Mastitis

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Here’s the RoshReview Question of the Week:

A 30-year-old woman presents to the office with right-sided breast swelling and pain. She is 8 weeks postpartum from a spontaneous vaginal delivery of a term infant and is currently breastfeeding. She states her right breast is very painful, swollen, and red, and she has had a fever for the last 2 days. Which one of the following is the most appropriate next step for this patient?

Check your answer and get a special discount at the link above!

For more on breastfeeding, see our prior breastfeeding episodes (Part I and Part II) with Dr. Erin Cleary 

Before we get into mastitis… Breastfeeding is challenging!

  • There are many benefits to breastfeeding

    • Decrease in breast cancer, ovarian cancer, diabetes, HTN, heart disease 

    • Recommendation for breastfeeding for first 6 months of life or longer 

    • Benefits to the infant as well 

  • However in the US, as high as 45% of women report early, undesired weaning

    • Can be because of many things; nipple pain, perception of low milk supply, difficulty with latch

    • Other social factors, ie. limited access to maternity leave, barriers to breastfeeding in the workplace  

    • Depression, previous negative breastfeeding experiences 

  • Also, many things can occur in breastfeeding that can be a challenge 

What can look like mastitis? 

  • Engorgement

  • Physiologic breast fullness that often occurs between day 3-5 postpartum 

  • Typically reassuring sign that mature milk is being secreted 

  • However, can cause symptoms of distention, pain, tenderness, firmness and even fever (usually lower fever) - which can make it easy to confuse with mastitis 

  • Slightly swollen and tender lymph nodes 

  • Can sometimes be very pronounced and there should be anticipatory guidance 

  • Treatment:

    • Overall, data on prevention is limited

    • Can try acupuncture, hot and cold packs, cabbage leaves - but all from systematic reviews have found insufficient evidence to recommend a particular treatment regimen 

    • Can use milk expression to relieve some symptoms 

  • Persistent breast pain with feeding

    • Can be caused by many things  

      • Nipple damage from baby or with overuse/misuse of pump

        • Infant with tight lingual frenulum “tongue tie” - can get frenotomy or frenectomy 

        • Can help observe pumping session and adjust level of suction or fit of flange with lactation consultants  

      • Psoriasis, eczematous conditions - need to apply emollient and reduce identifiable triggers 

      • Candida infections - topical azole and antifungal ointment or cream are ok, or even oral fluconazole 

      • Herpes simplex or zoster - can be seen a small, clustered tender vesicles

        • Treatment with oral antiviral therapy 

        • Stop breastfeeding on that side temporarily 

  • Galactocele - milk retention cyst 

    • Usually just a collection of fluid that is caused by obstructed milk duct - usually soft cystic masses 

https://creogsovercoffee.com/notes/2019/6/16/breastfeeding-part-ii-facts-and-myth-busting

  • Infant’s chest rests against maternal body

  • Infant’s chin touches the breast, tongue is down 

  • Lips flanged outward

  • Little or no areola is visualized 

  • Rhythmic sucking present 

  • Audible swallowing present

  • Latch is not uncomfortable or painful and nipple is not injured or misshapen after breastfeeding  

What is mastitis? 

  • Defined as inflammation of the breast 

    • Can occur spontaneously, but today we’re talking just about mastitis in the context of breastfeeding 

  • Can occur in about 10% of patients who are breastfeeding 

    • Is especially problematic because it can lead to discontinuation of breastfeeding 

  • Risk factors:

    • Infant attachment issues - ie. short frenulum, cleft lip/palate

    • Cracked nipples, local milk stasis 

    • Missed feedings 

    • Poor maternal nutrition 

    • Previous mastitis 

    • Primiparity

    • Use of breast pump 

    • Yeast infection 

  • Diagnosis

    • Usually is made clinically 

    • Presentation usually is:

      • Localized, unilateral breast tenderness + erythema 

      • Fever - usually high! >101.0F (38.5C)

      • Can also have malaise, fatigue, body aches, headache 

      • Rarely will need to have culture to identify organism 

    •  On exam: will find redness, tenderness on one aspect of a breast (can be in different quadrants)

      • Be sure to examine for fluctuance - is there an abscess?  

    • When to get imaging:

      • If you suspect abscess on physical exam 

      • If symptoms are not improving despite medical management 

      • Usually can diagnose via ultrasonography  

  • Treatment

    • Breastfeeding technique

      • Lactation consultation to improve technique 

      • Counsel that patient should not stop breastfeeding or pumping on that side, as stopping can lead to milk stasis and more likely to develop abscess 

      • Can continue breastfeeding!  

      • Usually, the baby is already colonized by the same organism 

    •  Medical management

      • Antibiotics are usually needed for 10-14 days

      • Possible treatments include:

        • Augmentin 875 mg BID 

        • Keflex 500 mg 4x/day (hard to do 4x/day meds) 

        • Clindamycin 300 mg 4x/day - can be used against MRSA 

        • Dicloxacillin 500 mg 4x/day 

        • Bactrim DS (160mg/800 mg) BID - can be used against MRSA, but usually may want to avoid in patients with preterm infants 

  • When to refer

    • Abscess

      • Usually needs to be drained 

      • Can often be done at the bedside, and usually will not need to refer to breast surgery if you feel comfortable 

      • However, can depend on individual provider’s level of comfort  

    •  Abnormal presentation/lack of response to treatment

      • Most mastitis should resolve after initial treatment, and recurrence is not common, but can result from inappropriate or incomplete antibiotic therapy 

      • Most abscesses do not recur 

      • Inflammatory breast cancer can resemble mastitis at times, but may be differentiated by skin thickening as well as axillary lymphadenopathy 

Postpartum Care

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Here’s the RoshReview Question of the Week:

A 23-year-old G1P1001 woman presents to the office for her routine postpartum visit. She is 6 weeks postpartum status post vaginal delivery of a healthy infant. Her pregnancy was complicated by diet-controlled gestational diabetes mellitus and obesity. She completes a 2-hour glucose tolerance test using a 75 g glucose load. Her fasting plasma glucose level is 85 mg/dL, and her 2-hour plasma glucose level is 130 mg/dL. Which of the following is the most likely diagnosis?

More Reading: ACOG Committee Opinion 736 from May 2018: Optimizing Postpartum Care 

Why Do We Care About PP Care? 

  • The days/weeks following birth are critical for patient and infant well-being 

    • Multiple physical, social, and psychological changes 

    • Recovery from delivery (either vaginal or cesarean) 

    • Challenges of breastfeeding

    • Lack of sleep, fatigue, pain, stress

    • New or exacerbation to mental health disorders 

    • Urinary or even anal incontinence 

  • Challenges 

    • Fragmented care between pediatric and obstetric care providers: 

      • As an example of what babies get: day 1-2 of life, day 3-5 of life, 1 month check up, 2 month, 4 month, 6 month, 9 month, and 12 month 

      • Just for well babies! 

      • If other complications, maybe more visits! 

    • Long time before we see our patients 

      • Usually, will see them at 4-6 weeks postpartum 

      • Initial lack of attention to maternal health needs - more than half of pregnancy related deaths occur after the birth of the infant! 

      • Instead of ongoing care, we have fragmented, one or two time visits 

A Call to Action 

  • Because of these issues, ACOG has wanted to increase awareness for the fourth trimester 

  • What we currently have - (FYI, this is me ranting about our current system because I’m a raging socialist. Feel free to chop as much as needed) 

    • 4-6 week visit x1 

    • Edinburgh postpartum depression screens to try and catch postpartum blues, but administered in the hospital and again at 4-6 weeks - can miss depression in the first month after birth

    • With COVID, often not letting family members or infants come to postpartum visits 

    • All pregnant patients receive health insurance through Medicaid, but this insurance stops at 6 weeks postpartum 

    • The US is also one of 7 countries in the entire world without paid maternity leave (WTF) 

    • On average, countries that provide paid maternity leave pay 77% of previous pay 

    • The UK has paid maternity leave minimum of 39 weeks. Most places have a minimum paid maternity leave of 12 weeks to a full year, and on average, globally, the paid maternity leave is 29 weeks. Average paternity leave is 16 weeks 

NY Times

  • What this results in

    • Less attendance of postpartum visits

      • Not wanting to use accrued family leave/sick days for appointments 

      • Unable to find someone to care for themselves/their infants to go to appointments 

      • Results in as many as 40% of patients don’t go to postpartum visits 

      • 23% of employed women return to work within 10 days postpartum, and an additional 22% return to work between 10-40 days pp!!!!! 

    • Less anticipatory guidance

      • With decreased time during pregnancy (due to covid) and also with not going to postpartum visits and not having PP visits soon enough → on a national survey, less than ½ of patients attending a PPV reported the received enough info about depression, birth spacing, healthy eating, importance of exercise, changes to their sexual response and emotions 

      • In randomized controlled trial, 15 minutes of anticipatory guidance before discharge, followed by phone call at 2 weeks reduced symptoms of depression and increased breastfeeding duration through 6 months among black and hispanic women  

    • More maternal morbidity and mortality 

  • What we want (and ACOG wants) 

    • Timing of postpartum visit be individualized and woman centered 

    • Initial assessment within 3 weeks postpartum to address acute issues 

    • Follow this up with ongoing care as needed - ie. well woman visit no later than 12 weeks after birth 

    • Insurance should allow for this care (don’t take it away after 6 weeks!)

      • American Rescue Plan Act - allows states to extend Medicaid coverage for pregnant people from 60 days to 1 year postpartum 

      • As of 4/2022: currently in effect for 13 states 

      • 14 states and DC planning to implement a 12 month extension 

      • 4 states with limited overage extension approved or proposed 

      • 4 states pending legislation to seek federal approval 

What should we be doing then for PP Care? 

  • Start early - begin anticipatory guidance even in prenatal care! 

    • Develop a postpartum care plan (Table 1 - can go through some of these things) 

    • Reproductive life planning 

      • Review desire for future pregnancies 

      • Counsel pregnancy spacing (avoid short interval pregnancy, within 6 months, and risks and benefits of pregnancy sooner than 18 months) 

      • Review contraception options if desired 

    • Build a support system 

      • Review: who will provide social and material support? Ie. family, friends

        • Can get social work involved if needed  

      • Identify providers that patient can call with questions

        • Primary care provider, Ob provider, psychiatry provider 

        • Pediatric provider 

        • Lactation support 

        • Care coordinator/case manager 

        • Home visitation 

        • Provide phone numbers or other contact information  

  • Intrapartum to Postpartum Care

    1. Early postpartum period contains substantial morbidity 

    2. Blood pressure evaluation no later than 7-10 days postpartum for those with hypertension

      1. Great studies regarding postpartum blood pressure checks via text message - easy for both patients and clinicians

      2. Decreases usage of emergency rooms 

      3. Those with severe hypertension should be seen within 72 hours!  

    3.  In person follow up earlier for patients with complications such as: 

      1. Cesarean section or perineal wound infection 

      2. Lactation difficulties 

      3. Chronic conditions like seizures that may require postpartum medication titration 

    4. WHO recommends follow up of all women and infant dyads at 3 days, 1-2 weeks, and 6 weeks - we don’t do this in the US! 

    5. Based off of this ACOG recommends first contact within 3 weeks (does not have to be in person, can be by phone) 

    6. Can set up postpartum care either in the prenatal period (we will usually make pp appointments for patients in the hospital or right before delivery) 

  • The components of postpartum care - these were really good from ACOG, so thought I would include 

    1. Mood and emotional well-being 

    2. Infant care

    3. Sexuality, contraception, birth spacing 

    4. Sleep/fatigue 

    5. Physical recovery 

    6. Chronic disease management 

    7. Health maintenance 

What about birth trauma? 

  • Remember that trauma is in the eye of the beholder

    • Many healthcare providers may not even be aware that their patient experienced trauma 

    • Allow patients to ask questions about their labor, childbirth course and review any complications 

    • Complications should be reviewed and how they can best be avoided in next pregnancy if possible (ie. reduce risk of preterm birth, preeclampsia)  

    • Referral to support group, mental health care specialist 

  • Pregnancy loss 

    • Remember to always review someone’s labor course and delivery!

      • May sound basic, but there are times when people miss a cesarean scar or even that someone had a pregnancy loss and congratulate the patient (omg)  

    • Emotional support and bereavement counseling with referrals if appropriate 

    • Review labs and path from loss 

    • Order other labs if needed (look at our stillbirth episode) 

Transition to ongoing care 

  • Refer to ongoing well woman care within 12 weeks 

  • Make sure that there is a good transition for birth control/continued prescriptions

    • Write this out in your notes/recommendations 

    • Many patients all of a sudden don’t have access to get their birth control because their obstetrician or midwife isn’t seeing them anymore 

    • Or, if their OB started them on an antidepressant, all of a sudden, they don’t get scripts anymore because they are not longer postpartum - make sure to help patients get appointments to their PCP or mental health care and transition them!  

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!

Thalassemias, feat. Dr. David Abel

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Here’s the RoshReview Question of the Week!

A 31-year-old G1P1 woman of Southeast Asian descent with a history of intrauterine fetal demise presents to your office for preconception counseling. She also reports a history of mild anemia due to alpha-thalassemia. You order DNA testing. Which of the following is most likely her genotype?

Check if you got the right answer and get a special deal on the CREOG Q-Bank at link above!

The Basics of Hemoglobin

  • The major oxygen carrying pigments of the body. Carries oxygen from the lungs to the tissues to meet the needs of cells for oxidative metabolism.

    • We carry almost two pounds of hemoglobin at any given time!

  • The hemoglobin molecule is a tetramer.

    • Typically, this tetramer is composed of two alpha chains and two non-alpha globin chains.

    • The molecular mass of a hemoglobin tetramer is large, approximately 64,000 daltons. 

    • The primary structure of a particular hemoglobin is determined by its covalent bonds between the amino acids that form these polypeptide globins, and it is this primary structure that determines the behavior of a particular hemoglobin.

  • Hemoglobin synthesis is controlled by two multigene clusters, the alpha and beta globin genes.

    • The alpha genes are on chromosome 16.

      • Both genes for alpha globin are duplicated, thus there are four genes at the alpha globin locus, with two genes inherited from each parent.

    • The beta genes are on chromosome 11.

      • The beta globin gene consists of two genes, one inherited from each parent. 

    • Each of these two gene clusters also contain other genes!

Common Hemoglobin Molecules and Embryology of Hemoglobin

  • Hemoglobin changes during fetal development.

    • The switch from embryonic to fetal to adult hemoglobin synthesis is a major mechanism by which the developing fetus adapts from the hypoxic intrauterine environment, as each hemoglobin has its own oxygen dissociation curve.

  • In the embryonic stage of development, there exists both zeta and epsilon globin chains that are synthesized by yolk sac erythroblasts.

    • The zeta gene is part of the alpha globin gene cluster, and the epsilon gene is part of the beta globin gene cluster.

      • Hb Gower-1: two zeta and two epilson chains

      • Hb Gower-2: two alpha and two episilon chains

      • Hb Portland: two zeta and two gamma chains. 

  • After the first trimester, the zeta and epsilon globin chains are replaced by hemoglobin F, the dominant hemoglobin in-utero.

    • Hb F is composed of two fetal gamma globin chains and two alpha globin chains.

      • The gamma gene is a fetal gene that is part of the beta globin gene cluster.  

  • Hemoglobin F declines in the third trimester of pregnancy and is slowly replaced by hemoglobin A, which consists of two alpha and two beta chains.

    • Also keep in mind that expression of delta globin begins near birth. The delta gene is also part of the beta globin cluster, and contributes to hemoglobin A2 (two alpha, two delta globins).

  • At birth, hemoglobin F accounts for approximately 75-80 percent of hemoglobin and hemoglobin A accounts for 20-25 percent.

    • Postnatally, hemoglobin F is slowly replaced by hemoglobin A so that infants do not rely heavily on normal amounts and function of hemoglobin A until they are between 4 and 6 months old. 

  • In adults, hemoglobin A makes up approximately 97%, hemoglobin A2 approximately 2.5% and less than 1% consists of hemoglobin F. 

The Basics of Hemoglobinopathy and Thalassemias

  • Hemoglobinopathies arise when a change occurs in the structure of a peptide chain or a defect compromises the ability to synthesize a specific polypeptide chain.

    • Can be qualitative or quantitative defects.

      • Thalassemias are quantitative disorders. 

  • Thalassemia is derived from a Greek term that roughly means “the sea” (Mediterranean) in the blood.  

    • It was first applied to the anemias frequently encountered in people from the Italian and Greek coasts and nearby islands. 

    • Individual syndromes are named according to the globin chain whose synthesis is adversely affected.

      • Alpha thalassemia represents either a reduction or complete absence of production of alpha globin chains

      • Beta thalassemia is a reduction or complete absence of beta globin production. 

    • Among the most common autosomal recessive disorders worldwide. More than 100 genetic forms of alpha thalassemia have been identified. 

  • By contrast, conditions such as sickle cell anemia represent a structural hemoglobinopathy, a qualitative defect.

Beta Thalassemias

  • Hemoglobin electrophoresis can be used to diagnose beta thalassemia. This can reveal:

    • Reduction in the expression of beta globin (b+) or

    • Complete absence of beta globin expression (b0).

  • Complete absence of beta globin expression is referred to as beta thalassemia major, aka Cooley’s anemia or transfusion-dependent thalassemia.

    • Little to no beta globin chain production and thus minimal to absence of hemoglobin A.

    • Symptoms usually manifest 6-12 months of life.

    • Since there is no hemoglobin A due to the lack of beta globin, hemoglobin F persists.

      • On a hemoglobin electrophoresis, you will see at least 95% of hemoglobin F, and  hemoglobin A2 will usually range between 3.5 and 7%.

      • The circulating red blood cells are very hypochromic, abnormal in shape, and the hemoglobin is markedly reduced, somewhere around 3-4 g/dl. 

    • Anemia of beta thalassemia major is so severe that long-term blood transfusions are usually required for survival.

      • The severe anemia results in extramedullary erythropoiesis, delayed sexual development and poor growth.

      • Death may occur by age 10 unless treatment with periodic blood transfusions is initiated.

  • Beta thalassemia intermedia, now referred to as non-transfusion dependent beta thalassemia, presents as a less severe clinical phenotype.

    • A moderate microcytic anemia is present.

      • On hemoglobin electrophoresis, up to 50% of hemoglobin F will be noted and just as in beta thalassemia major, hemoglobin A2 will usually range between 3.5 and 7%.

    • May result from different mechanisms:

      • I.e., inheriting both a mild and severe beta thalassemia mutation, or

      • The inheritance of two mild mutations, or,

      • The inheritance of complex combinations of mutations.

  • Beta thalassemia minor, also referred to as beta thalassemia trait, is caused by the presence of a single beta-thalassemia mutation and a normal beta globin gene on the other chromosome.  

    • Significant microcytosis with hypochromia on the blood smear but a mild anemia.

    • In general, thalassemia minor has no associated symptoms.

      • On hemoglobin electrophoresis, hemoglobin F is present up to 5%, and hemoglobin A2 at 4% or more. 

Alpha Thalassemias

  • The alpha thalassemias are more difficult to diagnose because the typical elevations in hemoglobin F and A2 that are seen in the beta-thalassemias we have just discussed do not occur. This makes hemoglobin electrophoresis difficult to use for diagnosis.

    • Instead, molecular testing (DNA sequencing) is required for diagnosis.

    • More than 100 genetic forms of alpha thalassemia have been identified, with phenotypes ranging from asymptomatic to lethal.

    • The severity of this disorder is usually well correlated with the number of non-functional copies of the alpha globin genes (a one, two, three, or four-gene deletion).

  • Silent Carrier: one alpha globin gene deletion.

    • Essentially has no clinical consequences.

    • On the CBC, the MCV is usually normal or perhaps mildly decreased.

  • Alpha Thalassemia Minor: two gene deletion.

    • If two genes on the same chromosome are deleted, this is known as a cis deletion.

      • More commonly seen in those of southeast Asian ancestry.

      • If both parents carry a cis deletion, their offspring will have a 25% chance of having no functional alpha globin genes.

    • If the two deleted genes are on different chromosomes, this is trans deletion.

      • More common in those of African descent

      • If both parents have a two gene deletion in trans, their offspring will always have the same two gene deletion in trans.

  • Hemoglobin H: three gene deletion, which results in a moderate microcytic anemia.

    • When the alpha chains are reduced, the beta chains pair together and form beta globin tetramers, which is what this hemoglobin H represents.

    • In some cases, instead of the three gene deletion, a two gene deletion occurs with a mutant (i.e., non-functional) alpha globin mutation, such as hemoglobin Constant Spring.

      • This is referred to as nondeletional hemoglobin H.

      • Individuals with this nondeletional hemoglobiin H have a higher percentage of hemoglobin H, more splenomegaly and more advanced disease.

    • Most individuals with hemoglobin H don’t require regular transfusions. The anemia is typically mild; however, the phenotype is variable

      • With the dilutional anemia that occurs during pregnancy, the need of a transfusion may be increased. 

  • Alpha thalassemia major, or hemoglobin Barts: Four gene deletion that results in a gamma tetramer.

    • Normal Hb A and Hb F are totally absent.

    • Hemoglobin Barts is incompatible with life and results in hydrops in-utero and stillbirth.

      • Its oxygen dissociation curve is markedly shifted to the left, so it holds onto oxygen and very little is released to the tissues.

      • Usually, the fetus or newborn will have marked anasarca and hepatosplenomegaly, with a hemoglobin level of 3-10 g/dL.

    • If a fetus is known to have alpha thalassemia major, multiple intrauterine transfusions can help these fetuses survive.  

      • Prenatal diagnosis of the thalassemias can be performed using either chorionic villi from CVS or using cultured amniocytes obtained from an amniocentesis.

    • A study at the University of California at San Francisco is looking at the use of in utero stem cell transplantation during pregnancy to essentially cure the fetus before birth. 

Take Home: When to Work Up for Thalassemia

  • If the MCV is decreased (<80), a hemoglobin electrophoresis is very reasonable.

    • Ferritin to assess for iron deficiency is also something that can be performed at the same time.

      • Hemoglobinopathy and iron deficiency can coexist!

  • If the MCV is decreased, and both a ferritin and hemoglobin electrophoresis are normal, molecular studies to assess for alpha thalassemia would be appropriate.