheets, it can seem like an absolute maze, and remembering what to do when is challenging. The ASCCP guidelines are free to review in PDF form and are probably your most useful resource. They also have a very handy smartphone app to help for clinic or problems on the go, but obviously these aren’t available to you in an exam setting. The OBG Project has a ton of helpful articles on Pap smear management as well!

*** It’s also important to know we’re anticipating a change in these guidelines sometime in 2020 from the ASCCP, so stay tuned! ***

Today we’ll try to break it down so mentally, you can remember these algorithms for the exam. We find it helpful to evaluate abnormal Pap management systematically. 

Start by separating Pap cytology results into “low grade,” which are ASC-US and LSIL cytologies, and “high grade,” which are ASC-H and HSIL pathologies. Next, you need to remember the age cut offs: 21-24, 25-29, 30-64, and 65+. Finally, for those over age 30, HPV status will be the next important step in the algorithm.

Let’s break it down:

Normal Cytology. The only potential abnormal in this category 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.

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

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

    • If at 1 year, negative HPV and negative cytology, then cotesting in 3 years.

    • If at 1 year, positive HPV and/or abnormal cytology, then perform colposcopy.

      • This intuitively makes sense. If HPV is persistent, it is more likely to cause dysplasia that may be better evaluated with colposcopy. 

 Low Grade (ASC-US, LSIL)

  • In women aged 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 women aged 25-29:

    • LSIL go to colposcopy.

    • ASC-US in this group can have two options: Reflex HPV testing or Repeat Cytology in 12 months.

      • If reflex HPV is positive, management would proceed the same as LSIL with immediate colposcopy.

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

      • If reflex HPV is negative, then repeat cytology can be performed in 3 years, as HPV-negative ASC-US has very low risk of CIN2+. 

      • If HPV testing is not performed, repeat Pap in 12 months is recommended. A 2nd ASC-US result or worse would then warrant colposocopy.

  • In women aged 30-64, ideally HPV testing is always available! The management algorithm overall doesn’t change much.

    • 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, as you would for a 25-29 year old.

    • ASC-US, HPV unknown: repeat cytology, as you would for a 25-29 year old.

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

  • In women aged 65+, Pap smears are likely only continuing at this point if there have been previous abnormalities, or a lack of screening. 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 in our low grade, we didn’t talk excisional procedures at all; low grade lesions should generally proceed to colposcopy before considering exicsion. 

High Grade (ASC-H, HSIL).

Any ASC-H result merits colposcopy, regardless of HPV status!

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

    • If CIN2/3 Not Present: Repeat colpo and cytology q6 months for two years.

      • If no additional high grade abnormalities are noted, then the patient returns to normal screening.

      • If HSIL persists for 24 months, then excision is recommended.

    • If CIN2/3 Is Present: then management is challenging! The risk of excision is the risk of preterm delivery with future pregnancy.

      • With CKC, this can be up to 3.5x greater risk, and with LEEP this risk is approximately 2x greater. 

      • Thus, with CIN2/3, observation or treatment may be pursued after engaging in shared decision-making with your patient.

      • With CIN 2, observation with q6month cytology and colposcopy is preferred.

        • The likelihood of regression spontaneously in this population may be as high as 43%. 

        • If 2x cytology and colposcopy results are normal, the patient may have cotesting in 1 year.

          • If colposcopy or cytology persist as abnormal for 1 year, repeat biopsy is recommended, with treatment with excision recommended by 2 years if not resolved.

      • With CIN 3, treatment is preferred.

        • The likelihood of regression with true CIN3 is much lower, thus prompting recommendation for excision to prevent invasive cancer.

        • If strongly desired, observation may be pursued with the same algorithm as above.

  • In women aged 25-29, women aged 30-64, and women aged 65+ receiving screening, the management of ASC-H and HSIL is the same!

    • ASC-H goes to colposcopy.

    • HSIL results can proceed immediately to excision or perform colposcopy first.

      • Most women with HSIL will have HPV+ testing. Even with negative HPV results, an HSIL test carries a 5-year risk of CIN3 of near 30% and an invasive cancer risk of 7%. Thus, it’s prudent to proceed with further testing in this scenario. 

    • If CIN 2 or 3 is found on colposcopy as result of either of these, then excisional therapy is recommended. 

After colposcopy and biopsies…

We’ve detailed the management of this for 21-24 year olds above, so we’ll leave this group out, as their management varies. Very kindly, if you’ve made it to colposcopy for anyone aged 25 or older, the management is the same.

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

  • 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.

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

CIN 1 or Less on colposcopic biopsies

  • If the initial Pap was low grade (ASC-US or LSIL):

    • Repeat co-testing at 12 months.

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

      • If there is an abnormality, then colposcopy should be performed.

  • If the initial Pap was high grade (ASC-H or HSIL): 

    • recommend repeat cotesting at 12 and 24 months.

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

      • If there is an abnormality, then colposcopy should be performed.

      • If HSIL is noted, then an excision should be performed versus re-review of prior pathology.

What if the result is “AGC”? Atypical glandular cells can have two categories: “atypical endometrial cells” and then “other.”

  • If any “other” type of AGC, patient should be evaluated with colposcopy and consideration of endometrial sampling. 

    • In patients younger than 35, endometrial sampling may be considered based on risk factors for endometrial cancer. 

    • In patients older than 35, endometrial sampling should be done routinely.

  • If “Atypical endometrial cells,” then endometrial biopsy and endocervical curettage should be performed. Colposcopy should be deferred generally until the results of the endometrial testing is known, and performed if endometrial testing reveals no abnormality.

  • Excisional procedures should be considered if there is concern for neoplasia or adenocarcinoma in situ (AIS). 

    • If no CIN2+, AIS, or cancer, then repeat co-testing should be performed at 12 and 24 months.

What if I get an AIS result from an excisional procedure?

  • In this case, simple hysterectomy is the preferred management. 

  • If future fertility is desired, conservative management with excision may be pursued, though likely should be done alongside GYN oncology! 

Cervical Cancer Screening and Prevention

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Today we discuss one of the basic screening tools of the OB-GYN office: the Pap smear. Named for Georgios (George) Papanikolau, credited for its creation around 1923, it is a test that has singlehandedly changed the face of cancer screening. With its widespread use, the incidence of cervical cancer in the US has dropped from 14.8 / 100k women in 1975, to 6.7 / 100k women in 2011. The converse also demonstrates the importance of this routine test: 50% of those diagnosed with cervical cancer have never had Pap screening, and 10% have not had screening within the preceding 5 years.

We also now know and can test for the presence of oncogenic strains of human papilloma virus, or HPV. Types 16 and 18 account for over 70% of cervical cancer worldwide, and 12 other strains account for the remaining majority of cases. Ongoing trials are looking at whether HPV screening may ultimately supplant cytology as the preferred 1st test, but HPV screening has added another excellent tool to help OB-GYNs discuss risk and prevent cancer in their patients.

Follow along with ACOG PB 168!

So what are the screening guidelines?
In the immunocompetent patient, they are as follows:

  • < 21 years: Screening should not be performed, even in the presence of behavior-related risk factors.

    • Only 0.1% of cervical cancer cases occur before age 20.

    • Women younger than 21 with no immunocompromising conditions generally clear HPV infection between 8-24 months after exposure. 

    • This population should have discussion about safe sex practices to avoid exposure to STIs including HPV, and strong consideration for HPV vaccination.

  • 21 - 29 years: Screening should be performed using cytology alone every 3 years.

    • Annual screening is discouraged in this group, as it exposes patients to a much more significant number of unnecessary procedures for minimal improvement in outcomes. 

    • HPV co-testing is not recommended in this group; however, HPV reflex testing in the event of an ASC-US Pap smear may be considered to determine need for colposcopy.

  • 30 - 65 years: Screening should be performed with cytology alone every 3 years, or cytology with HPV co-testing every 5 years. 

    • In this population, with a negative cytology and negative HPV test, the risk of developing CIN 2 or 3 in the next 4-6 years is extremely low, based on large database studies (approximately 0.08% risk over 5 years). The risk is higher, but also quite low, with cytology alone (0.26% over 5 years). This is the rationale for the screening interval being extended.

    • RCTs have demonstrated in this population that cotesting has a number of distinct advantages:

      • Cotesting has a higher detection rate of high-grade dysplasia in first round of screening, and decreases risk of CIN3 or cancer in subsequent screening.

      • Cotesting likely has a better pickup rate for cervical adenocarcinomas (vs. squamous cell) than cytology alone.

  • > 65 years, or post-benign hysterectomy: Screening should be discontinued, provided that:

    • There has been no history of CIN2, CIN3, or AIS in the preceding 20 years, and:

    • There are adequate negative prior results:

      • 3 consecutive negative cytology results within last 10 years, or

      • 2 consecutive negative cotest results within the last 10 years, with the most recent test performed within the past 5 years.

    • Women in this age group do get cervical cancer; however, the majority of these cases occur in women who are not screened, or in those who are underscreened.

    • The changes of menopause may also cause false positive Pap tests in this group, leading to likely unnecessary additional and invasive testing and procedures.

Behavioral risks, such as cigarette smoking, new or multiple sexual partners, or early sexual debut, may increase risk of HPV acquisition or persistence, but do not alter screening recommendations.

However, two particular conditions do merit changes to screening:

  • In utero diethylstilbestrol (DES) exposure:

  • DES was an estrogen that was manufactured and prescribed in the US during the 1930s until 1971. It was thought that the medication helped with premature birth or history of miscarriage, though by the 1950s it had been demonstrated to be ineffective.

  • ACOG states that annual cytology is reasonable in women exposed to DES in utero, as cohort studies have demonstrated a much higher incidence of clear cell adenocarcinoma of the vagina in women born to mothers who took DES or similar medications. DES has also been associated with other health problems in both men and women.

  • You can find a list of DES and related medications online at the CDC, and there is an interactive tool for patients to use to determine if they may be at risk.

  • HIV or immunocompromising conditions:

    • Women infected with HIV or with other immunocompromising conditions are less readily able to clear HPV infections. Thus, the recommendations in this population differ:

  • Screening should begin within 1 year of sexual activity, and no later than age 21.

  • In women less than 30, If the first screen is negative, it should be repeated in 12 months. If three consecutive annual screens are normal, screening may be spaced to regular intervals (i.e., q3 year cytology). HPV cotesting is not recommended.

  • In women older than 30, three annual tests should be normal, before moving to cytology alone or co-testing. Screening intervals should be every 3 years in this population, regardless of the method chosen. 

  • Screening should continue for the lifetime of the woman, and not stop at age 65.

What about HPV vaccination?

HPV vaccination has been an incredible advance for primary prevention of cancer. Currently available include a bivalent vaccine, a quadrivalent vaccine, and a 9-valent vaccine. All of these cover HPV types 16 and 18. The 9-valent vaccine covers up to 50% additional cases of cervical cancer versus the bivalent vaccine. The 9-valent vaccine should be given to boys and girls ages 9-26. 

  • For those receiving their first dose before age 15, only two doses given 6 months apart are needed. 

  • For those receiving it after age 15, 3 doses given at 0, 1-2, and 6 months apart are recommended. 

HPV vaccination is not recommended during pregnancy, but also hCG screening is not necessary prior to initiating the dose. If pregnancy interrupts the schedule, it should be resumed postpartum without need for redosing. Studies are ongoing to determine the safety of HPV vaccination during pregnancy. 

In June 2019, the CDC’s advisory council on immunization practices (ACIP) updated its HPV vaccination recommendations, to extend recommendation for vaccination for all persons up through age 45, after the FDA approved this in October 2018. While this hasn’t made it into official ACOG practice guidance yet, it’s safe to say that this is forthcoming!

Further Reading from the OBG Project:

USPSTF Releases Final Cervical Cancer Screening Guidelines – Including ‘HPV Only’ Option
Screening for Cervical Cancer in the Woman at Average Risk
What is the Most Efficient Method for Cervical Cancer Screening?
Cervical Cytology and HPV Screening in the HIV Positive Woman
Cervical Cancer Screening Strategies and Cost-Effectiveness: Which is the Best?

Vaccines II: MMR, Varicella, and HPV

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Let’s tackle the second part of our vaccinations series with some of the more common live-virus vaccines: MMR, Varicella, and HPV. Check out the CDC vaccine guides linked here.

MMR

  • Measles, mumps, and rubella - all are live attenuated strains of the virus

  • Should NOT be given during pregnancy

  • Immunity is about 97% against measles and rubella after 2 doses, and 88% against mumps after 2 dose

  • Given ideally before pregnancy to protect against congenital rubella

    • Otherwise, after pregnancy and not during

    • This is because during pregnancy, the adaptive immune system is not as robust as when one is not pregnant and higher risk of the live attenuated virus actually causing disease.

      • If an adult is not immune to MMR (and we screen for rubella during pregnancy), at least one dose should be given postpartum.

  • Ingredients

    • Chicken embryo cell culture - medium

    • Human diploid lung fibroblasts - medium

    • Vitamins, amino acids, sucrose, glutamate, human albumin, sorbitol, gelatin, sodium phosphate, sodium chloride

    • Fetal bovine serum - medium

    • Neomycin - antibiotic

  • Side effects

    • Can get rash, temperature, loss of appetite 2-3 days

    • Can get a VERY mild form of measles or mumps

    • Extremely rare: severe allergic reaction

Varicella

  • Protects against chickenpox and shingles

    • 88-98% effective at preventing varicella after two doses, and 85% effective after 1 dose.

    • Ideally given before pregnancy to protect against chickenpox complications during pregnancy (ie. pneumonia) and congenital varicella syndrome or neonatal varicella.

    • Don’t give it during pregnancy.

  • Ingredients

    • Human diploid cells with DNA and protein

    • Sucrose, gelatin

    • Sodium chloride, monosodium-glutamate, sodium phosphate, potassium phosphate, potassium chloride, EDTA

    • Neoomycin

    • Fetal bovine serum

  • Side effects

    • Common: sore arm, fever, mild rash, temporary pain and stiffness

    • Severe: (very uncommon) - severe infection, pneumonia

HPV

  • Gardasil 9 protects against human papilloma virus 16, 18 (causes 80% of cervical cancer cases), 6, 11 (90% of genital wart cases), and another 5 types (31,33,45, 52, 58) that can lead to cervical cancer.

    • 3 separate shots for people aged 15-45 - high efficacy, with close to 100% prevention of HPV virus

    • If 9-14, 2 shots are sufficient

    • Not currently recommended during pregnancy

      • Good time to give it: immediately pp in hospital (dose 1), then 6 weeks pp  

  • Ingredients

    • Vitamins, amino acids, mineral salts, carbohydrates

    • Amorphous aluminum hydroxyphosphate sulfate

    • Sodium chloride

    • Polysorbate 20

    • Neomycin, yeast protein

  • Side effects

    • Common: pain, redness, swelling of arm where shot was given

    • Less likely: fever, headache, feeling tired, nausea, muscle or joint pain.