For patients with osteoporosis, drug treatments with bisphosphonates, particularly zoledronate, may not reduce overall mortality rates, according to a 

 of 38 clinical trials of drug treatments for osteoporosis among 101,642 patients. 

Consequently, the authors of the analysis in 

 recommend that these medications be restricted to decreasing fracture risk.

The investigators searched Science Direct, MEDLINE, Embase and the Cochrane Library for randomized, placebo-controlled clinical trials published or in press between 2010 and April 2019; conference abstracts from annual osteoporosis society meetings were also included.

Of the 2,045 records screened, only 1.8% were included in the meta-analysis. The four inclusion criteria were clinical trials that were randomized, double-blind and placebo-controlled; drug treatments with proven antifracture efficacy; agents used at the approved dose for treatment of osteoporosis; and study duration of at least 1 year.

No significant connection was found between all drug treatments for osteoporosis and overall mortality rate: risk ratio (RR) = 0.98; 95% confidence interval (CI): 0.91 to 1.05 (

 = 0%). Clinical trials of bisphosphonate treatment also showed no significant association with overall mortality: RR = 0.95; 95% CI: 0.86 to 1.04.

The same relationship held true for zoledronate treatment as well: RR = 0.88; 95% CI: 0.68 to 1.13. However, there was evidence for heterogeneity of the overall results: 

 of a small number of clinical trials of drug treatments for osteoporosis in 

 indicated there may be a link with increased mortality, reflecting the comorbidity and age of the participants. 

But the current larger analysis found “no significant association between the mortality rates in the placebo groups of the clinical trials and the association of treatment with mortality for all drug treatments,” the authors wrote. 

There was less certainty, though, for the association between intravenous zoledronate treatment and mortality rates because of the heterogeneous results of the clinical trials. Specifically, two large studies of zoledronate treatment found 28% and 35% reductions in mortality, respectively, which were not observed in other clinical trials. 

Similarly, observational studies reported 25% to 60% reductions in total mortality rates, which were too great of a reduction to attribute to a decrease in fracture risk. “Therefore, the reduced mortality rates would likely be owing to the direct biological effects of these treatments rather than the reduced fracture risk,” the authors wrote.

In addition, observational studies of patients receiving bisphosphonate therapy who had lower mortality may not have measured confounding factors that could have contributed to this lower mortality.

Of the 2,045 records screened, only 1.8% were included in the meta-analysis.

The apparent reduction in mortality may be the power of the placebo effect, for which the authors cite a Women’s Health Initiative study that showed that women in the placebo group who had at least 80% adherence to placebo treatment attained a 36% lower overall mortality than those with less than 80% adherence, despite adjusting for multiple potential confounding factors.

The placebo effect is especially apropos for treating osteoporosis because only roughly 50% of women who take oral medications for the condition continue their regimen for 1 year, with even fewer continuing longer.

The authors said additional studies are needed to elucidate whether treatment with zoledronate reduces mortality rates in patients with osteoporosis.

Steven R. Cummings, MD; Li-Yung Lui, MA, MS; Richard Eastell, MD, FRCP; Isabel E. Allen, PhD.

Articles

The authors of the analysis in JAMA Internal Medicine recommend that these medications be restricted to decreasing fracture risk.

Additional studies needed on drugs for osteoporosis

Results from a longitudinal study suggest that bacteria in the cervicovaginal microbiome (CVM) may play a role in risk of progression of high-risk human papillomavirus (HR-HPV) to cervical precancer. 

If the connection is validated in future studies, it could hold promise for development of microbial biomarkers for progression risks of HR-HPV to cervical intraepithelial neoplasia 2 (CIN2).

, the findings are from a nested study within the placebo arm of the Costa Rica HPV Vaccine Trial, which included women aged 18 to 25. The authors looked at the prospective role of the CVM on the natural history of HR-HPV by assessing cervical samples from 273 women with HR-HPV taken during two visits. Their focus was on infection clearance, persistence, and progression to CIN2 and CIN3.

Analysis of the samples from Visit 1 showed that an abundance of 

 was associated with clearance of incident HR-HPV infections (Linear Discriminant Analysis [LDA] > 4.0) whereas 

 was the dominant biomarker for HR-HPV progression (LDA > 4.0). At Visit 2, increased microbial Shannon diversity was significantly associated with progression to CIN2 (P = 0.027).

Multivariate analysis showed that the positive association between Gardnerella and CIN2 progression was a result of the increased cervicovaginal diversity seen in the swabs from Visit 2.

A full multivariate model of key components of the CVM showed significant protective effects via Visit 1 genus 

 (OR = 0.41 [0.22 to 0.79]), fungal diversity (OR = 0.90 [0.82 to 1.00]) and functional cell motility pathway (OR = 0.75 [0.62 to 0.92]) whereas Visit 2 bacterial diversity (OR = 1.19 [1.03 to 1.38]) was shown to be predictive of progression to CIN2.

 that “rather than directly causing the CIN2+ lesions, [it] appears to induce a higher diversity CVM over time as measured at V2 which in turn mediates the observed effect of Gardnerella in HR-HPV disease progression.”

Further, “the association may be tied to the ability of 

 to be immunosuppressive in the cervicovaginal region. Whereas, it seems that the presence of commensal bacteria (e.g. 

) with the ability to stimulate a local immune response may be contributing factors to the clearance of incident HR-HPV infections.”

Additional prospective studies are needed, the researchers concluded, to establish a causal link between the CVM, the immune system, and the natural history of HPV.

How prevalent is HPV in vaccinated adolescents? 

Usyk M, Zolnik CP, Castle PE, et al. Cervicovaginal microbiome and natural history of HPV in a longitudinal study. PLOS Pathog. 2020;16(3). doi:10.1371/journal.ppat.1008376

Results from a longitudinal study suggest that bacteria in the cervicovaginal microbiome (CVM) may play a role in risk of progression of high-risk human papillomavirus (HR-HPV) to cervical precancer.

Cervicovaginal microbiome and HPV progression

Accelerated biological aging was seen in women who had severe menopausal vasomotor symptoms (VMS) on enrollment in the Women’s Health Initiative Observational Study (WHI-OS), or late-occurring VMS (at enrollment but not at/during their reported menopause transition, according to a 

The Journal of Clinical Endocrinology & Metabolism

“Previously, we discovered that VMS was associated with indicators of age-related health risks, such as cardiovascular disease (CVD) and osteoporosis,” said senior author Rebecca Thurston, PhD, a professor of psychiatry, psychology and epidemiology at the University of Pittsburgh. “We were interested in finding out if women with VMS had greater underlying epigenetic aging.” 

The investigators examined connections between menopausal VMS and biological aging in 1,206 participants of the WHI-OS (average age 65 years at enrollment) who retained both ovaries and were not taking hormone therapy. Recruitment for baseline assessment occurred between 1993 and 1998.

The sample comprised 55% non-Hispanic White women, 26% non-Hispanic Black women and 19% Hispanic women. Roughly one-third of the sample reported VMS at enrollment and 60% of the sample had VMS at some point during the menopause transition and/or at enrollment.

Connections between menopausal VMS and biological aging were assessed by two DNA methylation-based epigenetic aging indicators formerly linked to poor health outcomes: DNAm PhenoAge and DNAm GrimAge.

Although no single metric proposed to characterize biological aging is universally accepted, DNAm-based indications offer the advantage of being a broad-based marker of accelerated aging across a diverse set of bodily systems and indicate robust relationships with adverse health outcomes, including CVD, mortality and Alzheimer’s disease.

The study concluded that severe hot flashes at enrollment were significantly associated with higher DNAm PhenoAge compared to no hot flashes: odds ratio (OR) = 2.79; 

Late-occurring VMS were also associated with a significantly higher DNAm PhenoAge (OR = 2.15; 

 = 0.011), and significantly higher DNAm GrimAge (OR = 1.09; 

“We were not surprised that VMS were associated with greater epigenetic aging, given other findings linking them to health risks,” Dr. Thurston told 

. “However, to my knowledge, we are the first to show this association. But we do not know at this time why postmenopausal women with severe or late-occurring VMS have greater biological aging.”

Three factors significantly associated with greater epigenetic aging for both DNA indicators were racial/ethnic minority status compared to White women (

 = 0.001) and a higher body mass index (BMI) (

 < 0.0001). Greater pack years of smoking was also a significant risk factor for biological aging, but only for DNAm GrimAge (

The authors accounted for these factors in their analyses, and therefore associations between VMS and epigenetic aging were not explained by them.

Based on study results, “women with VMS, particularly later in life, should engage in healthy preventive health measures,” said Dr. Thurston, president of the North American Menopause Society (NMS).

The next two steps will be to investigate women at the time of their menopause transition, as opposed to the WHI women who are considerably older, and to use more rigorous measures of VMS, such as physiologic measures of VMS and prospective, self-report measures of VMS. 

Dr. Thurston is a consultant to Astellas Pharma, Virtue Health, Pfizer and Procter & Gamble.

Thurston RC, Carroll JE, Levine M, et al. Vasomotor symptoms and accelerated epigenetic aging in the Women’s Health Initiative (WHI).  

. 2020;105(4). doi:10.1210/clinem/dgaa081

Accelerated biological aging was seen in women who had severe menopausal vasomotor symptoms (VMS) on enrollment in the Women’s Health Initiative Observational Study (WHI-OS), or late-occurring VMS (at enrollment but not at/during their reported menopause transition, according to a study in The Journal of Clinical Endocrinology & Metabolism.

Vasomotor symptoms and faster epigenetic aging

Miscarriages and preterm birth (PTB) can be a difficult experience for expectant mothers, and many seek out positive support systems to help cope. As the world has become more digital, social media has become a support system for women who have experienced these events, according to new research published in 

The study aimed to better understand how Twitter users discuss the topics of miscarriage and PTB, analyze the trends and drivers, and describe the perceived emotional state of women who have experienced a miscarriage.

The authors obtained 291,443 Twitter posting on miscarriages and preterm births from January 2017 through December 2018. They applied Latent Dirichlet Allocation (LDA) to identify major topics in the data. LDA models are used for uncovering latent topics within a large set of text.

Words are assigned weights within particular topics given assumed probability distributions. The authors also used time series decomposition methods to assess temporal trends and identify major conversation drivers. In order to determine the emotional content of 7282 personal miscarriage disclosure tweets, the authors classified the tweets into six non-mutually exclusive categories: grief/sadness/depression, anger, relief, isolation, annoyance, and neutral. 

Based on their findings, the authors discovered that the topics in their data fell into eight groups: celebrity disclosures, Michelle Obama’s disclosure, politics, healthcare, preterm births, loss and anxiety, flu vaccine and ectopic pregnancies.

However, they noted that the political discussions around miscarriages were largely a result of a misunderstanding between abortions and miscarriages. Within miscarriage disclosures, grief and annoyance were the emotions most commonly expressed by users 50.6% (95%CI 49.1 – 52.2) and 16.2% (95% CI 15.2 to 17.3), respectively.

The authors also noted that postings increased with celebrity disclosures; celebrities were considered strong and brave for publicly discussing the topic and Michelle Obama’s disclosure generated substantial response. These celebrity disclosures also led to increased disclosures by women who had similar experiences.

For example, Obama’s disclosure resulted in a response approximately 3.6 times higher than the weekly average of postings in 2018. Postings also increased with pharmacists’ refusal of prescribed medications and with outrage over the high rate of preterm births in the United States.

Based on the results of their study, the authors believe that celebrity disclosures lead to the biggest increase in discussions of miscarriage on social media. They also believe that the results provide an insight of current public perceptions of miscarriage and illustrate how individuals use Twitter to share information and/or seek support.

A better understanding of how individuals who have experienced miscarriage use social media may be informative for clinicians who provide miscarriage care and treatment. 

Cesare, N., Oladeji, O., Ferryman, K., Wijaya, D., Hendricks, MuÃ±oz, K. D., Ward, A., & Nsoesie, E. O. (2020). Discussions of miscarriage and preterm births on Twitter. Paediatr. Perinat. Epidemiology. doi: 10.1111/ppe.12622

How are miscarriages discussed on social media? 

A package of nine individual bills has just been introduced that aim to improve health for black mothers in the United States. “Black Maternal Health Momnibus Act of 2020”

 is led by Senator Kamala D. Harris (D-CA) and Representatives Lauren Underwood (IL-14) and Alma Adams (NC-12). 

All three are members of the Black Maternal Health Caucus, founded in 2019 to improve black maternal health outcomes.

Statistics show that black women are nearly four times more likely than white women and more than twice as likely as women of other races to die from preventable, pregnancy-related complications. They also experience higher rates of maternal complications and infant mortality.

The Act is designed to fill gaps in existing legislation to comprehensively address every dimension of the black maternal health crisis in the nation. 

If passed, the bills included in it will result in the following

 Critical investments in social determinants of health that influence maternal health outcomes, such as housing, transportation, and nutrition; 

Funding for community organizations working to improve maternal health outcomes for black women;

Comprehensive study of the unique maternal health risks facing women veterans and investment in Veterans Administration maternity care coordination;

Growth and diversification of the perinatal workforce to ensure that every mother in America receives maternity care and support from people she can trust;

Improved data collection processes and quality measures to better understand the causes of the maternal health crisis in the United States and inform solutions to address it;

Investment in treatments for maternal health care and substance use disorders;

Improved maternal health care and support for women who are incarcerated;

Investment in digital tools like telehealth to improve maternal health outcomes in underserved areas; and

Promotion of innovative payment models to incentivize high-quality maternal care and continuity of health insurance coverage from pregnancy through labor and delivery and up to 1 year postpartum.

 100 organizations endorsing the Act are the American College of Obstetricians and Gynecologists, Society for Maternal-Fetal Medicine, American College of Nurse-Midwives, and Planned Parenthood.

Said Senator Harris in a press release about the legislative package, “Black women across the country are dying from pregnancy and childbirth complications at astounding rates and the disparity transcends income and education levels. It is critical that the federal government work with states, local health providers, and mothers and their families to address the crisis and save lives.”

1. Black Maternal Health Momnibus. Black Maternal Health Caucas. https://blackmaternalhealthcaucus-underwood.house.gov/Momnibus. Published March 18, 2020.

“Black Maternal Health Momnibus Act of 2020” is led by Senator Kamala D. Harris (D-CA) and Representatives Lauren Underwood (IL-14) and Alma Adams (NC-12).

‘Momnibus’ legislation aims to help black moms

When the first patient suspected of having COVID-19 appeared on L&D, it was like the arrival of a pregnant celebrity. We tiptoed carefully around her room, minimizing our visits as much as possible. We found ourselves constantly hitting the refresh button on her pending SARS-CoV-2 lab result, awaiting confirmation that the coronavirus had finally arrived. Only one physician, the attending, was permitted at the patient’s delivery.

In those early days, the protocols for other COVID-19-positive adults in the hospital were well-established, but the rules for pregnant patients were still being created on the fly. Were new mothers permitted visitors while in labor? Would they be allowed to breastfeed? Would they be permitted to even meet their newborns immediately after birth?

We were not even quite sure how COVID-19 would manifest in pregnancy. Suddenly we were second-guessing all our previous diagnoses. Did the new admit in room 7 really have atypical preeclampsia, or was her isolated thrombocytopenia actually caused by the new coronavirus? That patient with the gastrointestinal bug waiting in triage…should she be tested, too?

Changes to our residency program came swiftly. An emergency meeting was called a few days after the virus hit our state. We were told we would be divided into two teams, with half of the residents scattered into skeleton crews across the hospital and the other half sent home as backup in case anyone was exposed or fell ill.

I already had been working straight through for a couple of weeks when I was told I would be staying for a couple weeks more. Spending so much time in the hospital meant that news about the Coronavirus reached me in bits and pieces. Each morning I would drive to work in the dark and learn on the radio how many people had died during the night. Then each evening as I drove home in the dark, I would learn how many had died during the day.

Meanwhile, things on L&D gradually started to change. It seemed like each day brought a new set of rules. In an effort to minimize co-mingling among staff, our anesthesia, midwifery, and family medicine teams stopped attending our normally boisterous morning sign-outs. Suddenly, everyone had to start wearing masks.

All things considered, however, not much had changed on our floor. It turns out that delivering a baby during a global pandemic does not differ much from the days before we had ever heard of COVID-19. Elective inductions were still going ahead. We did skin-to-skin and delayed cord-clamping. Even the pregnant women who were COVID-19-positive could still have a relatively “normal” birth experience, albeit in a room of people covered head to toe in protective gear.

In fact, it was “on the frontlines” that I felt the most the distant from the pandemic itself. I felt guilty responding to messages from family and old friends, those not in medicine but trapped in their homes by an invisible enemy ravaging their cities and towns. 

And after getting past the familiarities, 

The truth is, I hardly felt like I was on the frontlines, maybe more 

. If battling COVID-19 is truly the violent conflict our president would have us believe it is, then I felt like I was still a few trenches away from the hand-to-hand combat.

That has not stopped us from adopting the language of soldiers. Residents speak of being 

. Our daily briefings from administration quote Winston Churchill and urge us to “Stay the course.” The residents outwardly smile at this drama, but each still clings to their N95 mask like it’s a Kevlar vest.

After 3 weeks in the hospital, it was time for me to return home for my pandemic-mandated shore leave. I would be at home for another 2 weeks, enough time for any sign of an infection to manifest itself.

I had been working 14-hour days and overnight weekend call and had only a tangential understanding of how the outside world had changed during that time. It was a shock. When did they close all the restaurants? What do you mean I can’t have my friends over for dinner? What is “Zoom” and how do my parents know how to use it?

The first time someone walking toward me on the sidewalk swerved away to preserve my government-mandated 6 feet of personal space I nearly burst out laughing. Later that day I texted my fiancÃ© from the supermarket, incredulous. 

Do you know they’ve hired someone whose job is to wipe down all the supermarket carts?

My own sense of hubris started to creep in slowly. At the hospital, passing a sign each day that cheerfully implored me to 

, I had lost touch with the awfulness of this disease. In this otherwise anxious world we now inhabit, it had been wonderful to do something as joyful as deliver babies every day. All the while, three floors above me, patients were dying on ventilators.

It was only after I left the wards that I really began to be afraid of COVID-19, after I was able to step back and see the bas-relief impression it had left in the world outside of the hospital. Now I sit glued to the radio for updates on the virus. I read articles from China on its effects on pregnant patients and brush up on the pathophysiology of ARDS. I call my parents every day. We “Zoom.”

 I am getting ready to return to the hospital. I know from my co-residents and from the numerous update emails from my department that things are different now. We are accepting transfers from inundated hospitals in the area and sanitizing and reusing dwindling supplies of PPE. COVID-19-positive pregnant women have had bad outcomes directly related to the virus. The world at my hospital is starkly different from the one I left-and it may have changed yet again by the time you read these words.

Physicians, especially those in training, are known for using humor to ride out difficult times.  When I return to L&D, I will likely try my best to smile, joke, and commiserate with my co-residents. But beneath a stifling N95 mask, I will be gritting my teeth.

Navigating patient care in L&D during the global COVID-19 pandemic gives one resident cause for pause and reflection. How would it manifest in pregnancy?

The last normal place in the hospital

A generation ago, the Internet gave patients unprecedented access to medical information and thereby changed the nature of doctor-patient interaction. Rather than physicians being the sole source of medical information, patients began accessing information online and then bringing it to their physicians for discussion.

 test changed the roles of doctor and patient yet again, as patients are now ordering genetic tests themselves and bringing the results to their physicians for interpretation. Whether this moves the doctor-patient relationship in the right direction is debatable; however, there is no debate that these test results can be clinically significant and must be handled appropriately. This article provides a foundation for doing so.

“Consumer” genetics, also known as “over-the-counter” genetics, is initiated by patients without the authorization of a clinician. It began in 2006 as an entertaining way of tracing family lineage and quickly became very popular, with more than 5 million people having submitted samples for analysis.

In 2015, the focus expanded from recreational into clinical when 23andMe began testing for Bloom Syndrome, a rare autosomal recessive disorder of gene BLM. 

 analysis was added in 2018, and the 23andMe panel now includes 13 genetic diseases.

 The company also offers carrier testing for autosomal recessive conditions (e.g., cystic fibrosis), which it markets to couples who are planning to have children.

Although 23andMe provides consumers with personalized information on numerous medical conditions, it does not provide one-on-one clinical interaction whereby this type of information is normally shared. Instead, consumers are notified when their results become available, and they can directly access the information online, where it is summarized in a “Genetic Health Risk Report.”

To prepare consumers for the possibility of “bad news”, they are required to watch an educational video prior to accessing any result that 23andMe deems “potentially sensitive” (e.g., 

The absence of a one-on-one relationship with a healthcare provider is a serious shortcoming, 

especially for patients who learn that they harbor a pathogenic mutation by reading a report on their mobile device. 

They are often emotionally devastated and frequently turn to their physicians for guidance.

Both the Genetic Health Risk Report and the educational video are of good quality, with the report having a demonstrated user comprehension rate of greater than 90% [J1]and the video having been created by certified genetic counselors.

However, the absence of a one-on-one relationship with a healthcare provider is a serious shortcoming, especially for patients who learn that they harbor a pathogenic mutation by reading a report on their mobile device.

 They are often emotionally devastated and frequently turn to their physicians for guidance.

In terms of responding to these patients, it is important to first understand the nature of the test. Although 23andMe’s methodology has high levels of both accuracy (> 99% concordance with Sanger sequencing (which has been the gold standard for genetic sequencing for 40 years) and reproducibility (> 99%), the test has numerous limitations.

First, because the saliva samples are collected in a non-clinical setting, specimen integrity could be compromised. This risk is elevated by the common practice of multiple friends or family members collecting, labelling, and submitting their specimens in the same setting.

Second, in contrast to high-end, clinical-grade labs, which always confirm pathogenic findings with Sanger sequencing before issuing a report, 23andMe’s reports are based on genotyping alone, without any confirmation. Finally, although there are more than 1000 pathogenic 

 mutations, 23andMe tests for only the three mutations that are common in the Ashkenazi Jewish population (

However, even among Ashkenazi Jews, this approach has limitations because they can occasionally have non-Ashkenazi mutations.

 So, given the numerous limitations, the US Food and Drug Administration requires 23andMe to include the following warning in its Genetic Health Risk Reports: 

This test is not a substitute for visits to a healthcare provider for recommended screenings…and should not be used to determine any treatments.

In returning to our hypothetical patient who wants to discuss her 23andMe results, there are several possible scenarios:

The report is positive for a pathogenic BRCA mutation.

Unless the patient made a mistake in collecting and labelling her specimen, the likelihood of her, indeed, having a pathogenic mutation is greater than 99%. However, because 23andMe’s methodology has numerous limitations and its reports contain a disclaimer, no treatment decisions should be made until the result is confirmed with a sample collected under medical supervision and processed by a high-end, clinical-grade lab.

To expedite this process, the lab should be informed of the mutation that was identified and asked to confirm its presence with single-site testing. This approach is both faster and less expensive than full panel testing. In most cases, the pathogenic mutation will be confirmed and the patient can be managed accordingly.

However, on rare occasions, the pathogenic mutation will not be confirmed, and the clinician will thus be left with conflicting results: a positive from 23andMe and a negative from a clinical-grade lab. This scenario should always be resolved in favor of the clinical-grade lab. 

Those labs not only have higher levels of accuracy, when performing single-site testing, they always confirm both positives and negatives with Sanger sequencing. A negative result on single-site testing from a high-end lab would thus represent two negative results (one by NextGen sequencing and one by Sanger sequencing). Because this methodology is vastly superior to the genotyping performed by 23andMe, conflicting results should always be resolved in favor of the clinical-grade lab.

While this is certainly better than a positive result, it means only that the patient most likely does not have one of the three Ashkenazi founder mutations. However, there are more than 1000 other pathogenic mutations that she could have.

In terms of responding to this patient, you should first explain the limitations of the 23andMe test and then use the discussion as an opportunity to determine whether she meets criteria for clinical-grade testing (Table 1).

Between 5% and 15% of women meet criteria, 1 in 400 harbor a pathogenic mutation, and many others will be identified as being high-risk negative (i.e., they do not have a pathogenic mutation but are nonetheless at very high risk of developing cancer.) The patient’s request to discuss her 23andMe result could thus serve as a gateway to clinical-grade testing and, with it, significant changes in her management.

The patient has not yet submitted her sample to 23andMe. She originally planned to undergo just genealogy testing (to determine her heritage), but asks if she should also have 

As in Scenario 2, your response to this patient should begin by updating her personal and family history to determine if she meets criteria for clinical-grade testing.

Ideally, practitioners can incorporate this “cancer” family history questionnaire (Table 1) into their existing electronic medical record system. If this results in the patient having such testing, then there is nothing to be gained by also testing with 23andMe. Positive results can be interpreted by the practitioner and/or in conjunction with a clinical genetic counselor.

On the other hand, if the patient does not meet criteria for clinical-grade testing (and thus does not qualify for insurance coverage), then the role of the 23andMe test is not as clear. On one hand, testing patients who do not meet formal criteria is usually discouraged because it wastes resources and exposes them to the risks of a false positive.

However, in this situation, the patient is spending her own money and the risk of a false positive is less than 1%. In addition, even if she suffers a false positive, the potential harm consists only of having to perform a second saliva (or blood) test and some temporary anxiety. The traditional reasons for discouraging testing are thus far from compelling.

There is also a growing concern that testing only in accordance with our current criteria may be missing almost 50% of patients who harbor pathogenic mutations. A study of patients with breast cancer found that incidence of pathogenic mutations was 8.7% in the 477 patients who met criteria and 7.9% in the 479 patients who did not meet criteria.

Similar results have been reported by other authors

 and also by 23andMe, which states, on it’s website, that 50% of pathogenic mutations have been found in patients who did not have a first-degree relative with breast or ovarian cancer (though the formal criteria include other cancers as well as second degree relatives).

With these added studies, a good argument can be made that testing should not be strictly limited to patients who meet criteria. In fact, the American Society of Breast Surgeons recently adopted just such a position and now recommends that all women diagnosed with breast cancer undergo germline genetic testing.

So, how should you respond when a patient who does not meet criteria for clinical-grade testing asks whether she should have 

Although 23andMe’s methodology detects only three mutations, they are among the most common mutations and the test is highly accurate in identifying them.

Given the somewhat poor sensitivity of the criteria that we use for clinical-grade testing, the relatively low cost of 23andMe’s test ($50-$100), and the fact that the patient would be spending her own money, there is little reason to dissuade her from having the test if she understands its limitations and the significance of the results.

Although consumer-initiated genetic testing should not be used to guide treatment, it can be helpful in identifying patients who harbor pathogenic BRCA mutations, particularly those who do not meet formal criteria and thus do not qualify for insurance coverage of clinical-grade testing.

The tools provided in these clinical scenarios may help guide practitioners in managing the patient who presents with a 23andMe genetic report.

 is a Past President of the American College of Obstetricians and Gynecologists and has practiced obstetrics and gynecology in Denver, Colorado, for 40 years.

 is President of Law and Medicine, Hershey, Pennsylvania.

1. 23andMe Statistics, Facts and History. https://www.reviewchatter.com/statistics-facts-history/23andMe/ Accessed November 13, 2018.

2. 23andMe. Reports included in all services. https://www.23andme.com/dna-reports-list/ Accessed January 10, 2020.

3. FAQs-23andMe for Medical Professionals. https.//www.Medical.23andMe.com-FAQ/

4. Pomerantz D. 23andMe had devastating news about my health. I wish a person had delivered it. https://www.statnews.com/2019/08/08/23andme-genetic-test-revealed-high-cancer-risk/ Accessed January 8, 2020.

5. 23andMe. Understanding our scientific process. https://medical.23andme.com/about-our-test/ Accessed January 10, 2020.

6. 23andMe. Do you speak BRCA? https://www.23andme.com/brca/ Accessed January 10, 2020.

7. Kauff ND, Perez-Segura P, Robson ME, Scheuer L, Siegel B, Schluger A, et al. Incidence of non-founder BRCA1 and BRCA2 mutations in high risk Ashkenazi breast and ovarian cancer families. 

8. NCCN Clinical Practice Guidelines in Oncology-Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. https://www.genomeweb.com/sites/default/files/nccn_guidelines_genfamhighrisk_breastovarianpancreatic_v1.2020/  

9. What are the NCCN guidelines for colorectal cancer screening in patients with hereditary nonpolyposis colorectal cancer (HNPCC) (Lynch syndrome)? https://www.medscape.com/answers/2500006-10897/what-are-the-nccn-guidelines-for-colorectal-cancer-screening-in-patients-with-hereditary-nonpolyposis-colorectal-cancer-hnpcc-lynch-syndrome./

10. Beitsch PD, Whitworth PW, Hughes K Patel R, Rosen B, Compagnoni G. Underdiagnosis of hereditary breast cancer: Are genetic testing guidelines a tool or an obstacle? 

11. King MC, Levy-Lahad E, Lahad A. Population-based screening for 

12. American Society of Breast Surgeons. Consensus guideline on genetic testing for hereditary breast cancer. https://www.breastsurgeons.org/docs/statements/Consensus-Guideline-on-Genetic-Testing-for-Hereditary-Breast-Cancer.pdf

During a routine office visit, a patient mentions that she recently submitted a saliva sample to 23andMe. The company performed BRCA analysis and the patient wants to discuss the results with you. How should you approach the discussion?

Managing BRCA results from 23andMe

Of women using reversible contraception in the United States, 16% use an intrauterine device (IUD) equaling 4.4 million women in 2014.

 Today, five IUDs are available: Paragard®, a non-hormonal copper IUD, and four hormonal intrauterine system (IUS) products containing levonorgestrel – Liletta®, Mirena®, Kyleena® and Skyla®.  These systems are categorized by the amount of levonorgestrel that they contain -52, 19.5 or 13.5 mg. The amount of hormone drives the efficacy, bleeding profile, and recommendations for length of use.

The 52-mg IUS has gained popularity as a highly effective, reversible contraceptive because of several advantages, including the ability to significantly decrease menstrual blood loss and improve dysmenorrhea. The US Food and Drug Administration’s first approval of a 52-mg IUS was for Mirena for a 5-year duration. In 2009, an indication for treatment of heavy menstrual bleeding was added.

 The second levonorgestrel 52-mg IUS, Liletta, was initially approved for 3 years for contraceptive use in 2015 and, as of October 2019, is approved for up to 6 years.

The drive to bring Liletta to market as a second levonorgestrel 52-mg IUS was based on cost barriers.  Unintended pregnancies, unintended births, and abortions are disproportionately high in women of low socioeconomic status (SES).

 While reasons for these findings are multifactorial, there is an established relationship between low SES and less effective use of contraception.

 When cost is removed as a barrier, use of long-acting reversible contraception (LARC) increases dramatically.

Under the Health Resources & Services Administration (HRSA), manufacturers participating in Medicaid can provide drugs at significantly reduced prices to eligible organizations/entities under the 340B Drug Pricing Program.

 Medicines360, the non-profit women’s health pharmaceutical company that brought Liletta to the US market, participates in the 340B Program and offers a price approximately three times lower than for Mirena.

 This significantly lower cost puts less burden on clinics and providers to stock the device and allows immediate access, which can help eliminate the need for multiple visits for IUD insertion.

  Immediate access improves IUD utilization, especially in women with public insurance, who will only receive an IUD about half the time when two visits are required.

A real-life assessment of this lower-cost levonorgestrel 52-mg IUS option at several Title X clinics in Utah resulted in an immediate increase in uptake.

 The low cost is financially supported through private sector sales, a model like the Toms Shoes and Bombas socks, wherein private sector sales support the ability for low or no cost in the public sector.  As a medical community, this opportunity allows all providers to participate in efforts to provide equitable care and expand access.

Liletta has a T-shaped polyethylene frame with the same dimensions as Mirena.

 The inserters differ slightly; the reloadable Liletta inserter is 2 cm longer than the non-reloadable Mirena one, and the Mirena inserter is slightly narrower than the Liletta inserter (4.3 mm vs. 4.8 mm). Despite these differences, reported successful insertion rates from phase 3 trials are 98% to 99% for both products.

 The vertical stem of the IUS contains a reservoir of levonorgestrel 52 mg covered by a release rate-controlling membrane.

 Liletta produces an initial release rate of 19.5 µg/day, which decreases slowly over time to 9.8 µg/day at the end of 5 years, mirroring the release rate of Mirena.

 For comparison, the levonorgestrel 13.5-mg IUS release rate at the end of its 3-year duration is 5 µg/day.

The calculated estimated release rates based on this information support using Liletta for contraception beyond 5 years.

 Liletta is under study in a prospective phase 3 clinical trial aimed at extending the approved duration of the levonorgestrel 52-mg IUS and evaluating the potential non-contraceptive benefits or side effects of the device among a diverse US population.

 This review provides key findings of the ongoing clinical trial and important discussion points that can be referenced during patient counseling to augment the shared decision-making process in contraceptive method selection.

Liletta is under study in a prospective phase 3 clinical trial aimed at extending the approved duration of this levonorgestrel 52-mg IUS.

Vol 65 No 05