EVENTS RCT Results: Does Vaginal Progesterone for Women with Twin Pregnancies Reduce Incidence of Preterm Birth?
BACKGROUND AND PURPOSE:
Rehal et al. (AJOG, 2020) examined whether vaginal progesterone compared with placebo significantly reduced the incidence of spontaneous preterm birth in twin pregnancy
Early vaginal progesterone for the preVention of spontaneous prEterm birth iN TwinS (EVENTS)
Setting
22 hospitals in England, Spain, Bulgaria, Italy, Belgium and France
Participants
Dichorionic or monochorionic diamniotic twin pregnancy
2 live fetuses at 11 to 13 week scan
Complicated pregnancies (e.g. early signs of TTTS or large NT) were excluded
Interventions
Progesterone (300 mg twice per day) vs placebo
Vaginal capsule self-administered twice daily beginning after randomization and stopped at 34 weeks or at time of delivery if prior to 34 weeks
Study design
Women were randomized 1:1, with stratification according to participating center
Intention-to-treat analysis
Logistic regression analysis used to determine difference in incidence of spontaneous preterm birth and adjust for covariates, including
Effect of participating center
Chrorionicity
Parity
Method of conception
Primary outcome
Spontaneous birth between 24w0d and 33w6d
Secondary outcomes
Preterm birth by week gestation
Neonatal complications
RESULTS:
1169 women were included
Progesterone group: 582
Placebo group: 587
There was no significant difference in incidence of spontaneous birth between 24w0d and 33w6d (P = 0.17)
Progesterone: 10.4%
Placebo: 8.2%
Adjusted odds ratio (OR) 1.35 (95% CI, 0.88 to 2.05)
There was no evidence of interaction between the effects of treatment and
Chorionicity | Parity | Method of conception: P = 0.56 | Adherence
There was weak evidence (post hoc analysis) of an interaction between preterm birth and cervical length (P = 0.08)
Increased risk for cervical length ≥30 mm: OR 1.61 (95% CI, 1.01 to 2.59)
Decreased risk for those with cervical length <30 mm: OR 0.56 (95% CI 0.20 to 1.60)
No statistical differences were found for
Stillbirth or neonatal death | Neonatal complications | Neonatal therapy | Poor fetal growth
Women with at least one serious adverse event (P = 0.08)
Fetuses with at least one serious adverse event (P = 0.06)
Post hoc analysis
Miscarriage or spontaneous preterm birth between randomization and 31w6d was reduced in the progesterone group relative to the placebo group
Hazard ratio 0.23 (95% CI, 0.08 to 0.69)
CONCLUSION:
Vaginal progesterone did not decrease the incidence of spontaneous preterm birth between 24w0d and 33w6d in unselected twin pregnancies
Cervical length may play a role in outcome with a potential reduction in preterm birth when cervical length <30, but increased risk for those with cervical length ≥30 mm
Thrombotic Events and COVID-19: How Often do they Occur and What are the Risk Factors?
BACKGROUND AND PURPOSE:
Patients with COVID-19 are at an increased risk of thrombosis although risk factors and incidence remain unclear
Bilaloglu et al. (JAMA, 2020) assessed the incidence and risk factors for venous and arterial thrombotic events in all hospitalized patients with COVID-19 at a large health system in New York City
METHODS:
Case series
Setting
Four hospitals between March 1 and April 17, 2020
Participants
Consecutive patients ≥18 years old
Hospitalized with confirmed COVID-19
Study design
Thrombotic events were identified from clinical notes and radiology reports
Venous events: Deep vein thrombosis (DVT) | Pulmonary embolism (PE)
Pregnant Women with COVID-19 at Time of Delivery: NYC Cohort Characteristics and Outcomes
BACKGROUND AND PURPOSE:
Khoury et al. (Obstetrics & Gynecology, 2020) characterized clinical features and disease course among the initial cohort of pregnant women during the COVID-19 pandemic in New York City admitted for delivery
METHODS:
Prospective cohort study (March 13 to April 12, 2020 with follow-up completed April 20, 2020)
Setting
Five New York City medical centers
Participants
Pregnant women admitted for delivery
Confirmed COVID-19
Study design
Data collected: Demographics | Presentation | Comorbidities | Maternal and Neonatal outcomes | COVID-19 clinical course
COVID-19 cases were defined as
Asymptomatic
Mild: no additional oxygen supplementation required
Critical: Respiratory failure | Septic shock | Multiple organ dysfunction or failure
RESULTS:
241 women included
Asymptomatic on admission: 61.4% | 69% remained asymptomatic
Clinical status at time of hospitalization for delivery
Mild: 26.5%
Severe: 26.1%
Critical: 5%
Singleton preterm birth rate: 14.6%
Critical outcomes
ICU admission: 7.1% of women (17 women)
Intubation during delivery: 3.7% (9 women)
Maternal deaths: 0 women
BMI ≥30 associated with COVID-19 severity (P=0.001)
Cesarean delivery rates
Severe COVID-19: 52.4%
Critical COVID-19: 91.7%
Linear trend across COVID-19 severity groups for cesarean risk (P<.001)
245 liveborn neonates
Resuscitation at delivery beyond normal requirements: 30%
NICU admission: 25.7% | Hospitalization <2 days in 62.4%
Newborn outcomes
Prematurity and low birth weight: 8.7% (most common complications)
RDS: 5.8%
No complications: 79.3%
97.5% of newborns tested negative for SARS-CoV-2 at 24 to 96 hours
IUFD: 2 cases
Case 1: 38 weeks without fetal movement | Symptoms of COVID-19 pneumonia including chest imaging | No supplemental oxygen required | Patient declined autopsy and further work up for COVID-19 | No abnormalities were seen on placental pathology
Case 2: 29 weeks of gestation | FGR <1%tile | HELLP syndrome | Severe COVID-19 pneumonia
CONCLUSION:
Majority of pregnant women admitted for delivery were asymptomatic for COVID-19
Approximately 1/3 remained asymptomatic
Obesity was associated with COVID-19 severity
For women with COVID-19 (particularly severe and critical) there is an increased risk for cesarean and preterm birth
Newborn screening is a mandatory state-based public health program that screens all newborn babies in the United States for a variety of serious but treatable health conditions, most of which are genetic.
The goal of the program is to reduce the severity of these disorders through early detection and treatments that improve the overall outcome and survival of affected babies. The United States NBS program screens around 4-million newborns each year, and is the most expansive genetic screening program in our country.
The NBS program relies on a collaboration of laboratories, pediatricians, public health programs, diagnostic centers, and hospitals. Its main functions are to
Screen all newborns within the first few days after birth
Identify babies who may have one or more health conditions
Diagnose the condition
Relay the diagnosis to the family
Establish a way for the newborn to get treatment
Ensure that children are connected to appropriate specialists who can follow up with the necessary treatment
Educate the public and physicians about the NBS
NBS Basics
NBS was first developed in the 1960s by Dr. Robert Guthrie, who suspected that his child had a condition called PKU (phenylketonuria)
NBS is often referred to as the PKU test, even though it now tests for many more conditions
The test is done using a small blood sample collected from a newborn’s heel 24 to 48 hours after birth
The blood is placed onto a special paper and sent to the state NBS laboratory for genetic and metabolic disorder screening
Screening for hearing loss and congenital heart disease also happens during this time, but does not involve blood testing | The baby is monitored from the outside to determine the amount of oxygen in the baby’s blood (to check for heart abnormalities) and whether the baby can hear
NBS will detect a treatable disorder in 1 out of every 300 newborns
Many of the disorders included in NBS programs can be treated, with good results
Often treatment will mean changing a child’s diet or providing the appropriate medicine
However, therapy needs to be started in time
Positive NBS screening tests are treated as an emergency so that children can receive their treatment as soon as possible, for the best chance of a good outcome. The lab will work quickly to contact doctors and the family to alert them to next steps
In most states, NBS does not require parental permission
This means that there is no need to opt into the test – it is automatically run on every baby
Although the program is mandatory, it is possible for parents to opt out of the NBS for religious reasons
What Disorders are Included in NBS?
A panel is the list of health conditions included in the screening. While all states require newborn screening, the conditions that newborns are screened for varies by state
Each state’s department of health is responsible for deciding which conditions on the NBS list will be included in its panel | Resources in the ‘Learn More – Primary Sources’ (Baby’s First Test’) can help you find what testing is available in your state
In general, the disorders include
Metabolic disorders (defects in chemical reactions within the body)
Common genetic disorders, such as cystic fibrosis or SMA (see ‘Related DNA@ObG Topics)
Blood disorders called hemoglobinopathies, such as sickle cell disease (see ‘Related DNA@ObG Topics)
Hearing loss
Heart defects
Most state NBS programs follow the guidelines recommended by the Advisory Committee on Heritable Disorders in Newborns and Children Screening
To be included, conditions usually meet the following criteria
The condition is a serious health problem, and early diagnosis and intervention with benefit the baby
The disorder has recognizable, early symptoms
A test for the disorder is available
Treatment options are available
Cost efficiency (cost of screening should be balanced against the cost of not screening)
Note: Newborn screening does not replace the genetic tests that are offered during pregnancy
Follow up
Positive results on the newborn screening test are usually confirmed with another test
Information regarding results from the NBS will often be communicated through the pediatrician
Additional counseling, including genetic evaluation, can be helpful to determine actual diagnosis
Residual dried blood spots (DBS) from the original newborn screening tests are kept in many states to improve the quality of the test and may be used for research
Consent procedures for DBS usage will vary from state to state.
Parents/guardians can provide permission (opt-in) for use of DBS for additional research
Education
Numerous studies have shown that expectant parents are interested in learning more about the NBS
Knowing more about NBS can help reduce anxiety, especially if there is a screen positive result
American Academy of Pediatrics and the American College of Obstetrics and Gynecology both support NBS/DBS education in the prenatal setting
Information on the NBS should be included in patient materials and brochures, and given out during the first trimester as well as several times throughout the pregnancy
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.
NIPS/NIPT: Non-Invasive Prenatal Screening
WHAT IS IT?
Noninvasive Prenatal Screening (NIPS) is also known as Noninvasive Prenatal Testing (NIPT). The NIPS test analyzes small pieces of DNA fragments that are shed from the placenta (which is usually, but not always, very similar to the DNA of the baby) and are circulating in the mother’s blood during the pregnancy. These DNA fragments are also referred to as cell-free DNA (cfDNA) because they are free floating and are not enclosed within a cell.
Where Does Cell-Free DNA Come From?
Our genetic material, DNA, is usually found in a structure within a cell called the nucleus
When a cell dies it breaks down, and pieces of the cell, including the DNA, are released into the bloodstream
These free-floating pieces of DNA are called cell-free DNA (cfDNA) and are found in the blood of all individuals
How Does NIPS Work?
NIPS is a blood test offered to pregnant women during pregnancy, usually in the first trimester between 10 and 13 weeks
The placenta connects the blood supply of the mother to the baby
Usually, though not always, the placenta’s genetic makeup is identical to that of the baby
When the placenta sheds old cells, the placental DNA circulates throughout mom’s blood
The blood sample that is taken from the mother will be analyzed for these circulating DNA pieces
However, in every pregnant woman, there is a mix of cfDNA in her blood, with fragments coming from both
Her own DNA
Placental DNA
The test requires a certain proportion of placental vs mother’s cfDNA to be present for test to work (referred to as ‘fetal fraction’)
Some NIPS tests are done at 9 weeks, but usually by 10 weeks there is a high enough fetal fraction for the test to return a result
The lab will analyze the cfDNA in the blood sample, and computer programs can then calculate whether the baby is at risk for extra or missing chromosomes
In addition, NIPS can report on whether the baby is male or female based on the sex chromosome pattern
What Disorders Does NIPS Look For?
NIPS was designed to look at a baby’s chromosomes
Chromosomes are packages of DNA that are found in everyone’s cells
A heathy person has 46 chromosomes (23 pairs of each chromosome) in every cell of their body
If a chromosome is missing or added, there may be serious health consequences
NIPS primarily looks for an extra copy of three different chromosomes (extra or missing chromosomes are also known as ‘aneuploidy’)
An extra chromosome 21 (trisomy 21, also known as Down syndrome)
An extra chromosome 18 (trisomy 18, also known as Edwards syndrome)
An extra chromosome 13 (trisomy 13, also known as Patau syndrome)
NIPS can also look for extra of missing copies of the X chromosome and Y chromosomes
These chromosomes determine the sex of the baby. XX determines a female sex and XY determines a male sex
The Accuracy of NIPS
The accuracy of the test is dependent on the disorder that is being looked at
NIPS is best at screening for Down Syndrome
In the event of a ‘positive screen’ for Down syndrome
A positive screen indicates that you are at high risk for having a baby with Down syndrome
However, a significant number of pregnancies will actually be normal (at least 10%)
Follow-up diagnostic testing is recommended
Depending on the laboratory, NIPS may also look for other additional genetic syndromes such as
Small pieces of chromosomes that are missing (also called microdeletions)
Rare aneuploidies (extra chromosomes other than 21, 18 and 13)
NIPS is not as good at predicting whether the pregnancy is at risk for these other types of rare genetic changes, compared to more common conditions like Down syndrome
NIPS is Only a Screening Test
The ‘S’ in NIPS stands for ‘screening.’ It’s there to emphasize that this test is used for screening only and is not diagnostic
NIPS
Is used to determine the likelihood (or chance) of certain genetic conditions in the baby
Is designed to estimate the risk for a genetic condition and can only tell us if that risk is increased or decreased
Cannot give a definitive answer regarding whether the baby has a genetic condition
False positive results
In some cases, a NIPS result can indicate that a baby has a genetic abnormality, when it is actually healthy
False negative result
In some cases, a NIPS result can indicate a baby is healthy when it actually has a genetic abnormality
Note: Because NIPS is a screening test and can only provide a risk and not a definite answer, confirmatory diagnostic testing (amniocentesis or CVS) should always be offered for a screen-positive result (see ‘Related DNA@ObG Topics below)
Some Reasons for a False Screening Result
False positive (test report shows a ‘positive screen’ result but baby is normal)
Since cell-free DNA (cfDNA) can also be of maternal origin, an abnormal result on NIPS can be indicative of a condition in the mother rather than the baby
The cfDNA is derived from placenta and not the baby. While the placental DNA usually reflects that of the baby, they are not always the same
False negative (test report is negative, but the baby is affected with a genetic condition)
Low fetal fraction (not enough of the baby’s DNA) that can be caused by
Conditions in the baby that can lead to a small placenta
Maternal obesity (increased amounts of maternal cfDNA)
PROFESSIONAL GUIDELINES
Common Guideline Highlights
All patients should be offered fetal aneuploidy screening
NIPS is an appropriate option vs standard ultrasound/serum marker screening.
It is the patient’s choice to accept or decline
Patients should be provided with adequate information to make an informed decision including
Risks
Benefits
Alternatives
An understanding that (1) a positive screening result does not necessarily mean the pregnancy is affected and (2) false negatives are possible
There is a baseline risk for birth defects despite testing (approximately 3 to 4%)
Post-test genetic counseling should be available to patients especially if there is a ‘screen positive’ result
Positive NIPS tests require that the patient be offered confirmatory prenatal diagnostic testing (amniocentesis or CVS) as well as pre and post-test counseling regarding the benefits/limitations of the screen
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.
What’s the Difference Between Screening and Diagnostic Testing?
SUMMARY:
There are two main types of prenatal genetic tests screening and diagnostic. Both tests are designed to give the parent or guardian information about the health of their baby.
A screening test looks for signs of trouble, to give a risk estimate: what is the chance that the baby may have a particular problem?
A diagnostic test assesses whether a baby with a positive screening result actually has a medical condition.
For instance, tests like mammograms or Pap smears are used to screen women to see who may be at risk of a particular health problem. Women with screen-positive results can receive diagnostic tests to tell them if they do have a medical issue, and if so, what it may be.
Screening and diagnostic tests are offered to every pregnant woman. The decision whether to have prenatal screening is always yours.
Here’s a summary of some ‘Genetic Basics’ to help with your decisions during pregnancy. You can find more detail in the ‘Related DNA@ObG Topics’ below.
Different Types of Genetic Problems
Chromosomal Disorder
DNA (the genetic code in our cells that that includes our genes) is usually packaged into 46 pieces called chromosomes | Sometimes there are more or less than 46 chromosomes, or pieces of chromosomes are missing or rearranged. These changes can cause problems, called genetic disorders
Example: Down syndrome (extra #21 chromosome)
Single Gene Disorder
Single gene disorders are caused by changes in one particular gene
Genes direct how key elements such as proteins are made
Even when the chromosomes look okay, a change within a gene can sometimes cause the cells to skip a certain protein, or build it incorrectly
Example: Sickle cell disease or cystic fibrosis (the DNA coding these genes has an error)
Cause not well understood
Overall birth defects are thankfully unusual (3 to 4% of all births)
Sometimes babies are born with problems where the cause is unclear
In these cases, a combination of genes and environment likely play an important role
Example: Most congenital heart disease
SCREENING TESTS:
Screening tests are designed to identify expectant mothers who may be at higher risk for having a baby with a particular condition
Example: Down syndrome screening doesn’t tell you if your baby has Down syndrome, but rather the chance the baby may have Down syndrome
Additional testing is usually offered if you have a positive screening result (see ‘’Diagnostic Tests’ below) to confirm whether or not the baby really does have a problem
Most screening is now done in the first trimester, but may also be done later in pregnancy
The benefit of screening tests is that they are not invasive. By using blood or saliva tests and ultrasound, these tests provide helpful information about your baby’s health without any immediate risk to the pregnancy
However, the key point is that screening tests can only point to a possibility – a ‘maybe.’ To know more, you need to follow up with diagnostic testing, which can provide more certainty
Screening Tests for Chromosomal Problems
Types of prenatal screening to assess Down syndrome and similar conditions include
Standard screening: Combination of ultrasound and a blood test
Cell-free DNA screen (also called NonInvasive Prenatal Screening [NIPS] or NonInvasive Prenatal Testing [NIPT]): A blood test that uses floating pieces of DNA from the placenta, found in your bloodstream
Screening Tests for Single Gene Disorders – Carrier Screening
Carrier screening is another type of test that looks for potential problems
Parents are tested to see if they ‘carry’ a change in a gene, called a mutation, that could cause a genetic condition | This is why parents with these changes are often referred to as ‘carriers’ and the test is called ‘carrier screening’
Everyone has two copies of each gene: one inherited from each parent. A carrier is usually healthy because only one of their genes is affected
Babies are not at risk for these disorders unless both parents are carriers and the baby inherits both changes (one from mother and one from father)
New technologies can now test parents for many disorders at the same time – this technology is referred to as ‘expanded carrier testing’
Your healthcare professional will discuss with you which carrier tests are appropriate for you and your family
DIAGNOSTIC TESTS:
While screening tells you about the risk of a genetic disorder, diagnostic tests can tell you whether your baby actually has a certain condition (although even with the best technology, sometimes certain genetic problems can be missed)
Diagnostic tests are used to confirm or rule out a suspected genetic problem by testing the baby’s cells which are floating in the amniotic fluid or placental cells directly
The cells used for diagnosis are obtained using a needle that can take a small sample of the amniotic fluid around the baby (amniocentesis) or from the placenta (chorionic villus sampling [CVS])
Once the laboratory has these cells, they look for chromosomal disorders or single gene changes | Because the entire genetic code is contained in each cell, if necessary, a laboratory can sequence all the genes or even all the DNA, if more analysis is needed
Before you agree to diagnostic testing, your doctor or a genetic counselor can help explain
The disorders that are being tested
The process of testing
Risks involved: There is a small risk for miscarriage. (However some experts believe, based on research, that there may be no increased risk if the baby looks normal on ultrasound)
ULTRASOUND TESTING:
Ultrasound is an important part of screening as well as diagnosis
Most women will have ultrasound done at some point during pregnancy
In the first trimester, aside from pregnancy dating, ultrasound can be used as part of standard screening for chromosomal problems
Anatomy scanning
The ultrasound images are looked at closely to make sure the baby’s anatomy looks appropriate for a particular gestational age
Some findings may suggest potential problems that need follow-up, sometimes with more ultrasound exams or possibly diagnostic testing
KEY POINTS:
It is important for every woman to understand the benefits, limitations and risks regarding a screen or diagnostic test | Every woman has a right to say no to a prenatal screen or diagnostic test
A baby may have a higher risk of having a specific condition or birth defect if there is a family history of that condition
Many conditions will occur by chance in a baby without any prior family history
Even if screening and diagnostic testing come back negative/normal, currently there is no test that can guarantee that the baby will be healthy
With every pregnancy, there is a 3-4% chance that the baby will have a birth defect
This also means that there is a 96-97% chance that the baby will be born normal/healthy!
Further testing can also be done after a baby is born, especially if there is concern regarding a particular genetic problem
Most babies, even those who are healthy, are screened at birth for additional disorders that can be treated early in childhood via newborn screening programs, also known as NBS (for more information see ‘Related DNA@ObG Topics’ below
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.
Diagnosis and Management of Atrial Fibrillation
SUMMARY:
Atrial fibrillation, the most common cardiac arrhythmia, increases stroke risk and can exacerbate underlying heart disease. The 2014 ACC/AHA/HRS Guideline for the Management of Patients with Atrial Fibrillation offers a comprehensive approach to treating this condition. A focused update released in 2019 includes new evidence in support of novel drugs and devices to prevent thromboembolism, as well as other clinical considerations. Of note, these recommendations apply to atrial fibrillation (AF) and atrial flutter, regardless of the pattern of arrhythmia (i.e. paroxysmal, persistent, or permanent).
Diagnosed by EKG or cardiac monitoring: Characteristic irregular rhythm without discrete p-waves
Workup at time of diagnosis should include
TTE | Thyroid function tests | CBC | Renal function and electrolytes | LFTs | CXR (if suspicion for heart failure or pulmonary disease) | Sleep study (if suspicion for sleep apnea)
Outpatient management appropriate for hemodynamically stable patients without evidence of severe volume overload or acute coronary syndrome
Note: Routine screening for AF in the general population is not currently recommended by the USPSTF | The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for AF (I statement)
Treatment Highlights
Mainstays of treatment for most patients are anticoagulation and rate control (typically beta blocker or nondihydropyridine calcium channel blocker)
For some patients, attempted cardioversion to sinus rhythm may be preferred initially
Invasive procedures to ablate AF or occlude the LAA are appropriate for select patients
KEY POINTS:
Valvular vs. non-valvular AF
Valvular: AF associated with moderate to severe mitral stenosis or mechanical heart valve
Non-valvular: All other AF (much more common)
Risk stratification
CHA2DS2-VASc: Estimates annual stroke risk for non-valvular AF, based on various demographic and comorbid factors
Anticoagulation is recommended for score ≥2 in men, ≥3 in women
Anticoagulation “may be considered” for score 1 in men, 2 in women; aspirin is also an option
Stroke risk can be weighed against bleeding risk using clinical calculators such as HAS-BLED
However per ACC/AHA “their clinical utility is insufficient for use as evidence”
Higher bleeding risk may warrant closer monitoring of anticoagulated patients, but should not necessarily preclude anticoagulation
Anticoagulation
Choosing an anticoagulant
Goal is to prevent thromboembolic events
Decision to start anticoagulation should always involve discussion of risks vs benefits
Medications
Warfarin
Indicated for all valvular AF
Goal INR 2-3
Non–vitamin K oral anticoagulants (NOACs) also known as direct-acting oral anticoagulants (DOACs)
Recommended over warfarin for non-valvular AF in absence of contraindications
All either superior or non-inferior to warfarin | Do not require INR monitoring | Have lower risk of major bleeding
All have reduced dose options for CKD
ESRD
Use warfarin or apixaban (limited data to support this)
Bridging
For patients with mechanical heart valves undergoing surgery or other invasive procedure, bridge with unfractionated or low molecular weight heparin to provide uninterrupted anticoagulation
For all others, a brief interruption of therapy without bridging is considered safe
Anticoagulation with antiplatelet therapy
Patients with AF and recent coronary stenting who are on triple therapy (oral anticoagulant + aspirin + P2Y12 inhibitor) may be narrowed to double therapy (warfarin, dabigatran, or rivaroxaban + P2Y12 inhibitor) to reduce bleeding risk
Dosing
Apixaban (Eliquis)
Usual dose: 5 mg twice a day
Adjusted dose: 2.5 mg twice a day if ≥2 of the following
Age: ≥80 years
Body weight: ≤60 kg
Serum creatinine: ≥1.5 mg/dL
Note: Caution with use of apixaban and the following
Other medications that can interfere with hemostasis: May increase risk of bleeding
Reduce dose by 50% in usual dosing regimen and do not use with 2.5 mg reduced dose | Dose does not need to be altered with clarithromycin
Combined P-gp and strong CYP3A4 inducers: Avoid concomitant use
Rifampin | Carbamazepine | Phenytoin | St. John’s wort
Dabigatran (Pradaxa)
CrCl >30 mL/min: 150 mg orally, twice daily
CrCl 15 to 30 mL/min: 75 mg orally, twice daily
Note: Exercise caution with use of dabigatran and the following
P-gp inducers rifampin: Avoid coadministration
P-gp inhibitors in patients with CrCl 30-50 mL/min: Reduce dose or avoid
P-gp inhibitors in patients with CrCl <30 mL/min: Not recommended
Rivaroxaban (Xarelto)
15 or 20 mg, once daily with food
Note: Exercise caution with use of rivaroxaban and the following
Avoid combined P-gp and strong CYP3A inhibitors and inducers
Anticoagulants: Avoid concomitant use
Renal impairment: Avoid or adjust dose
Hepatic impairment: Avoid use in Child-Pugh B and C hepatic impairment or with any degree of hepatic disease associated with coagulopathy
Alternatives to Anticoagulation
Since thromboemboli tend to develop in the left atrial appendage (LAA), non-pharmacologic strategies for minimizing stroke risk involve occluding or removing the LAA
Percutaneous LAA occlusion (Watchman device): For patients with a contraindication to long-term anticoagulation (however, must be able to receive periprocedural anticoagulation)
Surgical LAA occlusion/excision: Only for patients already undergoing cardiac surgery for another indication
Rate Control
Goal: To reduce symptoms, improve intra-cardiac hemodynamics and perfusion, and prevent tachycardia-induced cardiomyopathy
Choosing a rate control strategy
Beta blockers (metoprolol, carvedilol, atenolol) or nondihydropyridine calcium channel blockers (diltiazem, verapamil) are first-line
Avoid CCBs in heart failure with reduced EF
Second-line options include digoxin (possibly associated with increased mortality) and amiodarone (not for long-term use due to toxicities)
Strict (<80 bpm) vs. lenient (<110 bpm) rate control
Lenient approach acceptable as long as patient is asymptomatic and with preserved EF
Rhythm Control
Not superior to rate control and associated with increase in hospitalizations
May be indicated for new-onset AF, persistent symptoms, difficulty achieving rate control, young age, or tachycardia-induced cardiomyopathy
These approaches generally require expert consultation
Electrical cardioversion
In non-emergent setting, requires anticoagulation three weeks pre- and four weeks post-procedure (if duration of AF >48 hours or unknown)
Often preceded by TEE to exclude LA thrombus
Maintaining sinus rhythm
Typically achieved with antiarrhythmics (e.g. amiodarone, dofetilide, flecainide)
Caution: These drugs have significant side effects and toxicities
Catheter ablation
For symptomatic paroxysmal AF not responding to antiarrhythmic therapy
Stillbirth Management: The ACOG SMFM Consensus Document
SUMMARY:
Stillbirth is a devastating adverse pregnancy outcome, occurring in 1 out of 160 deliveries in the United States. It is often associated with non-modifiable, but common, risk factors such as race and pre-existing co-morbidities. Even after thorough evaluation, often the underlying cause remains unknown. ACOG has provided a comprehensive consensus document that addresses risk factors, causes, and management that includes bereavement support
Note: Nuchal cord not associated with increased risk of stillbirth
Genetics
Chromosomal anomalies
6 to 13% stillbirths | >20% if anatomic abnormalities are present
Most common chromosomal culprits: Trisomy 21 (31%) | Trisomy 18 (22%) | Trisomy 13 (8%) | Monosomy X (22%)
Because cells may no longer be viable at time of test, culture failure will often occur limiting utility of standard karyotyping | Amniocentesis or CVS prior to delivery can increase chance of obtaining a result because amniocytes and placental cells may still be viable (85% vs 28% yield)
Microarray analysis (preferred): Based on DNA technology and therefore does not require living tissue: Increases diagnostic yield to 41.9% of all stillbirths
Single gene disorders: Some single gene disorders are associated with stillbirth
Routine testing not currently recommended
Clinical scenario and family history are used to guide molecular testing and workup
Birth defects
Dysmorphic features and/or skeletal anomalies: 20%
Major malformations: 15 to 20%
Stillbirth Evaluation Algorithm
All stillbirths
Fetal autopsy (can include imaging) | Provides additional clinical information in approximately 30% of cases
Placental pathology (gross and microscopic) including cord and membranes | Provides additional clinical information in approximately 30% of cases
Genetics | Abnormalities seen in 8% of cases
If no other cause identified – add
Antiphospholipid antibody testing
Fetal-maternal hemorrhage testing
Other tests as indicated
FGR or hypertensive disorder – add
Antiphospholipid antibody testing
Fetal-maternal hemorrhage testing
Other tests as indicated
Suspected fetal anomaly – add
Other testing including molecular genetics based on findings
Other tests as indicated based on clinical scenario
“Remaining tests of limited utility”
KEY POINTS:
Key Components of Stillbirth Evaluation
Fetus & Placenta
Weight | HC | Fetal length | Placenta weight
Document abnormalities
Obtain genetics consent: Collect ≥1 of the following specimens in sterile tissue medium of LR (not formalin fixative)
Amniotic fluid (preferred if delivery not imminent)
Placental block 1cm x 1cm taken from below cord insertion site
Umbilical cord segment of 1.5cm
Internal fetal specimen – costochondral junction or patella | Do not send skin (cells usually will not grow)
Obtain consent for fetal autopsy
If consent not given: Limit investigation to external evaluation (by trained perinatal pathologist)
May include photographs and imaging (X-ray, ultrasound)
Maternal evaluation
Obstetric history (previous and present)
Comorbidities
Exposures: Smoking | Alcohol | Drug or medication use
Genetics work-up including 3 generation pedigree
Personal or family history: Arrhythmias | Including sudden death (e.g. for for prolonged QT syndrome)
Lab testing
Kleihauer-Betke or flow cytometry at time of stillbirth
Syphilis
Lupus anti-coagulant | Anticardiolipin | Beta-2 glycoprotein IgG and IgM antibodies (retest at 12 weeks if positive)
Based on clinical indication: Indirect Coombs | Glucose screening for LGA | Toxicology if abruption or suspected drug use
Management of a Stillbirth
Method and timing of delivery depend upon gestational age and maternal preference
Timing of delivery is not critical because coagulopathies uncommon
Second trimester
Medical induction of labor: D&C may be necessary for placental removal
D&E: May limit efficacy of autopsy
<20 weeks
Mifepristone: 200 or 600mg PO plus misoprostol
Evidence limited between 24 and 28 weeks
<28 weeks gestation
Vaginal misoprostol: 400 to 600mcg q3 to 6 hours | <400mcg associated with decreased efficacy
Addition of mifepristone 200 or 600mg PO 24 to 48 hours before misoprostol
<20 weeks: Good evidence to add
24 to 28 weeks: Evidence limited | reduces time to delivery but doesn’t improve overall efficacy compared to misoprostol alone
≥28 weeks: Use standard obstetric induction protocols
Prior uterine scar
< 24 weeks: Vaginal misoprostol
24 to 28 weeks: Further research required to determine safety and optimum dose “in whom lower doses of misoprostol (200 micrograms per dose) may be preferred”
≥28 weeks: Use standard obstetric induction protocols including cervical ripening with Foley
Women with increased risk of uterine rupture (e.g. classical): “Repeat cesarean delivery is a reasonable option” | Discuss risks and benefits
Principles of Bereavement Care
Support services: Consider referral to a bereavement counselor, peer support group, or mental health professional
Feelings of guilt and/or anger are common
Additional considerations
Good communication | Shared decision making | Recognition of parenthood | Acknowledge grief
Be aware of
Options including burials, cremation, and funerals | Emotional and practical support | Health professionals trained in bereavement care | Importance of self-care for health professionals
Recurrence Risk and Antepartum Surveillance
Evidence is limited however appears to be increased risk for recurrence
Antepartum surveillance
Comorbidities: Use recommended management guidelines
Obesity: Prepregnancy BMI of 35.0 to 39.9, consider beginning weekly antenatal fetal surveillance by 37w0d | prepregnancy BMI ≥40, consider beginning weekly antenatal fetal surveillance by 34w0d (ACOG PB 230)
Previous stillbirth ≥32w0d: Once or twice weekly beginning at 32w0d or 1 to 2 weeks prior to gestational age of last stillbirth
Previous stillbirth <32w0d: Individualize | Consider potential morbidity and cost for delivery due to false positive results
Growth ultrasound at 28 weeks to screen for fetal growth restriction
Fetal kick counts
Encourage awareness of fetal movement patterns
Shared decision making recommended due to lack of data to make specific recommendations
Timing of delivery
39w0d
If other comorbidities present: Time delivery as recommended for particular complication (see ‘Related ObG Entries’ below)
Maternal anxiety may warrant early term delivery (37 0/7 to 38 6/7) in women who are educated regarding increased fetal risks
Amniocentesis to confirm fetal lung maturity is generally not recommended
Note: While screening for acquired thrombophilia (lupus anticoagulant, IgG and IgM for both anticardiolipin and β2-glycoprotein antibodies) is recommended, routine aspirin use to prevent stillbirth is not advised due to lack of evidence for efficacy
SARS-CoV-2 (oropharyngeal and nasopharyngeal swabs) now negative
At the same time, fetal edema resolved
Case 2
30-year-old primigravid woman
No associated medical comorbidities aside from BMI of 32
20w1d: Presented at emergency department with COVID-19 symptoms
2 day history of cough and fever in the previous 48 hours
Positive for SARS-CoV-2
Pulse oximetry 99% on room air
Discharged home with mild COVID-19 with monitoring of maternal wellbeing via daily phone calls
21w2d (day 8): Fetal skin edema identified
No other fetal or maternal abnormalities detected | Amniocentesis performed and negative for SARS-CoV-2 or other viral infections
23w7d (day 22)
Fetal edema resolved
SARS-CoV-2 test now negative
CONCLUSION:
Authors report on 2 cases with fetal skin edema concordant with positive maternal SARS-CoV-2 testing that resolved spontaneously at the same time that the RT-PCR test became negative
The authors acknowledge that firm conclusions cannot be drawn from two cases
However, the authors also suggest that fetal skin edema may be related to COVID-19 infection in pregnant women and furthermore
Given these findings and the lack of reports of COVID-19 in the first and second trimesters, a close follow-up of these pregnancies may help to understand the effect on the fetus
One Step or Two Step: Which is the Best Method for GDM Screening?
BACKGROUND AND PURPOSE:
The best method for gestational diabetes mellitus (GDM) screening remains controversial
One-step approach: 75 g 2 hours OGTT using the IADPSG criteria
Recommended by: IADPSG | FIGO | WHO
Two-step approach: 50 g 1 hour GCT followed by a 3 hours 100 g OGTT
Recommended by: ACOG | ADA
Saccone et al. (The Journal of Maternal-Fetal & Neonatal Medicine, 2018) assessed the incidence of maternal and neonatal outcomes comparing one-step vs two-step approach
METHODS:
Systematic review and meta-analysis
Data sources
Electronic database from inception until June 2018
Inclusion criteria
RCTs that compared the one-step vs two-step method for screening and diagnosis of GDM
Study design
Large for gestation age (LGA): Defined as birth weight >90th percentile
Meta-analysis was performed using the random effects model
Treatment effects calculated as relative risk (RR) with 95% CI
Primary outcome
Incidence of LGA
Multiple secondary outcomes included
Maternal complications such as preeclampsia, preterm birth, induction of labor, shoulder dystocia and cesarean delivery
Neonatal adverse outcomes, including neonatal hypoglycemia or hyperbilirubinemia and NICU admission
RESULTS:
4 RCTs were included | Total of 2582 participants | Overall risk of bias was low
Control groups (2-step approach) among the 4 studies
2 trials: 50 g 1 hour GCT followed by 100 g 3 hours (OGTT)
1 trial: 50 g 1-hour test before randomization with exclusion if glucose ≥200 mg/dL
3-arm trial with two control groups (considered as 1 control group for this meta-analysis)
Two-step 50 g 1 hour followed by 100 g 3 hours OGTT
Two-step 50 g 1 hour GCT followed by 75 g 2 hours OGTT
Management of diabetes also differed with respect to use of insulin as exclusive first line medication as well as glucose target values
One-step approach was associated with a lower risk of adverse perinatal outcomes, such as
LGA (primary outcome): 2.9% vs 6.3%; RR 0.46 (95% CI, 0.25 to 0.83)
NICU admission: RR 0.49 (95% CI, 0.29 to 0.84)
Neonatal hypoglycemia: RR 0.52 (95% CI, 0.28 to 0.95)
The one-step approach was associated with lower mean birth weight
Mean difference −112.91 grams (95% CI, −190.48 to −35.33)
There was no significant difference in the incidence of GDM
One step: 8.3%
Two step: 4.4%
RR 1.60 (95% CI 0.93 to 2.75)
Authors performed a subgroup analysis removing the 3-arm trial (slightly different inclusion criteria, i.e. multiple gestations) and also differences in screening criteria compared to the other studies (Canadian Diabetes Association)
Incidence of GDM was increased with removal of this trial (12.6% vs 5.6%; RR 2.20)
Subgroup analysis was only performed for GDM incidence and not perinatal outcomes
CONCLUSION:
In this meta-analysis, the one-step approach to GDM screening was associated with better perinatal outcomes compared to the two-step approach
The authors state that
The argument against the one-step approach has been that it increases the incidence of GDM significantly, without proven improvement in maternal and/or perinatal outcomes Our meta-analysis of RCTs, however, provides level-1 evidence that the one-step approach significantly improves perinatal outcomes In particular, we found a 54% reduction in the risk of LGA
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