BRCA for the OB/GYN

/

Here’s the RoshReview Question of the Week:

A 37-year-old woman presents to your office for health care maintenance. She reports that her maternal cousin was diagnosed with advanced-stage breast cancer at the age of 35. Genetic testing was performed, and her relative tested positive for breast cancer susceptibility gene 1. Which of the following is associated with this condition?

Check your answer at the links above!

Follow along with ACOG PB 182

What are we talking about, exactly?

  • Certain germline mutations predispose patients to heritably higher risk of breast and ovarian cancer

  • In particular, you have probably heard of BRCA1 and BRCA2

    • Others you may or may not have heard of include: 

      • Lynch syndrome genes (MSH2, MLH1, MSH6, PMS2), 

      • PTEN, 

      • TP53 (Li-Fraumeni syndrome), and 

      • STK11 (Peutz-Jehger Syndrome), just to name a few!

  • However, we’ll spend today’s podcast focusing on BRCA specifically.

What exactly are the BRCA risks?

  • Estimates of carrier frequency range from 1/300 to 1/800 for either genes.

  • BRCA1 is found on Chr 17

  • BRCA2 is found on Chr 13

  • Both are tumor suppressor genes that function in DNA repair process.

    • The inherited mutation is non-functional or defective allele in some way, but patients usually have a second, functional copy.

    • If the second allele becomes nonfunctional due to somatic mutation, cancer can develop – 

      • Two-hit hypothesis of tumor suppressor genes.

  • Risk of breast cancer in person without BRCA by age 70: ~12% (1/8)

    • Risk in patient by age 70 with BRCA1/2: 45-85%

      • Also more likely to be “triple negative” breast cancer for hormone and HER2 receptor

  • Risk of ovarian / fallopian tube / primary peritoneal cancer:

    • BRCA1: 39-46% by age 70

    • BRCA2: 10-27% by age 70

    • Both associated with high grade, serous or endometrioid phenotype

  • BRCA1/2 also associated with prostate, pancreatic, uterine cancers as well as melanoma

Who should I send for genetic counseling?

  • If your patient has a new cancer, genetics recommended:

    • New ovarian epithelial cancers (including fallopian tube or primary peritoneal)

    • Breast cancer at age 45 or less;

    • Breast cancer, and have a close relative with breast cancer at age 50 or less, or a relative with ovarian cancers at any age; or with limited/unknown family history

    • Breast cancer with two or more relatives affected by breast cancer at any age

    • Breast cancer and two or more close relatives with pancreatic cancer or aggressive prostate cancer

    • Two breast cancer primaries, with the first diagnosed under age 50

    • Triple negative breast cancer at under age 60

    • Breast cancer and Ashkenazi Jewish ancestry at any age

    • Pnacreatic cancer and have 2+ close relatives with breast, ovarian, pancreatic, or aggressive prostate cancer

  • If your patient does not have a new cancer, genetics recommended based on the history of:

    • A first-degree or several close relatives that meet the above criteria

    • A close relative carrying a known BRCA1 or BRCA2 mutation

    • A close relative with male breast cancer

  • If you’re not sure but the history seems high risk, a referral to cancer genetics to discuss is always worthwhile – the histories above should definitely prompt your referral though! 

  • And as you’re taking family history - it bears special mention that both maternal and paternal histories are important!

    • Especially given association with male breast CA, prostate CA, melanoma – be sure to get both sides!

  • Genetics may recommend performing BRCA mutation testing, which can have a variety of possible outcomes:

    • True positive: pathogenic BRCA variant identified

    • True negative: no pathogenic variant identified in someone who has known BRCA variant in family

    • Uninformative negative: no pathogenic variant identified, but uninformative because of:

      • a) other family members not tested

      • b) family carries a variant, but it was not detected because of test limitations

      • c) family carries a high risk mutation in another gene

      • d) there is no high risk mutation

    • Variant of uncertain significance (VUS): abnormality detected in BRCA gene, but unknown whether the variant is associated with increased cancer risk

  • Patients should be informed about the possible outcomes before undergoing genetic testing so they are aware of potential limitations and importance of family testing.

    • Unintended consequences of testing can include anxiety/stress and family dynamic issues regarding need for disclosure.

  • Multigene panel testing also exists to look for mutations beyond BRCA and can be suggested by genetic counselors if indicated. 

How do I counsel and care for the patient with BRCA1 or BRCA2 mutation?

Screening

  • Breast:  broken out by age:

    • Age 25-29: clinical breast exam every 6-12 months and annual screen (preferably by MRI with contrast)

      • Avoid ionizing radiation at this younger age as this may increase risk of cancer

    • Age 30+: Annual breast mammography and MRI, generally alternating every 6 months, as well as continuing CBE q6-12 months

  • Ovarian:

    • TVUS and CA-125 monitoring routinely is not recommended

      • However, could be considered for short term surveillance around age 30-35 until patient undergoes risk-reducing BSO.

Medical

  • Breast:

    • Tamoxifen and raloxifene can be considered (SERMs)

      • Can be considered in patients age 35 or older and not planning on pregnancy, or on prophylactic mastectomy

      • Tamoxifen is used in pre-menopausal and post-menopausal women, and may reduce breast cancer risk by 62% in BRCA2 carriers, but has not been found to reduce risk of cancer in BRCA1 carriers (likely due to higher triple-negative rates in this pop)

      • Raloxifene has been found to be effective in reducing invasive breast cancer in postmenopausal women at increased risk, though not evaluated specifically in BRCA mutation carriers

        • Tamoxifen may have a more significant risk reduction based on one head-to-head trial

      • Recall side effects of SERMs: vasomotor symptoms, vaginal symptoms (dryness, itching, dyspareunia), and increased risk of VTE!

      • Tamoxifen: also associated with concern for endometrial hyperplasia. While generally preferred in pre-menopausal patients, consider this in patietns with risk factors for endometrial hyperplasia!

      • Raloxifene: other significant side effect is leg cramps! Does not act on endometrium so may be considered in patients with significant risk factors. 

    • Aromatase inhibitors

      • Two trials have shown reduction in breast cancer risk in at-risk postmenopausal individuals; could be considered as alternative if contraindication to SERM

      • Not used in premenopausal women because it would end up actually stimulating ovarian function (i.e., ovulation induction)

  • Ovarian:

    • OCPs are reasonable to use for cancer prophylaxis until BSO:

      • Reduction of ovarian cancer risk estimated at 33-80% for BRCA1, 58-63% for BRCA2

      • No increased risk of breast cancer in those with BRCA mutations using OCPs

Surgical

  • Breast: bilateral mastectomy

    • Can be offered to any patient with BRCA mutation; reduces risk by 85-100%, depending on procedure type

    • However, this is big surgery - should be referred to breast surgeon to discuss risks of surgery in short term (surgical issues like hematomas, flap issues, infection) and long-term (pain, numbness, swelling, breast hardnes)

      • 70+% of patients report satisfaction with choice to undergo mastectomy at a follow up of 14.5 years

  • Ovarian: bilateral salpingoophorectomy

    • Most effective option for risk reduction; should be considered by age 35-40 for BRCA1 patients, 40-45 for BRCA2 patients

      • This can be individualized based on patient’s family history and plans for childbearing

      • Also worth discussion of fertility-preservation with oocyte or embryo cryoperservation

    • Salpingectomy alone is not recommended at this time; however, the PB notes that salpingectomy followed by future oophorectomy could be reasonable to consider for some patients desiring this.

    • How to perform a risk-reducing BSO:

      • Perform a survey on entry - visualize peritoneal surfaces for any obvious disease and perform pelvic washings

        • Inspect diaphragm, liver, omentum, bowel, paracolic gutters, appendix, ovaries, falliopian tubes, uterus, bladder serosa, and cul-de-sac; biopsy any abnormal areas

      • All tissue from ovaries and fallopian tubes need to be removed!

        • Ligate IP 2cm proximal to the end of identifiable ovarian tissue

          • Beware of your ureter!

        • If hysterectomy not performed, tubes should be divided at insertion to cornua, and ovary removed from utero-ovarian ligament as close to uterus as possible.

      • Frozen pathology not necessary, as most malignancies identified from this procedure are occult

        • Your pathologist needs to know that the patient is BRCA-carrier though! This will prompt them to perform complete, serial sectioning of the tissue with microscopic screening (rather than representative sections typically performed with other benign BSO)

    • Hysterectomy can be considered simultaneously:

      • Advantages: simplifies hormone therapy (estrogen alone, vs E-P if retained); removal of cornual aspect of fallopian tube; reduce endometrial cancer risk if genetically-predisposed or taking tamoxifen

      • Disadvantages: bigger surgery, longer recovery, higher risk of complications from surgery

    • After BSO:

      • Patients who are premenopausal will need HRT to mitigate effects of early menopause and help with cardiovascular health and bone protection

        • Recall that HRT in the WHI increased risk of breast cancer in the estrogen-progesterone arm, but not in the estrogen-alone arm.

        • Given the higher rates of triple-negative breast cancer in BRCA population – HRT would not alter that course. Data suggests that HRT does not seem to reduce the protective effects of risk-reducing surgery overall.

      • In post-menopausal patients, this is controversial – other options are generally preferred to HRT for VMS management.

      • Local estrogen therapy for vaginal symptoms (genitourinary syndrome of menopause) is safe and effective in BRCA population – please use it! 

      • Ongoing surveillance after BSO is not necessary - so no need to collect CA125 or perform surveillance imaging. Patients should report any concerning symptoms.

Osteoporosis: An Update

/

Here’s the RoshReview Question of the Week!

A 53-year-old postmenopausal woman has a BMI of 19 kg/m². She is a chronic smoker and is taking steroids for rheumatoid arthritis. She drinks four alcoholic beverages per day. Her T score is −2.1. What can be a side effect of the recommended medication for her?

Check to see if your answer is right at the links above!

One of our first episodes from December 2018 was about osteoporosis, referencing the now withdrawn ACOG PB 129. ACOG has made a major change in its clinical practice documents that you’ll notice going forward – for future publications, Practice Bulletins will now have the new name change to “Clinical Practice Guidelines,” reflecting their main purpose as guideline documents. 

Committee Opinions will be split into two groups, known as “Clinical Consensus” and “Committee Statement” documents. There are also the categories of “Practice Advisories” and “Obstetric Care Consensus” documents.

ACOG’s new guideline nomenclature!

The first Practice Bulletin to get the CPG treatment is Osteoporosis. So let’s review CPG #1!  

Background

  • Osteoporosis is a generalized loss of bone mass and decline in bone quality, leading to increased fracture risk.

    • 8.2 million women >50 years old have osteoporosis (compared to 2 million men)

    • 71% of fractures in osteoporotic persons occur in women

      • 50% of women over 50 will have an osteoporotic fracture

    • Additional 27.3 million women have low bone mineral density (formerly known as “osteopenia”)

      • Unfortunately, only 24% of women aged 60 and older receive osteoporosis treatment in the year after a fracture.

  • Risk factors aside from female sex:

    • Age: as described above, particularly over age 50

    • BMI under 20 or body weight less than 127 lb

    • Smoking

    • Alcohol use (especially more than 3 drinks daily)

    • Parental history of hip/spine fracture

    • Conditions, disease, and medications associated with “secondary osteoporosis”

      • HIV/AIDS and antiretroviral drugs

      • Anorexia

      • Diabetes mellitus (T1 and T2)

      • Gastric bypass

      • Hyperparathyroidism

      • POI / premature menopause / Turner syndrome or use of Aromatase inhibitors, GnRH agonists, DMPA

      • Antiepileptic drugs

      • Chronic steroid use

      • And more!

    • Racial variation: white and Hispanic populations with highest fracture risk

      • However, Black patients and Hispanic patients are less likely than White patients to get DXA screening after a hip fracture and less likely to receive osteoporosis treatment when indicated.

      • Black women also have higher rates of 1 year mortality, destitution, and other major adverse events following a fracture compared to White patients.

      • Varying studies looking at this have suggested multifactorial reasons for this inequity, including healthcare practitioner bias, patient mistrust of the healthcare system, other social determinants of health, or some complex interplay of these factors.

  • Bone physiology

    • 90% of bone mass is acquired during childhood and adolescence. Peak bone mass in adolescence has been correlated with later-life fracture risk! 

    • Bone mineralization and buildup in puberty is modified and optimized by sex steroids, predominantly estrogen, in both young girls and boys. Peak density is achieved around age 19 in women, and 20.5 in men. 

    • In adulthood, bone is comparatively in physiologic equilibrium -- the formation of new bone (facilitated by osteoblasts) comes at a rate equal to, or slightly surpassed by, bone resorption (facilitated by osteoclasts). 

      • Over time, this begins to favor resorption more and more, and is part of aging. 

    • The loss of estrogen seen in menopause triggers a time-limited rapid bone loss in women that is not seen in men, and there are countering views on whether this is a pathologic or physiologic process. 

      • Age also plays a factor – an 80 year old patient is at much higher risk for fracture than a 50 year old patient with the same BMD.

  • Prevention strategies

    • In young patients, part of our well-patient counseling should be on prevention of osteoporosis.

    • Prevention boils down to physical activity and calcium/vitamin D supplementation

    • Activity

      • ACOG recommends routine aerobic physical activity and weight bearing exercise to maintain bone health and prevent bone loss.

        • Recommendation of CDC for 150-300 minutes/wk of moderate intensity, or 75-150 mins/wk of vigorous activity aerobic exercise (or some combination) advised.

        • Weight bearing exercises appear to show most benefit – specifically mentioned are free weights, resistance bands, jogging, stepping, and jump rope.

        • Advises that patients in menopausal transition and in menopause are intentional with exercise, as weight-bearing, high force exercise or high-intensity interval training (HIIT)-style exercise have demonstrated small but significant increases in BMD.

        • Tai chi in postmenopausal women gets special mention in improving balance, preventing falls, and may have beneficial effect on BMD and bone turnover.

    • Calcium and Vitamin D

      • ACOG recommends consumption of appropriate amounts of these nutrients

        • Calcium:

          • Age 19-50: 1000 mg

          • Age 50+: 1200mg 

        • Vitamin D: 

          • Up to 70: 600 IU

          • After age 70: 800 IU

          • Patients wth history of vitamin D deficiency may need additional

          • USPSTF and Endocrine Society do not recommend screening for vitamin D deficiency in asymptomatic adults (i.e., routine screening)

Diagnosis

  • Don’t just jump to your DXA! And to know who might benefit, an H&P are essential.

    • Height loss can be an indicator of asymptomatic vertebral fracture – consider doing vertebral imaging by Xray or DXA if:

      • a 0.8in (2cm) loss in height over 1-3 years, or 

      • a loss of 1.5 in (4cm) since peak height at age 20

    • Risk assessment tools can identify patients who may benefit from screening, the most common of which is the FRAX score

      • This tool is useful to identify patients prior to a DXA who may be at high risk of fracture, and to identify patients after a DXA who may benefit from osteoporosis treatment (more on that later)

    • Recommendations for when to get a DXA:

      • DXA is recommended universally in women 65 or older

      • DXA is recommended prior to age 65 in postmenopausal patients who have a pre-DXA FRAX score indicating an 8.4% or greater risk of major osteoorotic fracture in the next 10 years – 

        • This is equivalent to the 10-year risk of a 65-year old White woman without risk.

        • ***NOTE*** this is lower than previous recommendation, which was 9.3%

      • Finally, ACOG suggests repeat DXA only in patients with initial testing near treatment thresholds, or if risk factors change significantly (i.e., started new glucocorticoid therapy). 

        • Generally, this will be no sooner than 2 years after an initial screen.

        • For those of average risk, there is no consensus on whether or when repeat DXA should be performed.

  • Osteoporosis and low BMD are diagnosed using dual energy X-ray absorptiometry (DXA).

    • Osteoporosis is defined as a T-score of < - 2.5 standard deviations

    • Low BMD is defined as a T-score of -1 to - 2.5 standard deviations

      • The T-score is calculated by looking at an individual’s BMD measurements at hip or spine, compared to a mean for a healthy, young-adult reference population.

      • DXA will also report a Z-score, which compares an individual’s BMD versus the mean of the patient’s same age, sex, and ethnicity. 

        • ACOG notes that further research is needed to explore the contributors to T and Z score differences based on race/ethnicity. 

    • Osteoporosis can also be diagnosed by:

      • A history of a fragility fracture, including an asymptomatic vertebral fracture

      • A T score consistent with low BMD, and an increased risk of fracture as determined by a risk assessment tool such as the FRAX scale

        • Specifically,  a >20% risk of major fracture, or >3% risk of hip fracture, in the next 10 years.

Treatment: Fall Prevention

  • ACOG spends  a significant part of this document asking OB/GYNs to assess fall risk in patients with low BMD or osteoporosis. 

    • Identifying impairments in mobility, medical conditions or medications that may sedate or impair balance or gait; environmental factors in the home (i.e., loose throw rugs, poor lighting) is imperative for fall risk

    • Also encouraging patients, particularly seniors, to engage in exercise to help reduce risk as we mentioned before!

  • Unlike in the old Practice Bulletin, the new CPG doesn’t focus on the treatment of osteoporosis. This likely reflects the fact that most OB/GYNs do not treat osteoporosis primarily – worth referring to endocrinology to prescribe and monitor these therapies.

  • However, familiarity is good to have, so here’s a few pointers from our previous podcast!

    • Bisphosphonates: suffix of -dronate. Demonstrated efficacy of reducing fracture risk 35-65%. Often limited therapy less than 5 years due to limited data on use beyond then. Weird side effects -- significant reflux or esophageal trauma (stand upright 30-60mins after taking med), osteonecrosis of the jaw -- these are fortunately rare, but testable. 

  • Raloxifene: a SERM, has agonist effects on the bone and antagonist effects on breast and uterus, so good choice in patient with (risks of ) breast CA/uterine CA, with concomitant osteoporosis. Big side effect consideration is VTE -- consider carefully in someone with a history of stroke/PE/DVT. 

  • Calcitonin, Denosumab, recombinant PTH: other options but not worth your time – you’ll be referring to an endocrinologist to consider that

  • Hormone Replacement Therapy (HRT): not approved for primary treatment of osteoporosis, but has been shown to reduce risk of fracture in peri/postmenopausal women by 33-36%, based on the WHI study. A reasonable adjunct to have for patients with low BMD and no other considerations/contraindications. We covered HRT a long time ago as well in this podcast with Dr. Eger!

Vulvar Intraepithelial Neoplasia (VIN)

/

Here’s the RoshReview Question of the Week!

A 41-year-old woman, G2P2, presents to your office for postcoital bleeding. She has a history of laparoscopic hysterectomy for persistent cervical intraepithelial neoplasia 3. A vaginoscopy is performed and shows multiple lesions in the upper third of the vagina. One lesion located within a suture recess near the vaginal cuff is not able to be visualized in its entirety. Biopsy reveals a high-grade squamous epithelial lesion. Her social history is significant for smoking. Which of the following is the best therapy?

Check your answer at the links above and check out RoshReview’s CREOG question bank!

Follow along with ACOG CO 675!

What is Vulvar Squamous Intraepithelial Lesions (SIL) and why do we care? - previously called VIN 

  • VIN is increasingly common - esp in women in their 40s 

    • VIN has increased more than 4x from 1973 to 2000! 

    • VIN should be considered a premalignant condition

  • How do we classify?

    • Has changed a lot over time, but most recently we have used:

      • LSIL of the vulva - used for low grade changes that come from HPV infections (usually present as genital warts) 

      • HSIL of the vulva - used for high grade changes that comes from HPV infections (precancerous lesions) - used to be called “usual type” 

        • VIN, warty type 

        • VIN, basaloid type 

        • VIN, mixed (warty or basaloid) type 

      • Differentiated type - from things like lichen sclerosus 

    • The International Society for the Study of Vulvovaginal Disease ISSVD recommends these terms to unify the nomenclature of HPV-associated squamous lesions of the lower genital tract - all of these are based on histopathologic findings:

ACOG CO 675

How do we diagnose VIN? 

  • Unfortunately, no good screening strategies

    • Detection usually limited to visual inspection 

    • What does it look like?

      • Can vary. Most will be raised, but some can be flat 

      • Discoloration of the skin - white, gray, red, brown, or even black 

    •  Should biopsy to make definitive diagnosis if not sure of diagnosis of something else (ie. LS) 

      • Biopsy should be performed in postmenopausal women with apparent genital warts and in women of all ages with genital warts where topical therapies have failed 

      • Colpo can also be useful - just remember that you need to soak the vulva in acetic acid with a gauze pad for several minutes 

What do we do to treat? 

  • Treat all vulvar HSIL (VIN usual type) 

    • Surgery 

      • Wide local excision should be done if there is suspected to be cancer 

      • Can be occult invasion even if initial biopsy is vulvar HSIL 

      • Should include gross margin of 0.5-1 cm around tissue with visible disease 

      • May be altered to avoid injury to critical structures like clitoris, urethra, anus, or other structures 

      • However, if lesions in critical areas, should be referred to specialist to avoid impaired psychosexual function (ie. if extensive around the perineum, reaching back to anus or around the clitoris 

      • If clear margins in excised tissue, much lower risk of recurrence 

    • Laser Ablation Therapy 

      • Should be done if occult invasion is not a concern

      • Can be used for single, multifocal, or confluent lesions, although risk of recurrence may be higher than with excision 

      • Colpo can help delineate lesions of margins 

      • As with excision, 0.5-1cm margin to be treated 

      • Remember than unlike genital warts, the entire thickness of the epithelium must be treated

    • Medical Therapy 

      • Topical imiquimod 5% 

      • Regimens that have been published include 3x/week to affected area for 12-20 weeks 

      • Colpo assessment at 4-6 weeks 

      • Residual lesions require surgical treatment 

  • Surveillance

    • Recurrence rate is as high as 9-50% with all treatment regimens

      • Higher with positive margins

      • Lower in surgically treated patients 

    •  Follow up has been limited in most studies 

    • However, women with Vulvar HSIL are at high risk of recurrence during their life time 

    • If complete response to therapy and no new lesions at follow-up visits, scheduled 6 and 12 months after initial treatment should be monitored by visual inspection 

Puberty and Precocious Puberty

/

Here’s the RoshReview Question of the Week!

A 30-year-old woman brings her 7-year-old daughter for consultation. She noted the presence of clinical signs of puberty and is worried that this might be occurring too early for her age. Which of the following distinguishes central precocious puberty from peripheral precocity?

Check your answer by clicking the links above!

What is puberty? 

  • Physical process of maturation from child to adult that is capable of sexual reproduction 

  • Also process of cognitive and psychosocial maturation

  • Two main areas: 

    • Gonadarche - activation of the gonads by pituitary hormones (FSH/LH) 

    • Adrenarche - increase in production of androgens in the adrenal cortex 

  • Cause

    • Triggered by hypothalamic activation and production of GnRH in pulsatile fashion that leads to FSH and LH production 

    • Not completely understood what causes the hypothalamus to begin this process

      • Thought to be governed by many factors like general health, nutrition, genetic factors, and other environmental cues 

      • Interesting to think about since the age of menarche in Europe decreased from 17.5 to 12.5-13 years in the last few centuries 

  • Timing of puberty

    • On average, girls begin puberty at age 10-11

  • One other note 

    • Puberty can be a time of emotional distress 

    • Not only are patients usually preteens or teens, with multiple societal and home pressures (school, friends, parents, etc), they are also experiencing significant changes in their bodies 

    • Child psych studies have shown that clinical symptomatology for previously diagnosed psychiatric disorders increase steeply when they reach puberty, and for some, this is the first onset of psychological symptoms 

    • So for these patients, important to follow them and work closely with your peds colleagues 

What are the different components of puberty? 

Mnemonic: boobs, pubes, spurt, squirt - Defined by Marshall and Tanner in 1970 (yes, that Tanner!) 

  • Thelarche - breast development 

    • Usually first physical sign of puberty is breast buds 

  • Pubarche (adrenarche?) - growth of pubic hair, usually follows a few months after breast development begins 

    • Thelarche and pubarche form the basis for Tanner staging in girls: (image source)

  • Growth spurt  

  • Menarche - getting your first period; the average age in the US is around age 12

So what is precocious puberty? 

  • More on timing of puberty:

    • Usually, puberty begins around the age of 10

      • However, there is a wide range, and can be anywhere from age of 8-13. Remember, puberty is NOT just beginning of menstruation! 

      • It can be evidence of breast development, pubic hair growth, etc.  

    • Precocious puberty is evidence of puberty that starts 2.5 SD earlier than the populational norm

      • Classically, it’s been defined as breast budding before the age of 8 in girls, though there is some racial differences in the literature that range somewhere between the ages of 7-8, and there is an increasing trend of earlier puberty in the US.

      • For simplicity’s sake, we will use the age of 8 as our cut off – at least when we should start THINKING that there maybe signs of precocious puberty 

  • Incidence and Risks

    • This is a little difficult to assess 

      • You might expect it to be 2% because we are using 2 to 2.5 standard deviations from the general population in the US 

      • But… in a population-based study, breast and/or pubic hair development at age 8 occurred in 48% of Black females and 15% of white females in the US. At age 7, this was 27% and 7% 

      • But if you look at a different population, the results are drastically different 

      • So… definition of precocious puberty is overall problematic, especially in female children. Instead, need to take into other factors as well, such as obesity

  • Strong predominance for females (approximately 87% of those evaluated in one study) 

  • In about 80% of girls with precocious puberty, it will be idiopathic 

Why do we care about precocious puberty? 

  •  Psychosocial reasons

    • Early menarche is often associated with earlier timing of sexual debut 

    • Increased risk of teenage pregnancy and sexually transmitted infections (HPV) 

    • Children may not be prepared for the implications of puberty and sexual maturation 

  • Other implications/health 

    • Early closing of the epiphyseal plates can lead to shorter stature 

    • Increased risk of breast cancer, heart disease, diabetes, and all-cause mortality 

What causes precocious puberty? 

  • Central precocious puberty (CPP)

    • Definition: Early maturation of the HPO axis … what causes it? 

    • Idiopathic 

      • In about 80-90% of females, but only 25% of males 

    • Central nervous system lesions

      • Hypothalamic hamartomas 

      • Other CNS tumors 

      • Cranial radiation 

  • Peripheral precocity 

    • Usuall due to excess secretion of sex hormone 

    • Ovarian tumors - overall rare, but can be from granulosa cell tumors. Rarely, sertoli/Leydig cell tumors can cause androgenization 

    • Primary hypothyroidism 

      • Severe, long-standing hypothyroidism can occasional cause precocious puberty 

      • Thought is due to cross-reactivity and stimulation of FSH receptor by high levels of TSH (same alpha sub unit) 

    • Exogenous chemicals/sex steroids  

    • Adrenal tumors 

    • Congenital adrenal hyperplasia - though these patients may present as early as infancy 

    • McCune-Albright Syndrome

      • Super rare → triad of peripheral precocious puberty, irregular cafe-au-lait spots (coast of Maine), and fibrous dysplasia of the bone  

How do we work this up? 

  • As always, history and physical 

    • If you suspect, you should ask patient and guardian 

    • When did they first notice changes, and how long has this been going on for? 

    • How quickly has this been progressing? 

      • Has this been occurring in the last year, and there has been very quick development of breast tissue with rapid onset of menstruation? More concern for peripheral source or tumor 

      • What about growth? Rapid growth may suggest CPP. Slower growth might signal benign or idiopathic cause 

    • Any changes with headaches, vision changes (suggests CNS tumor) 

    • Possible exposure to exogenous chemicals? Is mom on hormone replacement therapy and using estrace gel or cream? Did the child somehow get into it? 

    • Physical exam 

      • Height, weight, and height velocity (not something we usually do, so this might be best evaluated by the patient’s pediatrician!) 

      • Look for signs of McCune Albright - are there cafe au lait spots? 

      • Pubertal staging (Tanner Staging) 

  • Testing to order 

    • Bone radiograph - we don’t generally do this, so maybe think of referring to pediatric endocrinology, especially for follow up

      • Usually a hand X-ray to look at the growth plates in the metacarpals, wrist, etc 

      • Can assess for advance in bone age or premature closure of the growth plates 

    • FSH, LH, estradiol, and testosterone 

      • Elevated estradiol with suppression of FSH or LH is suggestive of peripheral production 

    • Consider getting a brain MRI to r/o central lesion 

    • Pelvic ultrasound - this will allow us to see peripheral tumors 

    • Specifically in patients with precocious pubarche (ie. pubic hair growth, axillary hair growth, but no menarche) 

      • Measurement of adrenal steroids 

      • Early morning 17-OHP, DHEA, testosterone, androstenedione 

  • Also refer to pediatric endocrinology! 

  • Treatment is based off of the cause - which we won’t cover today, but:

    • Principles of treatment will be based off of child’s age, rate of progression, height velocity, estimated height 

    • Goal of treatment is to allow child to grow to normal adult height and also to relieve psychosocial stress 

    • Usually for children with CPP, can treat with GnRH agonist 

    • Again - usually this is done with pediatric endocrinology, so we will defer further management to them.

      • This episode is designed to help you figure out the initial stages if someone comes to you with this issue!

Updates in Preterm Birth Prevention

/

Check out reading for this episode: PB 234

Our last podcast on preterm birth prevention was 2 years ago in November 2019, right after the PROLONG trial was published… and there have been some major guideline changes! We’ll do prevention of preterm birth redux today, going over everything once again to provide the most up-to-date summarization of ACOG’s recommendations..

Also important: we still have podcasts on assessing/managing preterm labor where nothing has really changed! Be sure to check that out as an important CREOG topic!

Why care about preterm birth?

  • Exceedingly common: 10.2% of newborns in the USA are born prematurely.

    • PTB accounts for 75% of perinatal mortality and >50% of long-term neonatal morbidity (and associated costs)

  • Preterm birth rates are actually increasing in the USA:

    • Had decreased from 2007-2014, but as of 2019 had increased back to 10.2%

      • Driven primarily by increase in late preterm birth (34-36 wks)

      • Rates of early preterm birth  (less than 34wk)  largely unchanged since 2014 (2.8%)

  • Preterm birth rates are disparate amongst racial/ethnic groups:

    • White women: 9.3% rate of PTB, vs Hispanic 10%, non-Hispanic Black 14.4%, AI/AN 11.5%, Hawaiian/PI 11.8%. 

      • Non-Hispanic Black women also have a disproportionately higher rate of < 34wk PTB (4.9% vs 2.7% overall rate)

  • Preterm birth is not just spontaneous preterm birth:

    • 50% follow preterm labor

    • 25% follow PPROM

    • 25% are intentional, medically-indicated PTB for maternal or fetal indications

Risk factors for PTB

  • Clinical

    • Prior history: prior spontaneous preterm birth <34 weeks has about a 35% recurrence risk!

      • Number of prior PTBs (more) and degree of prematurity (earlier) significantly affect this risk

      • Preterm birth followed by term birth → risk lowers

      • Twin preterm birth → still higher risk for preterm birth in subsequent singleton gestation, and as high as 40% if twins born before 30 weeks!

    • Bacterial vaginosis: 2x increased risk of spontaneous PTB, more strongly associated in early pregnancy. 

      • Treatment has not been demonstrated consistently to reduce PTB risk though.

    • UTIs in pregnancy: conflicting results based on Cochrane reviews examining risk with asymptomatic bacteriuria or symptomatic UTIs and preterm birth risk

      • However still prudent to treat - risk of pyelonephritis → sepsis, which definitely increases risk.

    • Periodontal disease: conflicting results of risk and association

    • History of prior D&C: slightly increased risk in 21-study meta-analysis of 2 million women (OR 1.29), though mechanism is uncertain. Risk slightly increased with history of multiple D&C (OR 1.74).

    • Multiple gestation: Preterm birth rate in twins of 60.3%, with 19.5% born before 34 weeks.

      • Triplets born preterm 98.3% of time, with 82.6% born before 34 weeks.

    • Short cervical length: a transvaginal short cervical length under 25mm between 16-24 weeks is associated with higher risk of PTB in a variety of screened populations.

    • History of cervical conization: inconsistent data regarding risk, though likely pronounced risk if short interval from conization-to-conception or excision greater than 15mm deep. 

  • Other modifiable risks:

    • Tobacco use: likely due to vasoconstriction, hypoxic-ischemic pathways

    • Low maternal pre-pregnancy weight: BMI < 18.5

    • Interpregnancy interval < 18 months: some association in observational studies

    • Unintended pregnancy

      • Importantly for these last two, some observational data points to increased access to LARC and family planning services is associated with lower rate of preterm birth.

  • What about race?

    • As we’ve discussed on the show before: race as a risk factor needs to be studied further -- a social, not a biological construct

    • Chronic stress related to exposure to racism is a potential explanation

    • Social and economic disadvantage are persistently associated with increased risk of preterm birth, with some factors including:

      • Lower educational attainment

      • Residence in ZIP code/region/states with economic disadvantage

      • Lack of access to prenatal care

    • More work is needed in evaluating and exploring these mechanisms, and more work is desperately needed in evaluating ways to correct inequity 

Screening Strategies: Identifying Patients who may Benefit from Interventions:

  • Lots of things that have been tried:

    • Fetal fibronectin assay: in asymptomatic patient, has not been shown to be helpful given low PPV.

    • Home uterine contraction monitors

    • Ongoing research into biomarkers, microbiome research, cervical texture, genetic associations…

  • Best and most important screening strategy we have: transvaginal cervical length screening in the 2nd trimester (16-24 weeks)

    • TVCL beyond 24 weeks is less predictive overall.

  • Recommendation for universal assessment of cervix at the time of anatomy ultrasound, with TVUS then performed if suspicious:

    • TAUS under 36mm identifies 96% of patients with TVCL under 25mm, and 100% of patients with TVCL of 20mm or less.

      • This universal assessment of length outright with TVCL is debated, though the cervix should at least be visualized to assess for previa, and a TACL is a reasonable 1st screen.

  • What cervical lengths are important to remember?

    • Compared to old guidelines, ACOG simplifies things in this document. There are two primary lengths to remember (both transvaginally assessed):

      • 25mm 

      • 10mm

    • Then, there are a few major interventions that can be considered:

      • Progesterone, either vaginal or intramuscular (17-OHP)

      • Cerclage

      • Pessary

    • The recommendations and intervention options vary by the history/clinical scenario of the patient (summarized in the table from the PB), so let’s review from there!

ACOG PB 234

Singleton Pregnancy with No Prior History of Preterm Birth:

  • Shortened cervix under 25 mm:

    • Vaginal progesterone

      • Dosing: 200mg micronized, from time of dx until 34-37 weeks gestation (Varies by trial)

      • Effects:

        • Multiple trials demonstrating lowered risk of early preterm birth (less than 34 weeks) by approximately 50%.

        • OPPTIMUM meta-analysis of progesterone demonstrated vagP reduced risk of spontaneous preterm birth prior to 34 weeks by about 40%, with an NNT of 14 patients to prevent one sPTB before 34 weeks.

    • Intramuscular progesterone

      • Dosing: 500mg weekly IM

      • Effects:

        • Very few trials on this in this population (singleton, no PTB history)

        • The few direct trials of this that exist generally have not found benefit

        • Not recommended in this population.

    • Exam-indicated cerclage

      • Identified painless cervical dilation prior to 24 weeks

      • Effects:

        • Associated with pregnancy prolongation by approximately 34 days and increased neonatal survival in a meta-analysis of multiple study types → thus recommended practice if truly painless cervical dilation.

      • Technique notes:

        • Amniocentesis to assess for infection pre-procedure: 

          • limited data, no RCT described in bulletin. Retrospective data colored by amnio-performance was tied to more severe cases. 

        • Antibiotic and tocolytic use:

          • RCT of periop abx + indomethacin demonstrated improved pregnancy lengths in rescue cerclages receiving medications, but no difference in neonatal outcomes overall (good or bad) → reasonable to consider

      • Contraindications:

        • PPROM

        • Suspected infection

        • Preterm labor or active bleeding

        • Fetal demise or anomaly incompatible with life

    • Ultrasound-indicated cerclage

      • Cervical shortening without dilation prior to 24 weeks.

      • Prior ACOG recommendation: cerclage not indicated in this population (only rescue cerclage was indicated without history of PTB)

      • NEW ACOG recommendation: possibly of benefit with extreme cervical shortening < 10mm

        • Based on a subgroup analysis of 126 patients in a meta-analysis of 5 RCTs. 

          • CL < 25mm - cerclage did not reduce risk of PTB <34wk

          • CL < 10mm - cerclage reduced risk of PTB <35 weeks (39.5% vs 58%). 

        • Importantly -- none of these patients were on vaginal progesterone, nor are there trials comparing vagP to cerclage in this population, or their combined effect.

    • Pessary

      • Cervical pessaries can compress, elevate, and posteriorly rotate the cervix.

      • Trials overall have not demonstrated effectiveness of pessary in those with short cervix without prior history of PTB, alone or in combination with vaginal progesterone.

Singleton Pregnancy in Patient with Prior Spontaneous Preterm Birth

  • Cervical Length Screening

    • In addition to the usual screen, in patients with prior PTB history, serial cervical length assessment has been studied:

      • A TVCL under 25mm before 24 weeks had a sensitivity of 65% for PTB under 35 weeks; PPV 33%, NPV 92%. However, sensitivity and PPV is similar for just risk factor of prior PTB.

      • Many studies have assessed utility of cervical length screening, without definitive data to guide frequency/schedule of assessment.

      • Most protocols will perform screening starting at 16 weeks and repeat q1-4 weeks through 24 weeks.

        • Because treatment is available for short cervix (US-indicated cerclage, we’ll get to that in a minute!), even with absence of superb data, serial screening is reasonable to perform.

  • IM Progesterone

    • We talked about this controversy on our previous podcast with the Meis trial and the PROLONG trial. 

      • Meis trial: RCT 463 patients, IM progesterone vs placebo. Reduced risk of PTB before 35 weeks by about 33% (20.6% vs 30.7%). Overall considered to be a higher risk population than the PROLONG trial, which came later.

      • PROLONG trial: RCT 1740 patients, no difference in PTB before 35 wks (11% vs 11.5%) or neonatal outcomes.

    • SQ progesterone is also available, but there is no direct evidence to support its efficacy vs IM or other formulations. 

    • In the interim, ACOG and SMFM have released statements supporting shared decision-making and patient preference in using progesterone supplementation (IM or vaginal), given the mixed evidence.

  • Vaginal Progesterone

    • Vs placebo:

      • 3 blinded RCTs demonstrate no benefit in reducing recurrent PTB.

      • 5 trial meta-analysis lookig at vagP for use in short cervix with sPTB history demonstrated a reduction of preterm birth by about 40%. 

    • Vs 17-P:

      • Meta-analysis of 3 trials comparing 17-P to vag P demonstrated patients receiving vagP had lower risk of PTB before 34 weeks, though the trials were not blinded and excluded patients with short cervix. 

      • Meta-analysis of multiple progesterone supplementation strategies suggested more robust evidence for BagP in preventing PTB prior to 34 weeks

        • Including largely heterogenous trials with a variety of risk factors present, somewhat limiting outright applicability.

  • History-Indicated Cerclage

    • Indicated in those with prior spontaneous preterm birth due to painless cervical dilation in the 2nd trimester without identified etiology (i.e., abruption), or in those who have had cerclages in prior pregnancy

    • Can be placed in early 2nd trimester with good effect.

  • Ultrasound-Indicated cerclage

    • Five-trial meta-analysis demonstrates that in those with prior sPTB and TVCL <25mm prior to 24 weeks, cerclage reduces the rate of PTB by about 35% (28% vs 41%). 

      • Unknown if progesterone supplementation may augment this effect at all, and there are no trials comparing cerclage to vaginal progesterone vs cerclage in this population.

      • There are ways to do indirect comparisons between trials, and when this is performed the effect size observed seemed to be similar between vagP and cerclage. 

        • Thus, ACOG states that cerclage or vagP are acceptable options in those with prior sPTB and short cervix, and states that cerclage may be offered in addition to continuation of progesterone.

  • Pessary

    • Evidence has not demonstrated any efficacy of pessary alone.

Multifetal Gestations

  • Cervical Length Screening

    • Multifetal pregnancies will generally have a shorter cervical length in the 2nd trimester, but the short cervix remains an effective predictor of early preterm birth:

      • TVUS < 25 mm at 20-24wks had PPV of 75.5% for delivery prior to 37 weeks, and 25.8% for delivery before 28 weeks. 

      • TVUS < 20 mm had PPV of 61.9% before 34 weeks in a separate analysis. 

    • There are not a lot of data regarding screening, and as you’ll see, less consensus regarding effectiveness of intervention in twin pregnancies; thus, serial screening is not necessarily recommended. 

    • A single screen at the anatomy scan should still be performed at minimum, as it is with singleton gestations without prior history.

  • IM Progesterone

    • Trial of 661 twin pregnancies of placebo vs 17-P demonstrated no benefit; a Cochrane review of randomized trials actually found slight increase in risk of PTB before 34 weeks with 17-P (though no difference in perinatal outcomes)

    • In those with prior sPTB and subsequent twin pregnancy, 66 patient trial showed less delivery prior to 34 weeks (20.6% vs 46.9%), but mean gestational length didn’t differ, and no significant difference in neonatal outcomes.

      • Bottom line: can consider in those with prior history of sPTB, not for use in those without sPTB history (same as singletons)

  • Vaginal Progesterone

    • Outright use - not recommended:

      • Cochrane review: no difference in rates of PTB before 34 weeks, perinatal death, NICU admission, or respiratory distress vs placebo.

      • Two other meta-analyses with similar conclusions, and an RCT subsequent to these meta-analyses demonstrated no difference.

    • Short cervix - could be considered, but insufficient data to make recommendation:

      • Six RCTs with different doses/compounds, but when analyzed together, demonstrates likely reduction in PTB risk prior to 33 weeks with vaginal progesterone.

      • Diffferent meta-analyses have not found a significant difference.

  • Cerclage

    • Prophylactic (i.e., place in a cerclage without other risk factors than multiple gestations) -- no evidence to suggest benefit.

    • Ultrasound-indicated

      • Insufficient data to recommend at this time, though trials that exist overall are small and have not found significant benefit, though at least one meta-analysis has shown potential benefit if cervical length is <15mm. 

    • Exam-indicated/”Rescue” cerclage

      • New RCT (2020) of twin gestations with asymptomatic cervical dilation between 16’0 and 23’6 demonstrated reduced risk of PTB before a variety of cut points (24/28/32/34) in patients receiving rescue cerclage vs no cerclage

      • Small trial, but based on limited data, there may be some benefit -- so could consider! Major practice change!

  • Pessary

    • Two RCTs looked at prophylactic pessary, and a third looking at pessary for short cervix, did not find benefit. 

    • Many other trials are limited by power and methodology in this space, but generally also have not found benefit.

    • Overall, pessary is not recommended in higher order gestation.

Does activity restriction reduce PTB risk?

  • Super common question, and one that this update in the PB directly addresses:

    • RCT of 165 pregnant persons found no relationship between coitus and risk for recurrent PTB

    • Secondary analysis of 17-P RCT for short cervix demonstrated PTB at less than 37 weeks was more common among pts who were placed on an activity restriction, and after controlling for confounders PTB remained more common in those placed on restrictions.

      • Thus, based on available data, activity restriction is not recommended.

Summary:

  • Singleton pregnancies without history of PTB:

    • CL screening: visualize at anatomy scan, TVUS if suspected to be short

    • 17-P: not indicated

    • Vag P: indicated if TVCL is <25mm

    • Cerclage: possibly indicated, more strong evidence if TVCL < 10mm; OR can be used for “rescue” with dilated cervix (painless)

  • Singleton pregnancies with history of sPTB:

    • CL screening: consider serial length screening from 16-24 weeks

    • 17-P: can be considered

    • Vag P: can be considered, may be of stronger benefit if short cervix identified

    • Cerclage:

      • History-indicated: if prior cerclage, or history of painless cervical dilation leading to loss in prior pregnancy 

      • US-indicated: if TVCL < 25mm, can consider this versus vaginal P

      • Rescue: still available

  • Multiples:

    • CL screening: same as singleton: at least visualize at anatomy scan

    • 17-P: Not indicated, unless prior history of sPTB

    • Vag P: not indicated, unless short cervix identified

    • Cerclage:

      • US-indicated: limited inconclusive evidence

      • Rescue: can consider → major practice change!