2020 Cochrane Review Update: NSAIDs vs Other Analgesics for Soft Tissue Injury

BACKGROUND AND PURPOSE:

  • The best drug treatment for acute soft tissue injuries (bruise, sprains, strains, etc.) is not well known
    • NSAIDs are commonly recommended
    • Oral opioids for acute pain management may be leading to dependence
  • In an update to a 2015 Cochrane review, Jones et al. (Cochrane Database Syst. Rev. 2020) assessed the benefits or harms of NSAIDs compared with other oral analgesics for treating acute soft tissue injuries

METHODS:

  • Systematic review and meta-analysis
  • Data sources
    • CENTRAL | MEDLINE | Embase to January 2020
    • Other databases were searched to February 2019
  • Inclusion criteria
    • Randomized or quasi-randomized controlled trials
    • Trials included individuals soft tissue injury
    • Compared oral NSAIDs vs
      • Paracetamol (acetaminophen)
      • Opioid
      • Paracetamol plus opioid
      • Complementary and alternative medicine
  • Study design
    • Acute soft tissue injury definition: Sprain, strain, or contusion of a joint, ligament, tendon, or muscle occurring within 48 hours of inclusion in the study
    • Two review authors independently assessed studies for eligibility, extracted data, and assessed risk of bias
    • Quality of the evidence was assessed using GRADE criteria
  • Primary outcomes
    • Pain
    • Swelling
    • Function
    • Adverse effects
    • Early re-injury

RESULTS:

  • 20 studies included | Combined total of 3305 participants
    • 3 studies included children only | Remainder included predominantly young adults
    • Approximately 60% were male | 40% female
    • 7 studies recruited only people with ankle sprains
  • Certainty
    • Evidence related to pain relief was generally high certainty
    • There was a combination of certainty with most outcomes
  • No studies reported re-injury rates
  • No studies compared NSAIDs with oral complementary and alternative medicines

NSAIDs vs Paracetamol  

  • 11 studies | 1853 participants
  • No differences between the two groups for pain at
    • 2 hours (1178 participants, 6 studies; high-certainty evidence)
    • Days 1 to 3 (1232 participants, 6 studies; high-certainty evidence)
    • ≥7 days (467 participants, 4 studies; low-certainty evidence)
  • Little difference between the groups in numbers of participants with minimal swelling at ≥7 days 
    • 77 participants, 1 study; low-certainty evidence
  • Little difference between the groups for return to function at ≥7 days
    • 386 participants, 3 studies; very low-certainty evidence
  • NSAIDs may slightly increase the risk of GI adverse events compared with paracetamol
    • 1504 participants, 10 studies; low-certainty evidence
  • There was little difference in neurological adverse events between the NSAID and paracetamol groups
    • 1679 participants, 9 studies; low-certainty evidence

NSAIDs vs Opioids

  • 6 studies | 1212 participants
  • There was no difference between the groups in pain at
    • 1 hour (1058 participants, 4 studies; moderate-certainty evidence)
    • Days 4 to 7 (706 participants, 1 study; low-certainty evidence)
  • No important difference between the groups in swelling
    • 84 participants, 1 study, very low-certainty evidence
  • NSAID group were more likely to return to function in 7 to 10 days
    • 542 participants, 2 studies; low-certainty evidence
  • NSAIDs use less likely to result in GI or neurological adverse events compared with opioids
    • 1143 participants, 5 studies; moderate-certainty evidence

NSAIDS vs Paracetamol and Opioid Combination

  • 4 studies | 240 participants
  • The applicability of findings from these studies is questionable
    • The dextropropoxyphene combination analgesic agents used are no longer in general use (used in 2 of 4 studies)
    • The paracetamol doses were suboptimal
  • No difference between the groups in pain at
    • Day 1 (51 participants, 1 study; very low-certainty evidence)
    • Day 3 (149 participants, 2 studies; very low-certainty evidence)
    • Day 7 (138 participants, 2 studies; very low-certainty evidence)
  • No difference between groups for the following  
    • Swelling (230 participants, 3 studies; very low-certainty evidence)
    • Return to function at day 7 (89 participants, 1 study; very low-certainty evidence)
    • Risk of GI or neurological adverse events (141 participants, 3 studies; very low-certainty evidence)

CONCLUSION:

  • In the context of soft tissue injuries
    • No differences were found between NSAIDs and paracetamol at 1 to 2 hours and 2 to 3 days | There may also be no difference in pain at day 7 and beyond
    • NSAIDs may be slightly associated with more GI upset compared to paracetamol  
    • There is probably no difference between NSAIDs and opioids in pain at 1 hour, and there may be no difference at days 4 or 7
    • NSAIDs probably result in fewer GI and neurological adverse effects compared with opioids
  • The authors note that participants tended to be younger and these results really are not generalizable to adults ≥65 years of age

Learn More – Primary Sources:

Oral non-steroidal anti-inflammatory drugs versus other oral analgesic agents for acute soft tissue injury

RCT Results: Does Remdesivir Improve Clinical Status in Patients with Moderate COVID-19?

BACKGROUND AND PURPOSE:

  • In a controlled trial, remdesivir provided a clinical benefit to patients with severe COVID-19
  • Spinner et al. (JAMA, 2020) assessed the efficacy of 5 or 10 days of remdesivir treatment compared with standard care in patients with moderate COVID-19

METHODS:

  • Randomized, open-label trial (enrollment from March 15 to April 18, 2020)
  • Setting
    • 105 hospitals in the United States, Europe, and Asia
  • Participants
    • Hospitalized
    • Confirmed COVID-19
    • Moderate disease: Pulmonary infiltrates and room-air oxygen saturation >94%
  • Interventions
    • 10-day course of remdesivir
    • 5-day course of remdesivir
    • Standard care
  • Study design
    • 1:1:1 randomization
    • Remdesivir dosing: 200 mg IV on day 1 followed by 100 mg/d
    • Clinical status:  7-point ordinal scale ranging from death (category 1) to discharged (category 7)
    • Differences between remdesivir treatment groups and standard care were calculated using proportional odds models and expressed as odds ratios (OR)
      • An OR greater than 1 indicated difference in clinical status distribution in favor of category 7 
  • Primary outcome
    • Clinical status on day 11

RESULTS:

  • 583 patients began the study | 91% completion
    • Median age: 57 (IQR 46 to 66) years | 39% women
  • Comorbidities
    • Cardiovascular disease: 56%
    • Hypertension: 42%
    • Diabetes: 40%
  • Intervention groups
    • 10-day remdesivir: 197 patients
    • 5-day remdesivir: 199 patients
    • Standard care: 200 patients
  • Median length of treatment
    • 5-day group: 5 days
    • 10-day group: 6 days
  • Patients in the 5-day remdesivir group had significantly higher odds of a better clinical status (day 11) than those receiving standard care (P=0.02)
    • OR 1.65 (95% CI, 1.09 to 2.48)
  • No significant difference was seen in clinical status distribution on day 11 between the 10-day remdesivir group and the standard care group (P = 0.18)
  • Mortality by day 28
    • 5-day remdesivir: 1% (2 patients)
    • 10-day remdesivir: 2% (3 patients)
    • Standard care: 2% (4 patients)
  • Side effects were more common in the remdesivir treated patients vs standard care group for the following
    • Nausea (10% vs 3%)
    • Hypokalemia (6% vs 2%)
    • Headache (5% vs 3%)

CONCLUSION:

  • For patients with moderate COVID-19, a 10-day course of remdesivir had no significant impact on clinical status at day 11, compared to standard care
  • However, for a shorter course, authors conclude that

Patients randomized to a 5-day course of remdesivir had a statistically significant difference in clinical status compared with standard care, but the difference was of uncertain clinical importance

Learn More – Primary Sources:

Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19 A Randomized Clinical Trial


Is Pregnancy After Breast Cancer Safe for Women with BRCA Mutations?

BACKGROUND AND PURPOSE:

  • Pregnancy after breast cancer appears to be safe and is not associated with an increased risk of cancer recurrence
    • However, data are limited regarding pathogenic BRCA variants
  • Lambertini et al. (Journal of Clinical Oncology, 2020) investigated the impact of pregnancy on breast cancer outcomes in patients with germline BRCA mutations

METHODS:

  • Multicenter, retrospective cohort study (January 2000 and December 2012
  • Participants
    • Breast cancer diagnosis  ≤ 40 years
    • Deleterious germline BRCA mutations
  • Exposures
    • Pregnancy after breast cancer
    • No pregnancy
  • Study design
    • Survival analyses | Adjusted for known prognostic factors including adjusted for age at diagnosis, tumor size, nodal status, hormone receptor status, type of endocrine therapy, breast surgery, and BRCA mutation
  • Primary outcomes
    • Pregnancy rate
    • Disease-free survival (DFS)
  • Secondary outcomes
    • Pregnancy outcomes
    • Overall survival (OS)

RESULTS:

  • 1252 patients were included
    • BRCA1: 811 patients
    • BRCA2: 430 patients
    • BRCA1/2: 11 patients
  • Median age at time of pregnancy: 35.7 years | Median time from diagnosis to pregnancy 4.5 years
  • 195 women had at least 1 pregnancy after breast cancer
  • Pregnancy outcomes
    • Pregnancy rate at 10 years: 19% (95% CI, 17% to 22%)
    • Induced abortions: 8.2%
    • Miscarriages: 10.3%
    • Births: 76.9% of women | 9.2% preterm
    • Adverse outcomes
      • Pregnancy complications: 11.6%
      • Congenital anomalies: 1.8%
  • Median follow-up from breast cancer diagnosis was 8.3 years
  • No differences in survival detected between the pregnancy and nonpregnancy groups
    • Disease free survival
      • Adjusted hazard ratio (HR) 0.87 (95% CI, 0.61 to 1.23)
      • P = 0.41
    • Overall survival
      • Adjusted HR 0.88 (95% CI, 0.50 to 1.56)
      • P = 0.66

CONCLUSION:

  • Pregnancy after breast cancer in patients with BRCA mutations is not associated with unfavorable survival outcomes or pregnancy outcomes
  • For women with BRCA mutations, pregnancy after breast cancer is safe and does not worsen prognosis
  • The authors conclude that

These findings are of paramount importance for health care providers involved in counseling young patients with BRCA-mutated breast cancer who inquire about the feasibility and safety of future conception

Learn More – Primary Sources:


Pregnancy After Breast Cancer in Patients With Germline BRCA Mutations

MifeMiso RCT results: Mifepristone Plus Misoprostol or Misoprostol Alone for Miscarriage Treatment?

BACKGROUND AND PURPOSE:

  • Chu et al. (The Lancet, 2020) examined whether treatment with mifepristone plus misoprostol resulted in a higher rate of completion of missed miscarriage vs misoprostol alone

METHODS:

  • Multicenter, double-blind, placebo-controlled, randomized trial
    • Mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage (MifeMiso) Trial
  • Participants
    • ≥16 years
    • Missed miscarriage | Diagnosed by pelvic ultrasound up to 14 weeks GA
    • Patient opts for medical management of miscarriage
  • Interventions
    • Mifepristone group
      • Single 200 mg dose of oral mifepristone
      • Followed by a single dose of vaginal, oral, or sublingual misoprostol 800 μg 2 days later
    • Control group
      • Oral placebo
      • Followed by a single dose of vaginal, oral, or sublingual misoprostol 800 μg 2 days later
  • Study design
    • 1:1 randomization | Study group balancing performed for the following
      • Maternal age (<30 years vs ≥30 years)
      • Body-mass index (<35 kg/m2 vs ≥35 kg/m2)
      • Previous parity (nulliparous women vs parous women)
      • Gestational age (<70 days vs ≥70 days)
      • Amount of bleeding (Pictorial Blood Assessment Chart score; ≤2 vs ≥3)
      • Randomizing center
  • Masking: Participants, clinicians, pharmacists, trial nurses, and midwives masked to study group assignment throughout the trial
  • Power analysis: 335 women in each trial group required to provide 90% power to detect a difference of ten percentage points for primary outcome
    • Analyses based on intention-to-treat
  • Primary outcome
    • Failure to spontaneously pass the gestational sac within 7 days after assignment

RESULTS:

  • 711 women were randomized
    • Mifepristone and misoprostol group (mifepristone): 357 women
    • Placebo and misoprostol group (control): 354 women
  • Fewer women in the mifespristone group did not pass the gestational sac spontaneously within 7 days
    • Mifepristone: 17%
    • Control: 24%
    • Risk ratio (RR) 0.73 (95% CI, 0.54 to 0.99; p=0.043)
  • Fewer women in the mifepristone group required surgical intervention to complete the miscarriage
    • Mifepristone: 17%
    • Control: 25%
    • RR 0.71 (95% CI, 0.53 to 0.95; p = 0.021)
  • No subgroup effect was noted based on GA
  • Adverse events: There was no difference between groups

CONCLUSION:

  • The combination of mifepristone and misoprostol was more effective for the treatment of missed miscarriage than misoprostol alone
    • Benefits include reduced need for surgical intervention
  • The authors recommend

…women with missed miscarriage should be offered mifepristone pretreatment before misoprostol to increase the chance of successful miscarriage management, while reducing the need for miscarriage surgery

Learn More – Primary Sources:

Mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage (MifeMiso): a randomised, double-blind, placebo-controlled trial

Cochrane Review: Oral or Intra-Vaginal Anti-Fungal Treatment for Candidiasis?

BACKGROUND AND PURPOSE:

  • This Cochrane review by Denison et al. (Cochrane Database Sys Rev, 2020) is the second update of the original review
  • The authors assessed the effectiveness of oral versus intravaginal antifungals for the treatment of uncomplicated vulvovaginal candidiasis

METHODS:

  • Systematic review and meta-analysis
  • Inclusion criteria
    • RCTs
    • Any language
    • Trials that compared at least one oral antifungal with one intravaginal antifungal
    • Participants: Women ≥ 16 years  | Positive mycological diagnosis of uncomplicated vulvovaginal candidiasis
    • Exclusion: HIV positive | Imunocompromised | Pregnant | Breast feeding | Diabetic
  • Primary outcome
    • Relative effectiveness of clinical cure (presence of symptoms)
  • Secondary outcomes
    • Relative effectiveness for mycological cure
    • Safety | Side effects | Treatment preference | Time to first relief of symptoms | Costs

RESULTS:

  • 26 trials | 5007 participants
    • Trials were conducted in multiple countries
    • Overall risk of bias deemed to be high
    • 8 different medications were included (imidazole and triazole)

Oral vs Intravaginal Antifungals for Clinical Cure

  • There was probably little or no difference between oral and intravaginal anti-fungal treatment for clinical cure
    • Short-term follow-up (5 to 15 days)
      • Odds ratio (OR) 1.14 (95% CI, 0.91 to 1.43; 13 trials; 1859 participants)
      • Moderate-certainty evidence
    • Long-term follow-up (2 to 12 weeks)
      • OR 1.07 (95% CI, 0.77 to 1.50; 9 trials; 1042 participants)
      • Moderate-certainty evidence
  • Oral treatment probably improves mycological cure over intravaginal treatment at
    • Short-term follow-up
      • OR 1.24 (95% CI, 1.03 to 1.50: 19 trials; 3057 participants)
      • Moderate-certainty evidence
    • Long-term follow-up
      • OR 1.29 (95% CI, 1.05 to 1.60; 13 trials; 1661 participants)
      • Moderate-certainty evidence

Oral vs IntraVaginal Antifungals for Safety and Satisfaction

  • Safety
    • Low risk of participants withdrawing from the studies due to adverse drug effects for either treatment
      • 23 trials; 4637 participants
      • High-certainty evidence
    • It is undetermined whether oral treatments reduced the number of side effects compared with intravaginal treatments
      • OR 1.04 (95% CI, 0.84 to 1.29; 16 trials; 3155 participants)
      • Low-certainty evidence
    • The type of side effects differed
      • Intravaginal: Local reactions
      • Oral: Systemic effects | Especially GI symptoms and headaches
  • Patient satisfaction
    • Oral treatment was favored by participants
      • 12 trials; 2206 participants
      • Low-certainty evidence
    • Little or no difference in time to first relief of symptoms was seen between oral vs intravaginal treatments
      • 10 trials; 1910 participants
      • Low-certainty evidence
  • Costs were not reported in any trial

CONCLUSION:

  • Compared to intra-vaginal anti-fungal treatment, oral treatment does not appear to make a difference when it comes to clinical cure (perceived symptoms) but probably does improve clearance of candida from vaginal canal when compared to vaginal treatment
  • Oral treatment was also preferred by participants, though certainty of evidence was low
  • Upon review of these the results, Cochrane Reviews states that

The addition of new evidence does not change the conclusions of the review. The results of this review should be considered stable in terms of the antifungal medicines included. The frequency of future updates should be limited. No further updates are planned

Learn More – Primary Sources:

Oral versus intra-vaginal imidazole and triazole anti-fungal treatment of uncomplicated vulvovaginal candidiasis (thrush)

Lynch Syndrome

What is it?

Lynch syndrome, formerly known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC) is the most common hereditary cause of colon and endometrial cancer, and is thought to explain 3-5% of colorectal cancer cases. Approximately 1 in 279 American are affected with Lynch syndrome.

What causes Lynch Syndrome?

  • Lynch syndrome is caused by genetic changes, also called mutations, in one of 5 genes (a segment of DNA that codes for protein)
    • Most of these genes are involved in DNA repair – and act as the ‘spellcheckers’ of the cell
    • If there is a “spelling error” (a new change in the DNA code), these genes fix the error before the DNA copies itself to make more new cells  
    • Because of the work they do, they are called mismatch repair (MMR) genes
  • People that have Lynch syndrome are missing a working copy of one of these five genes and therefore accumulate genetic damage faster than average
    • Cancer is caused by an accumulation of genetic errors within cells
  • When a person has an inherited mutation in an MMR gene, the DNA repair process no longer works as efficiently as it should
    • Without these working repair genes, the damage builds up and these individuals are more likely to develop certain types of cancer
  • Individuals with Lynch syndrome are at increased risk for developing specific cancers such as
    • Colorectal | Uterine | Ovarian | Stomach | Small intestine | Urinary tract | Brain | Sebaceous gland
  • According to the National Comprehensive Cancer Network (NCCN), the most significant cancer risks are for
    • Colorectal cancer: 12 to 52% lifetime risk (compared to 5% for people with average risk)
    • Uterine (endometrial) cancer: up to 57% lifetime risk (compared to 3% for people with average risk)

How do Doctors Figure out if Someone has Lynch Syndrome?

There Are a Few Ways That a Person May Be Diagnosed with Lynch Syndrome

  • Testing cancer cells of someone who has colon cancer or endometrial cancer
    • Testing can be done on a piece of the tumor that can identify signs of poor DNA repair or missing repair proteins
  • Genetic testing to look for changes in the 5 Lynch syndrome repair genes
    • Done on a blood or saliva sample if there is a personal or family history suggestive of Lynch syndrome

Who Might Be Offered Genetic Testing For Lynch Syndrome?

  • The following questions can be used to help identify people who may be at higher risk
    • Has there been anyone affected with colorectal or uterine cancer before the age of 50?
    • More than one cancer, of any kind, in the same person (such as colon and uterine cancer)?
    • 10 or more colorectal polyps during someone’s lifetime?
    • Three or more family members (on the same side of the family) with colon, uterine or stomach cancer?
    • Numerous family members with colon cancer or other cancers?

Note: If you or someone in your family answers ‘yes’ to any of the above questions, a genetic counselor can help you decide if genetic testing for Lynch syndrome  is  a good idea

How is Lynch Syndrome Passed Along in Families?

  • Lynch Syndrome Is A Dominantly Inherited Condition
    • This means that a mutation in one copy of a MMR gene is sufficient to cause an increased risk for cancer
    • Individuals who inherit Lynch syndrome have a 50% chance to pass it onto each of their children
  • Testing children for Lynch syndrome usually occurs after the age of 18 because individuals with Lynch syndrome are not at an increased risk for childhood cancers
  • Individuals who did not inherit an MMR mutation do not have Lynch syndrome and therefore cannot pass it onto their children

Note: Since Lynch syndrome is an inherited condition, it is important to let family members know they may be at risk too | To protect your privacy, nobody should ever reach out to your family members without your knowledge and permission

How Does Knowing if You Have Lynch Syndrome Help if You Don’t Have Cancer?

  • Identifying people with Lynch syndrome is the best way to start early detection and prevent cancer

Colon Cancer Prevention

  • To reduce the risk of cancer, a person with Lynch syndrome will be offered extra screening, for example
    • Starting colonoscopy: Individuals with Lynch syndrome will begin colonoscopies at age 20 to 25 or 2 to 5 years before the earliest colorectal cancer in their family, compared to the general population start date at age 50
    • Timing of colonoscopy: Individuals with Lynch syndrome will get colonoscopies done every 1 to 2 years compared to the general population interval which is every 10 years

Note: A genetic counselor or oncologist will explain the details of an appropriate screening program for someone who is affected with Lynch syndrome | A colonoscopy is the only screen that can prevent colon cancer!

Uterine and Ovarian Cancer Prevention

  • There are recommended risk reduction options
    • Surgery: The National Comprehensive Cancer Network (NCCN) recommends a hysterectomy (removing the uterus) and oophorectomy (removing the ovaries) in women between the ages of 35-40 or after childbearing is complete
    • Medicine: Studies show that aspirin therapy in people who have Lynch syndrome lowers their risk of colon cancer and other cancers

Preimplantation Genetic Testing (PGT)

  • Since there is a 50% chance that a child will inherit a non-working MMR gene from a parent, some couples, where one of the prospective parents has Lynch syndrome, may consider PGT when it comes time to have a child
  • PGT is used together with invitro fertilization (IVF)
    • Fertilization occurs outside of the uterus
    • The embryo is tested and only embryos with normal functioning MMR genes are transferred to uterus
  • PGT can
    • Prevent genetic conditions, such as Lynch syndrome, from being passed onto a child
    • Eliminate a familial inherited genetic syndrome in future generations

KNOW YOUR RIGHTS

Genetic Information Non-discrimination Act of 2008 (GINA)

  • GINA prohibits the use of an individual’s genetic information to affect their eligibility or premium regarding health insurance and Medicare supplemental policies
  • GINA prohibits employers from requesting genetic information about their employees
  • GINA only protects predictive genetic information (such as increased susceptibility to cancer)
    • It will not protect an individual if they have manifested disease

GINA does not apply to

  • Life insurance
  • Disability insurance
  • Long-term care insurance

Who is not covered by GINA?

  • Members and families in the United States Military
  • Veterans who receive care through the Veteran’s Administration (VA)
  • Native American health service members
  • Federal employees covered by the Federal Employee Benefits Program (FEHB)
  • People who work for groups with 15 employees or less

Learn More- Primary Sources:

NIH MedlinePlus: Lynch Syndrome

American Cancer Society: Genetic Testing, Screening, and Prevention for People with a Strong Family History of Colorectal Cancer

ASCO (Cancer.Net): Lynch Syndrome

CDC: Lynch Syndrome

NIH GARD: Lynch Syndrome

Locate a Genetic Counselor or Genetics Services:  

Genetic Services Locator-ACMG

Genetic Services Locator-NSGC  

Genetic Services Locator-CAGC  

Locate a GYN Oncology Specialist:

Gyn Oncology Locator – SGO

Locate a Cancer Doctor

The DNA@ObG entries are meant for healthcare providers to share with patients as an educational tool. They are not intended as and do not constitute or substitute for medical or healthcare advice or diagnosis, and may not and should not be used for such purposes. Individuals should always consult with a qualified healthcare provider about their specific circumstances, including before starting or stopping any treatment, medical or otherwise. DNA@ObG content via this web site is provided with the understanding that The ObG Project is not engaged in rendering medical, counseling, legal, or other professional services or advice.

Hereditary Breast and Ovarian Cancer (HBOC) Syndrome

Hereditary Cancer: What is it?

  • Hereditary cancer is due to an inherited change in a gene (genetic mutation) that can be passed down through the generations
    • Only 5-10% of cancers are hereditary
  • Every person inherits numerous genes that protect them against cancer
  • Hereditary cancer is associated with an increased risk for cancer because one of these cancer protection genes does not work properly
    • People who have a mutation in a cancer susceptibility gene are born with these changes and can pass them on to their children
  • A genetic test can ’read’ the DNA code of specific genes and determine
    • If the DNA code is correct, which means the genes are working properly, or
    • If there is a serious genetic change that may interfere with how the gene works and therefore lead to an increased risk for cancer
      • These changes mean that a person is more at risk or ‘susceptible’ to certain cancers, but not all individuals with these genetic mutations will develop cancer
  • Learning that you have an inherited change in a gene that causes increased cancer susceptibility can help you learn more about your cancer risks and help you manage your health accordingly
  • A person with a higher chance of developing cancer may need modified screening recommendations that are tailored to their genetic risk
    • For example, mammograms may start when a woman is 25 instead of 40, and may occur more frequently

Hereditary Breast, Ovarian, and Pancreatic Cancer: Basics

  • People with this syndrome are at risk for developing certain types of cancer such as
    • Breast, ovarian, pancreatic, male breast cancer, prostate cancer, melanoma and others
  • Approximately 1 in 400 to 1 in 800 Americans have HBOC
  • Mutations or changes in the genes BRCA1 and BRCA2 are the most common cause of HBOC
    • BRCA1 and BRCA2 are tumor suppressor genes that are designed to protect us against cancer
    • When a person inherits a non-working copy of one of these genes, caused by a genetic mutation, they have an increased chance of developing cancer
  • Breast cancer
    • Mutations in BRCA1 and BRCA2 account for 50% of hereditary breast cancers
  • Ovarian cancer
    • Inherited genetic mutations are involved in more than 20% of ovarian cancers
    • Of that 20%, 65-85% of those mutations are in the BRCA1 and BRCA2 genes
  • Pancreatic Cancer
    • Pancreatic cancer has now been added to what is commonly known as Hereditary Breast and Ovarian Cancer Syndrome
  • Note: While people are most familiar with BRCA1 and BRCA2 genes, there are other genes that are associated with this syndrome (examples include PALB2, CHEK2, and TP53, among others)

How Much Higher is the Risk for Cancer with HBOC?

BRCA1

  • Female Breast Cancer
    • To age 50: 28% to 51% vs 1.9% in general population
    • To age 70: 46% to 87% vs 7.1% in the general population
  • Ovarian Cancer
    • To age 50: 8% To 23% vs 0.2% in the general population
    • To age 70: 39% to 63% vs 0.7% in the general population
  • Pancreatic Cancer
    • To age 80: Elevated risk vs 1% in the general population

BRCA2

  • Female Breast Cancer
    • To age 50: 23% to 35% vs 1.9% in general population
    • To age 70: 43% to 84% vs 7.1% in the general population
  • Ovarian Cancer
    • To age 50: 0.4% To 4% vs 0.2% in the general population
    • To age 70: 15% to 27% vs 0.7% in the general population
  • Pancreatic Cancer
    • To age 80: up to 7% vs 1% in the general population

Are you at risk for HBOC?

You may be at risk if you answer yes to any of the following questions

  • Have you or anyone in your family been diagnosed with breast cancer at or before the age of 45, or triple-negative breast cancer at or before the age of 60?
  • Have you or anyone in your family been diagnosed with more than one cancer?
    • Such as two breast cancers, or breast and ovarian cancer
  • Have you or anyone in your family been diagnosed with a rare cancer?
    • Such as ovarian cancer or male breast cancer
  • Do you have multiple family members on one side of the family that have had breast, ovarian or other cancers?
  • Do you have Ashkenazi Jewish ancestry?
  • Has anyone in your family been found to carry a genetic mutation that increases their risk for cancer?

Note: If you answered yes to any of these questions, you may want to talk to your doctor about genetic testing or seeing a genetic counselor

Cancer Genetic Testing

  • A genetic test can help determine if the DNA sequence in your cancer protection genes is correct, or if there is a genetic change that may cause the genes to malfunction and therefore increase your susceptibility to cancer
  • Traditionally a genetic test just looked at the two genes, BRCA1 and BRCA2
  • It is becoming more common to look at many more genes at once
    • Genetic panels can range from a few to more than 80 genes associated with different types of cancer and cancer predisposition syndromes
    • By discussing your situation with a genetic counselor and your physician, you can determine which is the right test for you

How Can A Genetic Test Impact Your Health Or Your Family’s Well-Being?

  • If you are found to have a cancer predisposition syndrome such as HBOC, your doctor can help personalize your cancer screening and discuss preventative medical and surgical options with you, such as
    • Breast cancer screening, including breast MRIs and mammograms, can start at an earlier age and be done more often
      • However, monitoring with mammograms and MRI is not a preventative strategy but rather an approach that can be used for early detection
    • Medications and surgeries that can reduce your chance of developing breast or ovarian cancer  
    • A care plan to look for changes that may give rise to related cancers
      • The goal is usually to find problems early, often before they actually become malignant and can be treated with simpler procedures rather than with chemotherapies or major surgeries
      • For example, yearly skin examinations to look for suspicious-looking moles that may become melanomas, or colonoscopies to look for polyps before they become colorectal cancers
  • Genetic results may be difficult to understand and are rarely clear-cut:
    • A genetic counselor can help you understand your results and clarify any inherited risks to you or your family (see related DNA@ObG entry on Cancer Basics)
    • The goal is always to help you make decisions that are right for you

Inheritance

  • Who is at risk?
    • If you are found to carry a genetic mutation in a gene that increases your risk for cancer, your first-degree family members (brothers/sisters, parents, and children) have a 50% chance of having the same mutation that you have
    • It is important to remember that even through the name, Hereditary Breast and Ovarian Cancer Syndrome, sounds like it only affects women, both men and women have the same chance of inheriting a mutation that causes HBOC
      • Recently, professional societies have included pancreatic cancer along with breast and ovarian cancer as part of the HBOC syndrome
    • Men are also at risk for prostate cancer, pancreatic cancer, male breast cancer and melanoma

KNOW YOUR RIGHTS

Genetic Information Non-discrimination Act of 2008 (GINA)

  • GINA prohibits the use of an individual’s genetic information to affect their eligibility or premium regarding health insurance and Medicare supplemental policies
  • GINA prohibits employers from requesting genetic information about their employees
  • GINA only protects predictive genetic information (such as increased susceptibility to cancer)
    • It will not protect an individual if they have manifested disease

GINA does not apply to

  • Life insurance
  • Disability insurance
  • Long-term care insurance

Who is not covered by GINA?

  • Members and families in the United States Military
  • Veterans who receive care through the Veteran’s Administration (VA)
  • Native American health service members
  • Federal employees covered by the Federal Employee Benefits Program (FEHB)
  • People who work for groups with 15 employees or less

Learn More – Primary Sources:  

CDC: Does Breast or Ovarian Cancer Run in Your Family?

American Cancer Society: Genetic Counseling and Testing for Breast Cancer Risk

ASCO (Cancer.net): Hereditary Breast and Ovarian Cancer

NCI: The Genetics of Cancer 

ASCO Information for Patients (cancer.net): The Genetics of Cancer  

ASCO Information for Patients (cancer.net): Hereditary Breast and Ovarian Cancer

FORCE: Hereditary Cancer and Genetics  

NIH: Genetic Discrimination  

ACOG Patient FAQs: Multigene Panel Testing for Cancer 

NIH MedlinePlus: BRCA 1 Gene

NIH MedlinePlus: BRCA 2 Gene

NIH MedlinePlus: Ovarian Cancer

Locate a Genetic Counselor or Genetics Services:  

Genetic Services Locator-ACMG

Genetic Services Locator-NSGC  

Genetic Services Locator-CAGC  

Locate a GYN Oncology Specialist:

Gyn Oncology Locator – SGO

Locate a Cancer Doctor

The DNA@ObG entries are meant for healthcare providers to share with patients as an educational tool. They are not intended as and do not constitute or substitute for medical or healthcare advice or diagnosis, and may not and should not be used for such purposes. Individuals should always consult with a qualified healthcare provider about their specific circumstances, including before starting or stopping any treatment, medical or otherwise. DNA@ObG content via this web site is provided with the understanding that The ObG Project is not engaged in rendering medical, counseling, legal, or other professional services or advice.

Drugs & Radiation: Drugs in Pregnancy and Breastfeeding – Helpful Resources

SUMMARY:

Many women who are newly pregnant or planning on getting pregnant will be confronted by decisions regarding their medications. While most medications during pregnancy are safe for the baby, it is important to note that some medications can cause birth defects, developmental disabilities, prematurity, or miscarriage. Identifying which medications are safe and how to best support you before pregnancy, during the pregnancy, and after birth, is an important conversation that should happen with your doctor.

Staying Healthy During Pregnancy

  • Medication during pregnancy is extremely common
    • Most women take at least one medication during their pregnancy
  • Many women have chronic conditions that require medication during pregnancy including
    • High blood pressure | Asthma | Diabetes | Depression
  • Pregnancy can induce new health problems or make old health problems that need treatment recur
  • As a woman’s body and weight shift during pregnancy, the amount of medication she takes (dosage) may need to change as well
  • While it is important not to start any new medications in pregnancy without speaking to your obstetric provider, it is just as important not to stop or change how you take your medications without a discussion
    • A basic principle is that a healthy mother gives a baby the best chance of a good outcome
    • Some women need to take medicines throughout their pregnancy to help control certain health conditions | Stopping some of these medications could be detrimental to mother and baby
      • Common examples: Stopping drugs that prevent seizures or asthma attacks may result in a relapse and could harm the pregnancy
    • Dose and timing: Some medicines are safe during certain parts of the pregnancy and unsafe during others | Modifying how much medicine you take could create a safer option for mother and baby
  • Some medications are known to cause birth defects and should be avoided (e.g. oral isotretinoin also known as Accutane®)  
    • However, many medications are safe or have not been found to be associated in humans with birth defects or harm to the baby
  • When discussing medications with your provider, make sure to include all drugs or substances you use or have taken recently, including vitamins, or herbal or ‘natural’ supplements, as they may have important biologic effects  

What if You Take Medications Before You Know You’re Pregnant?

  • Many women will take certain substances before they know they are pregnant
    • While some of these exposures may be concerning, most are not likely to cause harm.  A discussion with a healthcare provider or a referral to genetic specialists, when necessary, will usually sort out if there are any issues
  • Factors taken into consideration when determining if a drug is dangerous in pregnancy include the following
    • How much medication is taken (the dose)
    • When during the pregnancy the medication is taken 
    • Other health conditions a woman might have 
    • Other medications a woman is taking  

Breastfeeding and Medication

  • There is much evidence that shows the clear benefits of breastfeeding, and many medications are considered safe to use while breastfeeding | CDC provides excellent information on the benefits of breastfeeding (see ‘Learn More – Primary Sources’ below)
    • However, some medications may pass into breast milk and be of concern
    • This is important information to know because some new mothers may have medical conditions that will require treatment after delivery  

What if You Need to Take Medication While Nursing?

  • Women who are nursing should have open conversations with their physician and pharmacist about any medications that they may be taking or want to take
    • Healthcare professionals are well aware of the many benefits of breastfeeding and will work with a mother to prevent medication from being a roadblock to breastfeeding whenever possible

Hot topic: Breastfeeding and COVID-19

  • In general, breast milk is ideal for infants, including newborns whose mothers have COVID-19
  • There may be some concerns where women with COVID-19 are on experimental medication | Your physician will discuss risks and benefits of these drugs including breast feeding
  • There are some researchers (such as MotherToBaby – see references below) that are studying pregnancy, breastfeeding and COVID-19 and are actively enrolling new mothers with confirmed or suspected COVID-19 infection into their studies

Where to find information about drugs in pregnancy

  • The CDC strongly cautions against making decisions based on ‘lists you find online’ and goes on to state   

Instead use the lists as a starting point to talk with your doctor. Don’t stop or start taking any type of medication that you need without first talking with a healthcare provider. A conversation with a healthcare provider can help ensure that you are taking only what is necessary.

Helpful Online Sites with Professional Oversight  

Mother to Baby

From ‘About Us’: MotherToBaby, a service of the non-profit Organization of Teratology Information Specialists (OTIS), is the nation’s leading authority and most trusted source of evidence-based information on the safety of medications and other exposures during pregnancy and while breastfeeding. Our information service is available to mothers, healthcare professionals, and the general public.  They are also conducting studies related to COVID-19 and breastfeeding

CDC: Treating for Two: Medicine and Pregnancy

Learn More – Primary Sources  

CDC: Breastfeeding

FDA: Pregnant? Breastfeeding? Better Drug Information Is Coming

CDC: COVID-19: If You Are Pregnant, Breastfeeding, or Caring for Young Children

Locate a Genetic Counselor or Genetics Services: 

Genetic Services Locator-ACMG 

Genetic Services Locator-NSGC

Genetic Services Locator-CAGC

Locate a Maternal Fetal Medicine Specialist 

Maternal Fetal Medicine Specialist Locator-SMFM 

The DNA@ObG entries are meant for healthcare providers to share with patients as an educational tool. They are not intended as and do not constitute or substitute for medical or healthcare advice or diagnosis, and may not and should not be used for such purposes. Individuals should always consult with a qualified healthcare provider about their specific circumstances, including before starting or stopping any treatment, medical or otherwise. DNA@ObG content via this web site is provided with the understanding that The ObG Project is not engaged in rendering medical, counseling, legal, or other professional services or advice.

Universal Screening on Admission to Labor Floor: Latest COVID-19 Prevalence Results

PURPOSE:

  • Many hospitals have implemented universal COVID-19 screening for all women admitted for delivery
  • An NYC health system found a 13.5% prevalence of infection in asymptomatic women early in the pandemic
  • Miller et al. (Obstetrics & Gynecology, 2020) examined the prevalence rates of infection with universal screening in Chicago

METHODS:

  • Prospective case series
  • Setting
    • Chicago hospital system (April 8 to April 27, 2020)
    • Acceleration phase of the pandemic
  • Participants
    • Pregnant women
    • Admitted to the hospital for delivery
  • Study design
    • Universal COVID-19 testing for delivery: Implemented April 8
    • Scheduled deliveries:  Tested 12 to 36 hours before admission 8 hour turnaround time
    • Unscheduled deliveries: Tested in triage | 2 hour turnaround time
    • All women asked about possible COVID-19 symptoms at time of admission
  • Management protocols
    • Positive test: Managed in a dedicated COVID-19 unit
    • Asymptomatic: Managed on routine labor floor | Health care workers used PPE until the test result available
    • Patients and one allowed support person received procedure masks on arrival
    • Support persons screened for symptoms but not tested

RESULTS:

  • Total of 635 pregnant
  • Test results
    • Positive for SARS-CoV-2: 3.6% (23 women)
      • Positive but asymptomatic on presentation: 43.5% (10 women)
  • Symptoms on presentation
    • Reported symptoms on presentation: 3.3% (21 women)
      • Positive for COVID-19: 61.9% (13 women)
    • Did not report symptoms on presentation: 96.7% (614 women)
      • Positive for COVID-19: 1.6% (10 women)

CONCLUSION:

  • Symptoms alone did not reliably identify pregnant women with COVID-19 on admission to labor and delivery units
    • In this study, positive test rates were higher than those reported in the general population, leading the authors to suggest that infection rates in the general population, where testing is generally limited to symptomatic patients, may be higher
  • Sutton et al. (NEJM, 2020) in a similar paper also found a much higher prevalence of infection with universal screening of pregnant women admitted for delivery in NYC
    • 215 pregnant women (all were screened)
    • Symptomatic: 1.9% | All were positive on testing
    • Asymptomatic women: 99.5% | 13.7% positive on testing
    • 87.9% of women had no symptoms of Covid-19 at presentation
  • The authors in the NEJM paper conclude that

The potential benefits of a universal testing approach include the ability to use Covid-19 status to determine hospital isolation practices and bed assignments, inform neonatal care, and guide the use of personal protective equipment

Access to such clinical data provides an important opportunity to protect mothers, babies, and health care teams during these challenging times

Learn More – Primary Sources:

Clinical Implications of Universal Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Testing in Pregnancy

Universal Screening for SARS-CoV-2 in Women Admitted for Delivery

Point-of-Care Test for Preeclampsia: Glycosylated Fibronectin

BACKGROUND AND PURPOSE:

  • Glycosylated fibronectin (GlyFn) is a biomarker that has potential as a point-of-care (POC) diagnostic test for preeclampsia (PE) | Could be of particular benefit in low resource regions
    • Elevated GlyFn with PE may be related to differential glycosylation due to oxidative stress in PE
  • Nagalla et al. (BJOG, 2020) assessed the performance of GlyFn POC test for PE in a large Southeast Asian cohort vs biomarkers currently available and in use

METHODS:

  • Prospective case-control study
  • Setting
    • India
  • Participants
    • Pregnant women at ≥20 weeks
      • Normotensive and protein/creatinine ratio <0.3
      • PE: Hypertension and protein/creatinine ratio ≥0.3
      • Gestational hypertension: Hypertension and protein/creatinine ratio <0.3
  • Study design
    • GlyFn levels were determined using a POC device
    • Current marker levels, i.e. PIGF, sFlt-1, and PAPPA2 were determined by immunoassay
    • Logistic regression modelling and receiver-operating characteristic (ROC) curves were used to assess performance
    • PPv and NPV reported at specific thresholds

RESULTS:

  • Total of 798 pregnant women
    • Normotensive: 469
    • PE: 135
    • Gestational hypertension: 194
  • All patients were being evaluated for new onset hypertension | Prevalence of PE: 17%
  • The following were significantly associated with clinically defined PE (P<0.01)
    • Increased levels of GlyFn: Area under the ROC (AUROC) 0.99 (95% CI, 0.98 to 0.99)
    • Increased levels of sFlt-1: AUROC 0.86 (95% CI, 0.83 to 0.89)
    • Increased levels of PAPPA2: AUROC 0.96 (95% CI, 0.94 to 0.97)
    • Decreased levels of PlGF: AUROC 0.96 (95% CI, 0.94 to 0.98)
  • Patients with gestational hypertension
    • 48% were positive for more than two PE biomarkers
    • 70% of these delivered preterm
  • NPVs and PPVs for GlyFn
    • NPV: >99% regardless of PE prevalence (at 5%, 7% and 17%)
    • PPV: ranged depending on prevalence from from 42% (5% prevalence) to 74% (17% prevalence seen in this study)

CONCLUSION:

  • The use of the GlyFn POC test in a low/middle-income country was validated for PE diagnosis
  • Overall, all the biomarkers studied demonstrated good test performance for the diagnosis of PE, with GlynFn exhibiting superior discriminatory results
  • Further studies required in asymptomatic population prior to using GlynFn as a broad based screening test

Learn More – Primary Sources:

Glycosylated fibronectin point-of-care test for diagnosis of preeclampsia in a low resource setting: a prospective Southeast Asian population study

Cochrane Review 2020: Are Progestogen-Releasing IUDs Effective for Managing Heavy Menstrual Bleeding?

BACKGROUND AND PURPOSE:

  • Use of the levonorgestrel-releasing intrauterine system (LNG-IUS) can reduce menstrual blood loss by up to 90%
  • Bofill Rodriguez et al. (Cochrane Systematic Review – Intervention, 2020) determined the effectiveness, patient acceptability, and safety of progestogen-releasing intrauterine systems to reduce heavy menstrual bleeding (HMB)

METHODS:

  • Systematic review and meta-analysis
  • Inclusion criteria
    • RCTs
    • Trials in women of reproductive age treated with LNG-IUS devices vs
      • No treatment | Placebo | Other medical/surgical therapy for HMB
  • Study design and data analysis
    • Two authors independently extracted data, assessed risk of bias and determined certainty of evidence using GRADE criteria  

RESULTS:

  • 25 RCTs were included | Combined total of 2511 women

LNG-IUS vs Other Medical Therapy

  • Other therapies investigated were
    • Norethisterone acetate
    • Medroxyprogesterone acetate
    • Oral contraceptive pill
    • Mefenamic acid
    • Tranexamic acid
    • Usual medical treatment (patient choice of suitable oral treatment)
  • The LNG-IUS may improve HMB, with lower menstrual blood loss using various bleeding assessment tools
    • The alkaline hematin method: Mean difference (MD) 66.91 mL (95% CI, 42.61 to 91.20; 2 studies, 170 women; low‐certainty evidence)
    • The Pictorial Bleeding Assessment Chart: MD 55.05 (95% CI 27.83 to 82.28; 3 studies, 335 women; low‐certainty evidence)
  • Uncertain whether the LNG-IUS has any effect on women’s satisfaction up to one year
    • RR 1.28 (95% CI 1.01 to 1.63; 3 studies, 141 women; very low‐certainty evidence)
  • The LNG‐IUS probably leads to slightly higher quality of life compared with other medical therapy using the following scales  
    • The SF‐36: MD 2.90 (95% CI, 0.06 to 5.74; 1 study: 571 women; moderate‐certainty evidence)
    • The Menorrhagia Multi-Attribute Scale: MD 13.40 (95% CI, 9.89 to 16.91; 1 trial, 571 women; moderate‐certainty evidence)
  • Serious adverse events were similar between LNG-IUS and other medical therapies
    • RR 0.91 (95% CI 0.63 to 1.30; 1 study, 571 women; moderate‐certainty evidence)
  • Compared to LNG-IUS, women using other medical therapy are probably more likely to
    • Withdraw from treatment for any reasons; RR 0.49 (95% CI, 0.39 to 0.60; 1 study, 571 women, moderate‐certainty evidence)
    • Experience treatment failure: RR 0.34 (95% CI 0.26 to 0.44; 6 studies, 535 women; moderate‐certainty evidence)

LNG‐IUS vs Endometrial Resection or Ablation (EA)

  • Bleeding outcome results are inconsistent
    • Effect of LNG-IUS vs EA are probably similar when comparing rates for the following  
      • Amenorrhea | Hypomenorrhea | Eumenorrhea
    • Uncertain whether there is a difference in quality of life
  • Women with the LNG-IUS are probably more likely to have any adverse event
    • RR 2.06 (95% CI, 1.44 to 2.94; 3 studies, 201 women; moderate‐certainty evidence)
  • Women with the LNG‐IUS may experience more treatment failure (persistent HMB or requirement of additional treatment) at one year follow up
    • RR 1.78 (95% CI, 1.09 to 2.90; 5 studies, 320 women; low‐certainty evidence)
  • Women with LNG-IUS may be more likely to require hysterectomy at one year follow up
    • RR 2.56 (95% CI 1.48 to 4.42; 3 studies, 400 women; low‐certainty evidence)

LNG‐IUS vs Hysterectomy

  • Uncertain whether LNG_IUS had any effect on HMB compared with hysterectomy
    • Amenorrhea: RR 0.52 (95% CI, 0.39 to 0.70; 1 study, 75 women; very low‐certainty evidence)
  • It is uncertain whether there is a difference between LNG-IUS and hysterectomy for the following
    • Satisfaction at five years
    • Quality of life via SF-36
  • Women in the LNG‐IUS group may be more likely to have treatment failure requiring hysterectomy for HMB at 1‐year follow‐up
    • RR 48.18 (95% CI, 2.96 to 783.22; 1 study, 236 women; low‐certainty evidence)

CONCLUSION:

  • LNG-IUS vs other medical therapies may improve heavy menstrual bleeding and quality of life
  • Bleeding outcomes with LNG-IUS were similar to endometrial ablation although LNG-IUS may be associated with more adverse events
  • This study yielded uncertain results when comparing LNG-IUS to hysterectomy

Learn More – Primary Sources:

Progestogen-releasing intrauterine systems for heavy menstrual bleeding