FDA Withdraws Makena Approval for US Market

FDA approval for Makena, a drug used to reduce risk for preterm birth, has been formally withdrawn. The withdrawal also includes all generics (17-alpha hydroxyprogesterone caproate [17-OHPC]). Regarding any current medication in distribution, the FDA states that “Patients who have questions should talk to their healthcare provider.” Both ACOG and SMFM have addressed the situation.

ACOG

Intramuscular 17-OHPC is not recommended for the primary prevention of preterm birth in patients with a history of spontaneous preterm birth

In summary, at this time, the body of evidence is equivocal regarding the effectiveness of 17-OHPC, and the referenced FDA action will limit access to 17-OHPC for patients

SMFM

We agree with the FDA determination and discourage continued prescribing of 17-OHPC, including through compounding pharmacies

We agree with the FDA that there is no evidence of benefit with continued treatment

Patients currently receiving 17-OHPC can be counseled that the FDA’s Center for Drug Evaluation and Research (CDER) has not identified evidence of harm from discontinuation prior to 37 weeks of gestation

RESEARCH SUMMARY:

The authors of the PROLONG trial (Progestin’s Role in Optimizing Neonatal Gestation) reported on the use of 17α-hydroxyprogesterone caproate (17-OHPC) for the treatment of preterm birth (PTB)

In this study population, 250 mg 17-OHPC did not decrease recurrent PTB and was not associated with increased fetal/early infant death

On October 29, 2019, the FDA advisory committee recommended that the drug be withdrawn from the market (9 to 7 vote). On October 5, 2020, the Center for Drug Evaluation and Research (CDER) proposed that Makena be withdrawn from the market. At that time, the decision was made to hold further meetings and discussions. Based upon further follow-up, the CDER briefing materials for the Advisory Committee meeting (October 17-19, 2022) states

Makena has not been shown to improve neonatal outcomes from premature birth, is no longer shown to be effective for its approved use, and has known risks

The 1,708-person confirmatory trial designed to verify Makena’s clinical benefit instead failed to show that Makena has any benefit to newborns. Data from this trial, taken together with other evidence, also fail to show that Makena reduces the risk of recurrent preterm birth

For these and other reasons detailed herein, Makena should be withdrawn from the market

Background to PROLONG Trial

• A previous study, on behalf of the NICHD, demonstrated success of IM 17-OHPC in preventing PTB (see ‘Learn More – Primary Sources)
  • Meis et al. (NEJM, 2003): 250 mg IM 17-OHPC reduced recurrent preterm birth (PTB) in women with a prior spontaneous PTB (SPTB)
    • Relative risk [RR] 0.66 (95% CI, 0.54–0.81)
• The current PROLONG study was a ‘confirmatory trial’, performed with FDA input as a requirement for the FDA accelerated approval pathway

PROLONG Methods

• Double-blind randomized controlled trial (RCT)
• Participants
  • ≥18 years
  • Singleton pregnancy
  • Currently 16w0d to 20w6d
  • Previous history of singleton SPTB (birth between 20w0d and 36w6d following preterm labor or PROM)
• Groups (IM injection 1 in upper outer quadrant of the gluteus maximus) weekly until delivery or 36 weeks
  • 17-OHPC (250 mg)
  • Placebo
• Stratified by
  • Study site
  • GA at randomization
• Primary outcomes
  • PTB < 35 weeks
  • Composite neonatal morbidity and mortality index

PROLONG Results

• PTB < 35w0d (p=0.72)
  • 17-OHPC: 11.0%
  • Placebo: 11.5%
  • Relative risk (RR) 0.95 (95% CI, 0.71–1.26)
• Neonatal composite index (p=0.73)
  • 17-OHPC 5.6%
  • Placebo 5.0%
  • RR 1.12 (95% CI, 0.70–1.66)
  • Note: No differences seen in any of the individual components that were part of the composite index

KEY POINTS:

Sibai et al. Obstet Gynecol, 2020

Meis Trial

• Well designed and conducted
• Highly statistically significant results
  • Prespecified criterion threshold of alpha=0.015 was met regarding benefit of 17-OHPC
  • Preterm birth <37 weeks: Relative risk (RR) 0.66 (95% CI, 0.54 to 0.81; P<.001)
  • Preterm births <35 weeks: RR 0.67 (95% CI, 0.48 to 0.93)
  • Preterm birth <32 weeks: RR 0.58 (95% CI, 0.37–0.91)
• Subgroup analysis: Number of prior preterm birth | Race | Marital status | Smoking or substance use
  • Confirmed generalizability

Prolong Trial

• Population studied was very different from that of the Meis trial (non-US)
• Trial is underpowered based on observed event rates
  • For 90% power, PROLONG required 3,600 women for preterm birth <35 weeks and 6,000 women for neonatal composite outcome
• PROLONG not powered for subgroup analysis, but Meis et al. did look at US subgroup and found that while not statistically significant
  • Direction and magnitude of effect <32 weeks and neonatal composite index were similar to the Meis trial

Authors’ Conclusion

We assert PROLONG was underpowered, based on substantially lower observed preterm birth rates than anticipated, and therefore was a false-negative study, rather than the Meis trial being a false-positive study

Careful assessment of these two trials is critical as removal of 17α-hydroxyprogesterone caproate from the U.S. marketplace may have substantial effects on public health

Learn More – Primary Sources:

FDA Commissioner and Chief Scientist Announce Decision to Withdraw Approval of Makena

ACOG Practice Advisory: Updated Clinical Guidance for the Use of Progesterone Supplementation for the Prevention of Recurrent Preterm Birth

SMFM Special Statement: Response to the Food and Drug Administration’s withdrawal of 17-alpha hydroxyprogesterone caproate

17-OHPC to Prevent Recurrent Preterm Birth in Singleton Gestations (PROLONG Study): A Multicenter, International, Randomized Double-Blind Trial

Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. (NEJM, 2003)

Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee Meeting Announcement: MAKENA supplemental new drug application

Re-examining the Meis Trial for Evidence of False-Positive Results (Sibai et al. Obstetrics & Gynecology, 2020)

FDA Briefing Materials for Withdrawal of Makena Approval (2022)

FDA: UPDATED INFORMATION: October 17 – 19, 2022: Hearing Announcement involving the Obstetrics, Reproductive, and Urologic Drugs Advisory Committee

Do Proton Pump Inhibitors Increase the Risk for CVD in Patients with Type 2 Diabetes?

BACKGROUND AND PURPOSE:

• Proton pump inhibitors (PPIs), used for treating gastric-acid related diseases, have been linked with cardiovascular disease (CVD)
  • How PPI use affects type 2 diabetes (T2D) patients, who are more likely to use PPIs and more likely to develop CVD, is unclear
• Geng et al. (Journal of Clinical Endocrinology & Metabolism, 2022) evaluate the associations of PPI use with risks of CVD and all-cause mortality in patients with T2D

METHODS:

• Secondary analysis of prospective cohort study
• Population
  • Patients in the UK Biobank with preexisting T2D
• Exposure
  • PPI use
• Primary outcomes
  • Coronary artery disease (CAD)
  • Myocardial infarction (MI)
  • Heart failure (HF)
  • Stroke
  • All-cause mortality

RESULTS:

• 19,229 adults with T2D
  • Median follow up: 10.9 to 11.2 years
• PPI use was significantly associated with higher risks of
  • CAD: HR 1.27 (95% CI, 1.15 to 1.40)
  • MI: HR 1.34 (95% CI, 1.18 to 1.52)
  • HF: HR 1.35 (95% CI, 1.16 to 1.57)
  • All-cause mortality: HR 1.30 (95% CI, 1.16 to 1.45)
• The results were consistent in the subgroup analyses stratified by factors including
  • Indications of PPI | Antidiabetic medication use | Antiplatelet drug use
• Analyses in a 1:1 propensity score-matched cohort of PPI users vs nonusers yielded similar results

CONCLUSION:

• PPI use among patients with T2D is associated with an increased risk of CVD events, compared to non-use
• The authors state

The benefits and risks of PPI use should be carefully balanced among patients with T2D, and monitoring of adverse CVD events during PPI therapy should be enhanced

Learn More – Primary Sources:

Proton Pump Inhibitor Use and Risks of Cardiovascular Disease and Mortality in Patients with Type 2 Diabetes

ACOG Committee Opinion on Delayed Cord Clamping

SUMMARY:

For both ‘vigorous’ term and preterm infants, ACOG recommends waiting at least 30 to 60 seconds after birth before clamping the umbilical cord. The committee opinion provides a comprehensive literature and evidence review. ACOG states

In term infants, delayed umbilical cord clamping increases hemoglobin levels at birth and improves iron stores in the first several months of life, which may have a favorable effect on developmental outcomes

Delayed umbilical cord clamping is associated with significant neonatal benefits in preterm infants, including improved transitional circulation, better establishment of red blood cell volume, decreased need for blood transfusion, and lower incidence of necrotizing enterocolitis and intraventricular hemorrhage

Benefits include

• Term infants
  • Increased hemoglobin levels and iron stores
• Preterm infants
  • Improved transitional circulation
  • Better establishment of RBC volume
  • Decreased blood transfusion
  • Lower risk of NEC and IVH

Note: There was no evidence for increased risk of PPH

Caution: The committee opinion notes that there may be a small risk for jaundice requiring phototherapy in term infants and therefore the delivery center should have the necessary infrastructure to monitor and treat, if necessary

Immediate Umbilical Cord Clamping

When is delayed cord clamping not appropriate?

• Maternal reasons
  • Hemorrhage
  • Hemodynamic instability
  • Abnormal placentation (e.g., previa, abruption etc.)
• Fetal / Neonatal reasons
  • Need for immediate resuscitation
  • Placental circulation not intact
    • abruption
    • previa
    • cord avulsion
    • IUGR with abnormal cord Doppler

NOTE: ACOG states

Maternal hemodynamic instability or the need for immediate resuscitation of the newborn on the warmer would be an indication for immediate umbilical cord clamping

Cord Milking

• Based on the latest evidence (see ‘Learn More – Primary Sources’ below) that found a higher risk of IVH in preterm infants (23 to 27 weeks) following cord milking, ACOG states

…cord milking should not be used for extremely preterm infants (less than 28 weeks of gestation)

…there is insufficient evidence to either support or refute umbilical cord milking in infants born at 32 weeks of gestation or more, including term infants

Learn More – Primary Sources:

ACOG Committee Opinion 814: Delayed Umbilical Cord Clamping After Birth

Eclampsia and Role of Magnesium Sulfate

SUMMARY:  

Eclampsia is a severe, life-threatening manifestation of preeclampsia.  While long-term neurologic damage is rare, there is risk of maternal hypoxia and death. Most women will experience signs such as headaches or visual changes prior to a seizure.

Eclampsia

• Defined as convulsions during pregnancy and/or postpartum
  • Tonic-clonic, focal, or multifocal
  • New onset
  • Unexplained by other neurologic pathology
• Consider other underlying cerebral conditions when
  • Seizures occur 2 to 3 days postpartum
  • Patient on magnesium sulfate

Note: Not all women will demonstrate classic features of preeclampsia (hypertension, proteinuria)

Magnesium Sulfate – How to Use  

• Magnesium sulfate is the treatment of choice for seizure prophylaxis (ACOG recommended dosing) 
  • Loading dose of 4–6 g of magnesium sulfate administered per infusion pump over 20–30 minutes (i.e., slowly) followed by a maintenance dose of 1-2 g per hour as a continuous intravenous infusion  
  • Continue 24 hours postpartum
• Recurrent seizures
  • Additional dose of 2-4 g can be infused over 5 minutes
• Refractory seizures
  • Sodium amobarbital: 250 mg IV in 3 minutes
  • Thiopental or phenytoin: 1,250 mg IV at a rate of 50 mg/minute
  • Patient should be managed in ICU
  • Consider neuroimaging
• IM option
  • 10 g initially as a loading dose (5 g IM in each buttock) followed by 5 g every 4 hours
  • Use if IV access limited
  • Mix with 1 mL xylocaine 2% to alleviate pain

Note: Magnesium sulfate should not be considered an antihypertensive agent

Magnesium Sulfate – When to Use

• Severe features of preeclampsia 
  • Administer to all women 
• No severe features of preeclampsia and systolic BP > 140 and < 160 mm Hg or diastolic BP > 90 and < 110 mm Hg 
  • There is no consensus on this matter as prophylaxis will reduce eclampsia but 1 in 100 to 129 women need to be treated and side effects (although not life threatening) will increase
  • ACOG states that the decision to use magnesium sulfate when severe features are not present should be the decision of the “physician or institution, considering patient values or preferences, and the unique risk-benefit trade-off of each strategy” 

Delivery and Postpartum 

• Vaginal delivery
  • Continue infusion 24 hours postpartum
• Cesarean
  • Begin infusion (if not yet running) before surgery and continue 24 hours postpartum
  • Discontinuing prior to operative vaginal birth or cesarean section to avoid uterine atony or anesthetic drug interactions is not recommended

 Prevention of Magnesium Sulfate toxicity 

• Place Foley to monitor renal function (hourly output)  
• Confirm normal serum creatinine  
• Serial evaluation of patellar deep tendon reflexes 
• Monitor respiratory rate  
• Serum magnesium levels not routinely required
  • Monitor serum magnesium levels in setting of renal dysfunction and/or absence of patellar reflexes 
  • Maintain serum concentrations 5 to 9 mg/dL (4–7 mEq/L) range  
• Predictive symptoms of magnesium sulfate toxicity  
  • Loss of deep tendon reflexes >9 mg/dL (greater than 7 mEq/L)  
  • Respiratory depression >12 mg/dL (greater than 10 mEq/L) 
  • Cardiac arrest >30 mg/dL (greater than 25 mEq/L) 

Pending toxicity 

• Notify appropriate health care provider  
• Discontinue magnesium infusion  
• Administer supplemental oxygen  
• Obtain a serum magnesium level  
• Reverse magnesium 
  • 10 mL of 10% calcium gluconate IV (1 g total) and over 3 min (i.e., slowly) to avoid hypotension and/or bradycardia 
  • Calcium effect (competitively inhibits magnesium at neuromuscular junction) can wear off if magnesium level stays high 
  • Furosemide may help increase urinary excretion
• Respiratory arrest: Intubation and assisted ventilation as indicated

Other Prophylactic Agents

• Magnesium sulfate is superior to diazepam, phenytoin and lytic cocktail (chlorpromazine, promethazine, pethidine) in reducing significantly the risk of seizure recurrence  
  • Cochrane Review 2010: Magnesium sulfate reduced eclampsia compared to phenytoin (relative risk 0.08, 95% CI 0.01 to 0.60)   
• Morbidity related to pneumonia, mechanical ventilation and admission to an intensive care unit are significantly reduced with the use of magnesium sulfate compared with phenytoin  
• Magnesium sulfate does not cause maternal or newborn CNS depression 
  • Diazepam or lorazepam does stop or shorten seizures, but risk of maternal apnea and/or cardiac arrest
• Diazepam and phenytoin may be considered if
  • Patient on these medications to treat epilepsy
  • Magnesium sulfate is contraindicated
    • Myasthenia gravis | Hypocalcemia | Moderate-to-severe renal failure | Cardiac ischemia | Heart block | Myocarditis

Learn More – Primary Sources:

National Partnership for Maternal Safety: Consensus Bundle on Severe Hypertension During Pregnancy and the Postpartum Period 

ACOG Practice Bulletin 222: Gestational Hypertension and Preeclampsia

Management of pre-eclampsia: issues for anaesthetists 

Acute pulmonary oedema in pregnant women 

Cochrane Review: Magnesium sulphate and other anticonvulsants for women with pre-eclampsia 

HPV Vaccine Recommendations Including Guidance for Ages 27 to 45

SUMMARY:

The most recent evidence-based HPV vaccine recommendations address when to administer the vaccine and dosing.  One area that has elicited more recent guidance focuses on whether to offer the HPV vaccine to individuals over the age of 26.

• The FDA (October 2018) extended approval of HPV vaccine to individuals age 27 to 45 years
• ACIP (June 2019) voted to
  • Expand routine and catch-up HPV vaccination in males through 26 years of age who are inadequately vaccinated
  • Offer HPV vaccine to individuals age 27 to 45 years who have not been adequately vaccinated based on shared clinical decision making
• ACIP published their final recommendations (August 2019) in the CDC’s Morbidity and Mortality Weekly Report

Children and adults aged 9 through 26 years: HPV vaccination is routinely recommended at age 11 or 12 years; vaccination can be given starting at age 9 years. Catch-up HPV vaccination is recommended for all persons through age 26 years who are not adequately vaccinated.

Adults aged >26 years: Catch-up HPV vaccination is not recommended for all adults aged >26 years. Instead, shared clinical decision-making regarding HPV vaccination is recommended for some adults aged 27 through 45 years who are not adequately vaccinated. HPV vaccines are not licensed for use in adults aged >45 years.

These recommendations for children and adults aged 9 through 26 years and for adults aged >26 years apply to all persons, regardless of behavioral or medical risk factors for HPV infection or disease.

For persons who are pregnant, HPV vaccination should be delayed until after pregnancy; however, pregnancy testing is not needed before vaccination.

Persons who are breastfeeding or lactating can receive HPV vaccine. Recommendations regarding HPV vaccination during pregnancy or lactation have not changed.

• ACIP suggests considering the following points for shared-decision making with adults who are 27 to 45 years of age
  • HPV is very common, usually transient and asymptomatic
  • Although typically acquired in young adulthood, some adults are at risk for acquiring new HPV infection
  • A new sex partner is a risk factor, while those in long-term, mutually monogamous partnerships are not likely to acquire a new HPV infection
  • HPV types: Sexually active adults will likely have been exposed to some HPV types, but not all HPV types are vaccine targets
  • There is no antibody test to determine immunity
  • HPV vaccine has high efficacy in persons not yet exposed to vaccine-type HPV
  • Lower vaccine effectiveness may be expected in those with HPV risk factors
    • Multiple lifetime sex partners | Previous infection with vaccine-type HPV | immunocompromising conditions
  • HPV vaccines are prophylactic only and can’t prevent infection progression, improve time to clearance or treat HPV-related disease
• In summary, the CDC states

For adults aged 27 years and older, clinicians can consider discussing HPV vaccination with people who are most likely to benefit. HPV vaccination does not need to be discussed with most adults over age 26 years

CDC Dosing Schedule 

• <15 years: 2 doses spaced 6 to 12 months apart
• ≥15 years: 3-dose schedule
  • Initial dose
  • Second dose at 1 to 2 months after initial 
  • Third dose at 6 months after initial 

Updated ACOG HPV vaccine recommendations 

• Routine HPV vaccination is recommended for females and males 
• Target age is 11 to 12 years but can be given through age 26
  • Can be given from age of 9 
• Do not test for HPV DNA prior to vaccination
  • Vaccinate even if patient was tested and is HPV DNA positive
•  If not vaccinated between 11 to 12 years
  • Vaccinate between 13 to 26 years (catch up period)
  • Offer regardless of sexual activity, prior exposure to HPV, or sexual orientation 
• Women 27 to 45 years and previously unvaccinated
  • Use shared clinical decision making
• ACOG “does not recommend that an individual who received the quadrivalent HPV vaccine be revaccinated with 9-valent HPV vaccine, including those aged 27 to 45 years who previously completed some, but not all, of the vaccine series when they were younger”
• Pregnancy
  • HPV vaccine is not recommended during pregnancy
  • Pregnancy testing prior to HPV vaccination not recommended
  • If vaccination schedule is interrupted by pregnancy, resume postpartum with the next dose
  • HPV vaccine can and should be given to breastfeeding women ≤26 who have not been vaccinated
  • The CDC encourages pregnant patients and healthcare professionals to report to the manufacturer and VAERS system if vaccine was administered during pregnancy | How and where to report is described in “CDC: HPV Vaccine Safety” in Learn More-Primary Sources below  
• Counsel to expect mild local discomfort and that this is not a cause for concern
  • Watch adolescents for at least 15 minutes following vaccination due to risk of fainting in this population

AAP  

• The AAP has also endorsed the CDC HPV recommendations
  • The HPV vaccine should be normalized as a standard of care
  • Recommendation should be clear and unambiguous 
  • AAP provides multiple strategies (see ‘Learn More – Primary Sources’ below) to engaging with patients including focusing on cancer prevention benefits for all children 

ACS

• The ACS endorses ACIP CDC guidance regarding HPV guidance except for the approach to take with individuals who are 27 to 45 years and not adequately vaccinated

The ACS does not endorse the 2019 Advisory Committee on Immunization Practices recommendation for shared clinical decision making for some adults aged 27 through 45 years who are not adequately vaccinated because of the low effectiveness and low cancer prevention potential of vaccination in this age group, the burden of decision making on patients and clinicians, and the lack of sufficient guidance on the selection of individuals who might benefit

Adjuvant HPV Vaccine to Prevent CIN Recurrence 

• ACOG recommends considering adjuvant HPV vaccine for unvaccinated individuals 27 to 45 years who are undergoing treatment for CIN 2+

Learn More – Primary Sources:

FDA Approves Expanded Use of Gardasil 9 to Include Individuals 27 Through 45 Years )ld 

CDC: HPV Vaccine Recommendations 

Human Papillomavirus Vaccination for Adults: Updated Recommendations of the Advisory Committee on Immunization Practices (MMWR) 

CDC: Clinical Overview of HPV 

ACOG Committee Opinion 809: Human Papillomavirus Vaccination 

ACOG Practice Advisory: Adjuvant Human Papillomavirus Vaccination for Patients Undergoing Treatment for Cervical Intraepithelial Neoplasia 2+ 

AAP: How Pediatricians Can Recommend HPV Vaccination to Parents and Caregivers 

CDC HPV Vaccine Safety 

CDC: HPV Educational Materials For Clinicians 

ACS: Human Papillomavirus Vaccination 2020 Guideline Update 

Transvaginal Ultrasound in the Evaluation of Postmenopausal Bleeding

SUMMARY:

Postmenopausal uterine bleeding needs to be evaluated quickly and transvaginal ultrasound can play an important role in the initial work-up.

Endometrial Thickness  

• Measure the maximum anterior-posterior thickness on a long-axis transvaginal view 
• Transvaginal ultrasound is appropriate for the initial evaluation  
• Thin endometrial echo  
  • Defined as ≤4mm   
  • Endometrial fluid should not be included in measuring endometrial thickness
  • >99% NPV for endometrial cancer 
  • Cannot exclude all pathology, including endometrial cancers such as uterine papillary serous, mucinous, clear cell  
• Thickened endometrium is not diagnostic of a particular pathology  

Recommended Management 

• Transvaginal ultrasound  
  • Should only be used as an initial evaluation if there is low prior probability for cancer or hyperplasia   
  • Additional evaluation is required if persistent/recurrent bleeding  
  • Either transvaginal ultrasound or endometrial sampling are ‘reasonable’ alternatives as first line – both not required if low risk
  • Proceed to endometrial sampling if abnormal endometrium is seen on transvaginal ultrasound  
• Endometrial sampling  
  • First-line test if clinical risk factors are present (see ‘Endometrial Cancer: The Basics’ in ‘Related ObG Topics’ below) or clinical presentation is suspicious  
  • Outpatient endometrial sampling using disposable device is method of choice  
  • NOTE: Proceed to hysteroscopy with D&C if persistent or recurring bleeding and blind sampling is negative for endometrial hyperplasia or malignancy 

KEY POINTS:  

• If transvaginal ultrasound image inadequate proceed to following options  
  • Sonohysterography | Office hysteroscopy | Endometrial sampling   
• If insufficient tissue on endometrial sampling 
  • Transvaginal ultrasound can be used to further evaluate and if a thin echo is seen and bleeding has stopped, no further work-up is necessary  
  • Persistent/recurrent bleeding needs a histologic evaluation even in the presence of a thin echo 
• Postmenopausal women who are not bleeding 
  • Transvaginal ultrasound should not be used as a screening tool for endometrial cancer in this population  
  • If an endometrial echo >4mm is found incidentally, this is not an automatic ‘trigger’ for further evaluation but rather should be placed in context and “individualized … based on patient characteristics and risk factors”  

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Learn More – Primary Sources:  

ACOG Committee Opinion 734: The Role of Transvaginal Ultrasonography in Evaluating the Endometrium of Women With Postmenopausal Bleeding

ACOG Recommendations on Marijuana Use During Pregnancy and Lactation

SUMMARY:

The US Surgeon General released an advisory regarding marijuana use during pregnancy and the potential for adverse outcomes. This advisory echoes concerns of ACOG and AAP regarding potency and potential harms during pregnancy and adolescence. Use in pregnancy has doubled (3.4 to 7%) and appears to be associated with adverse outcomes including LBW. ACOG’s updated committee opinion on marijuana use in pregnancy and lactation, due to reported association between marijuana use and impaired neurodevelopment in the offspring, recommends that the use of marijuana in the pre-conception, pregnancy, or lactation periods should be discouraged.

KEY POINTS:

Background 

• Prevalence of marijuana use (self-reported) during pregnancy: 2-5% 
  • May be as high as 28% in young, urban and disadvantaged populations 
•  Up to 60% of women using marijuana may continue use during pregnancy  
  • Data suggests that women are not aware of risks and consider marijuana to be cheaper and safer than tobacco

Pharmacology 

• Tetrahydrocannabinol (THC) is the active substance  
  • Distributed rapidly to the brain and fat 
  • Metabolized by the liver 
  • Half-life:  20-36 hours in occasional users and may be up to 4 to 5 days in heavy users 
  • Excretion: Up to 30 days 
• Fetal THC levels are
  • Approximately 10% of maternal levels (animal models)
  • Found in breast milk (human studies)

Perinatal Risks and Outcomes  

CNS Effects Including Visual and Behavioral Outcomes 

• Cannabinoid receptors have been detected in humans as early as 14 weeks gestation and endocannabinoids may be important for neurodevelopment
• Animal models suggest that exogenous cannabinoids may interfere with normal brain development
• Children exposed to prenatal marijuana may have
  • Lower scores on tests of visual problem solving
  • Visual-motor coordination
  • Decreased attention span
  • Behavioral problems 

Structural malformations 

• Available evidence does not suggest increased risk for fetal structural malformations 

Perinatal death 

• Marijuana use does not increase risk of perinatal death
  • Relative risk (RR) 1.09; 95% CI, 0.62 to 1.91
• Some studies have shown higher risk of stillbirth but may be confounded by cigarette smoking and other factors
  • RR 1.74; 95% CI, 1.03 to 2.93

Birth weight 

• Some studies have shown an association between marijuana use and lower birth weight (<10th percentile) even after adjusting for tobacco use
• A meta-analysis with primary outcome of birth weight <2,500 did not show a difference when adjusted for other factors, such as tobacco use, but did identify possible effects when data was stratified by
  • Weekly users
  • Use in the 1st and 2nd trimesters 

Preterm birth

• A meta-analysis with primary outcome of preterm delivery <37 weeks did not a show a relationship when adjusted for tobacco use
  • Possibility exists that tobacco “may be an important mediator for some “adverse pregnancy outcomes”

Note: For perinatal death/stillbirth, birthweight and preterm birth, data derived from meta-analysis (see ‘Learn More – Primary Sources below) and other more recent studies

Breastfeeding 

• There are insufficient data on the effects of marijuana use on breastfeeding infants 
• Bertrand et al. (Pediatrics, 2018) identified significant transfer of cannabinoids into breast milk following marijuana us (see ‘Related ObG Topics’, below)
• At this time, both ACOG and AAP recommend that marijuana use during lactation should be discouraged

Medical Marijuana Use 

• The FDA does not evaluate nor regulate medical marijuana use 
• There are currently no indications for use in pregnancy 
• ACOG recommends the following
  • Encourage women to discontinue marijuana use
  • Avoid prescribing or suggesting the use of marijuana for medicinal purposes during pre-conception, pregnancy, or lactation periods 
  • Identify alternative therapies with better safety profiles

Other Counseling Notes

• All pregnant women, or those planning to become pregnant should be asked about their use of alcohol, tobacco, and drugs including marijuana
• Discuss potential adverse events
  • More research is necessary to determine whether marijuana is an isolated risk factor for adverse outcomes or whether findings are a result of confounding related to other factors (e.g., tobacco use, other substances, socioeconomic factors, nutrition) or recall bias
• ACOG recommends that patients should be made aware that screening for substance use allows for the provision of treatment when necessary and not to punish
• In addition, the ACOG guideline states

…patients should also be informed of the potential ramifications of a positive screen result, including any mandatory reporting requirements

Seeking obstetric–gynecologic care should not expose a woman to criminal or civil penalties for marijuana use, such as incarceration, involuntary commitment, loss of custody of her children, or loss of housing

Learn More – Primary Sources:

ACOG Committee Opinion 722: Marijuana use in pregnancy

ACOG Breastfeeding Page

AAP: Marijuana Use During Pregnancy and Breastfeeding – Implications for Neonatal and Childhood Outcomes

Maternal Marijuana Use and Adverse Neonatal Outcomes: A Systematic Review and Meta-analysis

U.S. Surgeon General’s Advisory: Marijuana Use and the Developing Brain

ACOG Recommendations: When to Deliver Medically Complicated Pregnancies

SUMMARY:

ACOG has developed important guidance on the timing of medically indicated late-preterm and early-term deliveries in collaboration with SMFM. The recommendations are based on placental, fetal and maternal complications.

• Placental Indications
• Fetal Conditions
• Maternal Conditions
• PROM and Stillbirth

KEY POINTS:

• Antenatal Corticosteroids 
  • Anticipated late-preterm delivery: Administer single course of antenatal corticosteroids within 7 days of delivery if patient has not received a previous course 
  • Medically indicated late-preterm delivery should not be delayed for administration of corticosteroids 
• Lung maturity testing 
  • Amniocentesis for determination of fetal lung maturity should not be used to guide timing of delivery (even in poorly dated pregnancies) 
• Data are lacking for some conditions, such as dehiscence or chronic abruption 
  • In these cases, individualize timing of delivery

Placental Indications  

• Previa (otherwise uncomplicated): 36w0d – 37w6d  
• Accreta, increta, percreta (otherwise uncomplicated) : 34w0d – 35w6d  
• Vasa previa: 34w0d – 37w0d 
• Prior classical cesarean: 36w0d – 37w0d  
• Previous uterine rupture: 36w0d – 37w0d  
• Prior myomectomy requiring cesarean: 37w0d – 38w6d  
  • May require delivery similar to classical section (see above) if surgery was more extensive and complicated
  • With less extensive surgery, delivery may be considered as late as 38w6d
  • ACOG states

Timing of delivery should be individualized based on prior surgical details (if available) and the clinical situation

Fetal Conditions 

• Oligohydramnios (DVP <2cm) isolated and uncomplicated : 36w0d – 37w6d (or at time of diagnosis if later) 
• Polyhydramnios (otherwise uncomplicated): 39w0d – 39w6d  
• Fetal growth restriction (FGR) – singleton
  • Uncomplicated and EFW between 3rd and 10th percentile: 38w0d – 39w0d
  • Uncomplicated and EFW <3rd percentile: 37w0d (or at time of diagnosis if later) 
  • UA Doppler decreased end diastolic flow without absent end diastolic flow: 37w0d (or at time of diagnosis if later) 
  • UA Doppler absent end diastolic flow: 33w0d – 34w0d (or at time of diagnosis if later) 
  • UA Doppler reversed end-diastolic flow: 30w0d – 32w0d (or at time of diagnosis if later) 
  • Note: Concurrent condition (e.g., oligohydramnios, preeclampsia, hypertension): 34w0d – 37w6d 
• Multiple gestation – uncomplicated  
  • Di-di twins: 38w0d – 38w6d   
  • Mono-di twins: 34w0d – 37w6d   
  • Mono-mono twins: 32w0d – 34w0d   
  • Note: Triplets and higher: Individualize 
• Alloimmunization 
  • At-risk and not requiring intrauterine transfusion: 37w0d – 38w6d  
  • Note: Requiring intrauterine transfusion: Individualize 

Maternal Conditions 

Chronic hypertension  

• Uncomplicated, no meds: 38w0d – 39w6d  
• Uncomplicated, controlled on meds: 37w0d – 39w6d  
• Difficult to control: 36w0d – 37w6d  

Gestational hypertension 

• Without severe BP: 37w0d (or at time of diagnosis if later) 

• With severe BP: 34w0d (or at time of diagnosis if later) 

Preeclampsia 

• Without severe features: 37w0d (or at time of diagnosis if later) 
• With severe features 
  • Stable maternal-fetal status: 34w0d (or at time of diagnosis if later)  
  • Unstable or complicated by HELLP: Soon after maternal stabilization (guided by maternal/fetal status and gestational age)
  • Before viability: Soon after maternal stabilization (guided by maternal/fetal status and gestational age) 

Diabetes 

• Pregestational diabetes 
  • Well-controlled: 39w0d – 39w6d   
  • With vascular complications, poor control, or prior stillbirth: 36w0d – 38w6d   
• Gestational diabetes 
  • Well-controlled on diet: 39w0d – 40w6d   
  • Well-controlled on meds: 39w0 – 39w6d  
  • Note: Poorly-controlled: Individualize 

HIV 

• Intact membranes & viral load > 1,000 copies/mL: 38w0d   

• Viral load <1,000 copies/mL and antiretroviral therapy: ≥39w0d  

Intrahepatic cholestasis of Pregnancy 

• Bile acids ≥100 micromol/L: 36w0d
• Bile acids <100 micromol/L: 36w0d to 39w0d | Delivery <36 weeks may be required depending on clinical findings and lab values 

PROM and Stillbirth

• Ruptured membranes  
  • Preterm PROM (PPROM): 34w0d to 36w6d
  • PROM (≥37w0d): Generally, deliver at time of diagnosis 
• Previous stillbirth: Individualize
  • Early term birth not routinely recommended
  • “…maternal anxiety with a history of stillbirth should be considered and may warrant an early term delivery (37 0/7 weeks to 38 6/7 weeks) in women who are educated regarding, and accept, the associated neonatal risks”

Learn More – Primary Sources:

ACOG Committee Opinion 831: Medically Indicated Late-Preterm and Early-Term Deliveries

USPSTF Recommends Universal Screening for Hepatitis C

SUMMARY:

• USPSTF has reviewed available evidence and has updated its hepatitis C screening guidance. HCV is the most common chronic blood-borne pathogen in the US with potential for significant morbidity and mortality if left untreated. The prevalence of chronic HCV infection in the US is approximately 1.0% (2013 to 2016), with 44,700 new HCV infections in 2017. There has been an increase in acute infections over the last decade primarily due to increased injection drug use and better surveillance.

• The USPSTF recommends screening for HCV infection in adults aged 18 to 79 years
• Population: All asymptomatic adults aged 18 to 79 years without known liver disease
• B level recommendation
  • Offer or provide this service
  • There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial

The USPSTF concludes with moderate certainty that screening for HCV infection in adults aged 18 to 79 years has substantial net benefit

Risk Assessment

• Screen all adults ages 18 to 79 years
• Risk factors to consider
  • Injection drug use: Consider screening adolescents <18 years or >79 years
    • Young adults (ages 18 to 30): Approximately 30% are infected
    • Older adults: 70% to 90% are infected
• Pregnancy
  • Screen pregnant adults  

Because of the increasing prevalence of HCV in women aged 15 to 44 years and in infants born to HCV-infected mothers, clinicians may want to consider screening pregnant persons younger than 18 years

Screening Test

• Anti-HCV antibody testing followed by polymerase chain reaction testing for HCV RNA
  • HCV infection can be detected by anti-HCV screening tests (enzyme immunoassay) 4 to 10 weeks after infection
  • Delayed seroconversion may occur in immunocompromised individuals (e.g., those with HIV infection)

Screening Intervals

• “Most adults need to be screened only once”
  • Consider more frequent screening for individuals with ongoing risk (e.g., ongoing injection drug use)
  • Data is limited to determine optimal screening interval for those at continued risk or whether pregnancy impacts need for additional screening

KEY POINTS:

Hepatitis C Overview

• Acute Hepatitis C occurs within the first 6 months after exposure to HCV
• Many individuals will remain asymptomatic
• 15% of patients will spontaneously clear the virus within 6 months
• Signs and symptoms of acute HCV infection
  • Fever | Fatigue | Dark urine | Clay-colored stool | Abdominal pain | Loss of appetite | Nausea and vomiting | Joint pain | Jaundice
  • Most individuals with newly acquired HCV infection will be asymptomatic | 20 to 30% will exhibit symptoms
  • Symptoms will usually appear within 2 to 12 weeks (range: 2–26 weeks) 
• Signs and of chronic HCV infection
  • Most people are asymptomatic or have non-specific symptoms (e.g., chronic fatigue and depression)
  • Many eventually develop chronic liver disease, which can range from mild to severe, including cirrhosis and liver cancer
  • Chronic HCV infection is typically not recognized until asymptomatic people are identified as HCV-positive when screened for blood donation or liver function tests return an abnormal result (e.g., elevated ALT), often during routine evaluation 

Hepatitis C Treatment

Acute

• The same regimens recommended for chronic HCV infections are recommended for acute infection

Chronic

• Current antiviral therapies can result in sustained virologic response (SVR; absence of detectable virus 12 weeks after completion of treatment)
  • SVR is indicative of a cure of HCV infection
  • Over 90% of HCV infected persons can be cured of HCV infection regardless of HCV genotype with 8-12 weeks of oral therapy
  • CDC provides a link to currently approved FDA therapies to treat hepatitis C (see ‘Learn More – Primary Sources’ below)

Other considerations

• Advise abstinence from alcohol and acetaminophen during acute infection                
• Evaluate for hepatitis B and HIV infection
• Vaccinate against Hepatitis A and Hepatitis B
• Evaluation for advanced hepatic fibrosis with
  • Elastography or liver imaging (US or CT Scan)
  • FIB-4 Score (see ‘Learn More – Primary Sources’ below for calculator)
  • Lab tests: ALT | AST | Albumin | Bilirubin | INR | CBC
• Provide education on how to prevent HCV transmission to others

Other Professional Recommendations

• AASLD/IDSA
  • One-time, routine, opt out HCV testing is recommended for all individuals aged 18 years and older
  • One-time HCV testing should be performed for all persons less than 18 years old with behaviors, exposures, or conditions or circumstances associated with an increased risk of HCV infection
  • Periodic repeat HCV testing should be offered to all persons with behaviors, exposures, or conditions or circumstances associated with an increased risk of HCV exposure
  • Annual HCV testing is recommended for all persons who inject drugs and for HIV-infected men who have unprotected sex with men
  • As part of prenatal care, all pregnant women should be tested for HCV infection, ideally at the initial visit
• CDC
  • All adults 18 years and older (except in settings where the prevalence is <0.1%)
  • All pregnant persons should be screened for HCV during each pregnancy (except in settings where the prevalence of HCV infection is < 0.1%)
  • All persons with risk factors (eg., persons with HIV, prior recipients of blood transfusions, persons who ever injected drugs and shared needles, and persons who are born to an HCV-infected mother) should be tested for HCV, with periodic testing while risk factors persist

Learn More – Primary Sources:

Screening for Hepatitis C Virus Infection in Adolescents and Adults – US Preventive Services Task Force Recommendation Statement

AASLD / IDSA: HCV Testing and Linkage to Care

CDC Recommendations for Hepatitis C Screening Among Adults — United States, 2020

CDC link to FDA therapies to treat hepatitis C

Hepatitis C Questions and Answers for Health Professionals

Reported Prevalence of Maternal Hepatitis C Virus Infection in the United States

SMFM Consult Series #56: Hepatitis C in pregnancy—updated guidelines

Fibrosis-4 (FIB-4) Calculator – Clinical Calculators – Hepatitis C Online (uw.edu)

Gestational Diabetes Mellitus: Screening and Management

SUMMARY:

Gestational diabetes mellitus (GDM) has become increasingly prevalent worldwide.  Class A1GDM refers to diet-controlled GDM. Class A2GDM refers to the clinical scenario where medications are required. The following synopsis highlights key practice points from various professional organizations. 

• Screening for GDM – One or Two Step?
• Who Should be Screened Early?
• Screening for Diabetes and Pre-Diabetes in The Postpartum Period
• What Are Glucose Target Levels?
• Diet and Exercise
• Pharmacologic Treatment
• Fetal Monitoring
• When to Deliver?

Screening for GDM – First or Second Trimester?

• ACOG supports the ‘2 step’ approach (24 to 28 week 1 hour venous glucose measurement following 50g oral glucose solution), followed by a 100g 3 hour oral glucose tolerance test (OGTT) if positive
  • Note: Diagnosis of GDM is based on 2 abnormal values on the 3 hour OGTT
    • ACOG recommends that currently there is insufficient evidence to diagnose GDM based on only one abnormal value
    • Patients with only one elevated value may require additional surveillance
• ACOG does not recommend routine screening for GDM <24 weeks 
• The USPSTF
  • Recommends screening for gestational diabetes in asymptomatic pregnant persons at ≥24 weeks of gestation or after (B recommendation)
  • Current evidence is insufficient to assess the balance of benefits and harms of screening for gestational diabetes in asymptomatic pregnant persons <24 weeks of gestation (I statement)
• ACOG and ADA prefer use of Carpenter and  Coustan vs national Diabetes Data Group (NDDG) criteria because the higher NDDG thresholds may result in missed opportunities to treat patients would would benefit from GDM diagnosis
  • Fasting blood sugar: <95 mg/dL (5.3 mmol/L)
  • 1 hour blood sugar: <180 mg/dL (10.0 mmol/L)
  • 2 hour blood sugar: <155 mg/dL (8.6 mmol/L)
  • 3 hour blood sugar: <140 mg/dL (7.8 mmol/L) 

Who Should be Screened Early?

The ACOG update is based on ADA criteria | Consider early screening in pregnancy if patient is overweight with BMI of ≥25 kg/m3 (23 in Asian Americans), and one or more of the following

• Physical inactivity
• Family history of diabetes – 1st degree relative (parent or sibling)
• Black, Hispanic, Native American, Asian American, or Pacific Islander
• Previous pregnancy history of
  • GDM
  • Macrosomia (≥ 4000 g)
• Hypertension (140/90 mm Hg or being treated for hypertension) 
• HDL cholesterol ≤ 35 mg/dl (0.90 mmol/L)
• Fasting triglyceride ≥ 250 mg/dL (2.82 mmol/L)
• PCOS
• Conditions associated with insulin resistance (e.g., acanthosis nigricans, morbid obesity)
• Hgb A1C ≥ 5.7%, impaired glucose tolerance or impaired fasting glucose | If A1C>6.5%, diagnosis of pregestational diabetes is met and GCT/GTT not needed
• Cardiovascular disease
• HIV
• 35 years or older 
• Other factors suggestive of increased risk for pregestational diabetes

Note: The ADA (2025) uses 130/80 as the BP threshold for hypertension diagnosis 

(more…)

COVID-19 Testing: CDC Guidance on Virus and Antibody Testing

• Summary
  • Specimen Collection
  • How is SARS-CoV-2 RNA Testing Performed?
  • Diagnostic Testing
  • Screening Testing
  • How Early Will a Test Be Positive?
  • Performance of RT-PCR Viral Tests
• Antibody Testing
  • General CDC Antibody Guidance
  • What Are the Different Types of Antibody Tests?
  • When Can Antibody Testing be Helpful?
  • Vaccination and Test Interpretation
• Learn More – Primary Sources

NOTE: Information and guidelines may change rapidly. Check in with listed references in ‘Learn More – Primary Sources’ to best keep up to date.

SUMMARY:

The CDC has provided guidance on both viral testing for SARS-CoV-2 as well as the role of antibody testing. Testing for the presence of the virus during the pandemic remains the current diagnostic standard. While antibody testing can play a role for public health teams to understand the spread of the disease, currently its use as a diagnostic test for individuals remains limited. A COVID-19 vaccine will not affect the results of SARS-CoV-2 viral tests.

Viral Testing

Specimen Collection

• Obtain an upper respiratory specimen for initial diagnostic testing
  • A nasopharyngeal (NP) specimen collected by a healthcare professional  or
  • An oropharyngeal (OP) specimen collected by a healthcare professional  or
  • A nasal mid-turbinate swab collected by a healthcare professional or by a supervised onsite self-collection (using a flocked tapered swab)  or
  • An anterior nares (nasal swab) specimen collected by a healthcare professional or by onsite or home self-collection (using a flocked or spun polyester swab)  or
  • Nasopharyngeal wash/aspirate or nasal wash/aspirate (NW) specimen collected by a healthcare professional
• Lower respiratory tract specimens
  • Collect and test sputum in patients who develop a productive cough | Induction of sputum is not recommended
  • Under certain clinical circumstances (e.g., those receiving invasive mechanical ventilation), a lower respiratory tract aspirate or bronchoalveolar lavage sample should be collected and tested as a lower respiratory tract specimen

How is SARS-CoV-2 RNA Testing Performed?

RT-PCR

• Usually performed using real-time reverse transcription polymerase chain reaction (RT-PCR)
  • Qualitative detection of RNA
• Multiple tests on the market that can target various genes
  • Envelope (env) | Nucleocapsid (N) | Spike (S) | RNA-dependent RNA polymerase (RdRp) | ORF1
• A positive test can only determine presence of SARS-CoV-2 RNA and not whether the virus is intact and capable of infecting others

Antigen

• Antigen tests can quickly detect fragments of proteins found on or within the virus by testing samples collected from the nasal cavity using swabs
• The benefit of antigen testing is speed, with results potentially available within minutes
• However, antigen tests, while very specific for the virus, are not as sensitive as molecular PCR tests
  • Positive antigen results: Highly accurate but higher chance of false negatives | Negative antigen results may still need PCR confirmation prior to treatment decisions or to prevent inadvertent spread of SARS-CoV-2

Note: Prior receipt of a COVID-19 vaccine should not affect the results of SARS-CoV-2 viral tests (NAAT or antigen)

Breath Sample Analysis

• FDA has issued an emergency use authorization (EUA) for a diagnostic test that detects chemical compounds in breath samples associated with a SARS-CoV-2 infection
• Test is performed by a qualified, trained operator under the supervision of a health care provider licensed or authorized by state law to prescribe tests
• Results available in <3 minutes

Diagnostic Testing

Signs or Symptoms of COVID-19

• Positive test
  • NAAT: Indicates infection regardless of vaccine status
  • Positive antigen test result may need confirmatory testing if the person has a low likelihood of SARS-CoV-2 infection (e.g., no known exposure to a person with COVID-19 within the last 14 days or is fully vaccinated or has had a SARS-CoV-2 infection in the last 3 months)
  • Isolate if positive test: Discontinue isolation 5 days after symptom onset and at least 24 hours after the resolution of any fever (without the use of fever-reducing medications) | Continue to wear mask around others for 5 additional days
    • Some individuals may require extended isolation and precautions (e.g., severely immunocompromised)
    • Testing is not recommended to determine when infection has resolved
    • Loss of taste and smell may persist for weeks or months after recovery and need not delay the end of isolation​
• Negative test
  • If symptoms are consistent with COVID-19, may be a false negative | Isolation and further discussion with healthcare professional recommended

Testing to determine resolution of infection

• May be appropriate for severe illness or immunocompromise
• “For all others, a test-based strategy is no longer recommended except to discontinue isolation or precautions earlier than would occur under the symptom-based strategy”

Screening Testing

No Symptoms and No Close Contact with Someone Known to Have a COVID-19 Infection

• Asymptomatic or presymptomatic infection contribute to community SARS-CoV-2 transmission
  • May help with re-opening of businesses, communities, and schools
• Point-of-care tests (e.g., antigen tests) can be particularly helpful due to short turn-around times
• Quarantine not required while results are pending
• Examples of screening programs
  • Testing employees in a workplace setting
  • Testing students, faculty, and staff in a school or university setting
  • Testing a person before or after travel

How Early Will a Test Be Positive and How Long Until Negative?

• In patient with COVID-19 infection who tested positive using a nasopharyngeal swab
  • Earliest detection: Day 1 of symptoms
  • Peak levels highest within week 1 and therefore probability of detection will be highest during that time
  • Viral load declines by week 3 and therefore virus more likely to be undetectable in to week 4
  • Infection severity: More virus may be present in patients with severe disease and therefore it may take longer to obtain a negative test result vs someone with a mild COVID-19 infection

Performance of RT-PCR Viral Tests

• RT-PCR specificities are close to 100% because they target specific RNA sequences of the SARS-CoV-2 virus
• False negative results may be due to
  • Inappropriate timing of collection vs symptom onset
  • Poor sampling technique (need to sample at the back of the nose)
• False positive results may occur due to lab error or contamination
• However, even with good analytic performance, PPV and NPV are related to prevalence and therefore can differ between geographic regions
  • In a setting with high COVID-19 prevalence, a negative test does not necessarily rule out the possibility that an individual is infected with SARS-CoV-2

Antibody Testing

General CDC Antibody Guidance

• According to the CDC

Antibody testing does not replace virologic testing and should not be used to establish the presence or absence of acute SARS-CoV-2 infection

Antibody testing is not currently recommended to assess for immunity to SARS-CoV-2 following COVID-19 vaccination, to assess the need for vaccination in an unvaccinated person, or to determine the need to quarantine after a close contact with someone who has COVID-19

Some antibody tests will not detect the antibodies generated by COVID-19 vaccines

Because these vaccines induce antibodies to specific viral protein targets, post-vaccination antibody test results will be negative in persons without history of previous infection, if the test used does not detect antibodies induced by the vaccine

• In general, antibodies will be detectable 7 to 14 days after illness onset and will be present in most people by 3 weeks
  • Infectiousness likely decreased by that time
  • Evidence suggests some degree of immunity will have developed
• IgM and IgG can appear together, usually within 1 to 3 weeks
  • IgG antibodies appear to persist for at least several months
  • Some individuals may be infected but will not develop antibodies
• Neutralizing antibodies can also be identified and are associated with immunity
• FDA requires companies providing antibody testing to obtain an EUA

What Are the Different Types of Antibody Tests?

• Antigenic Targets
  • Spike glycoprotein (S): Present on viral surface and facilitates virus entry
  • Nucleocapsid phosphoprotein (N): Immunodominant and interacts with RNA
  • Protein targeting is important to reduce cross-reactivity (cause of false positives which may occur with other coronaviruses like the common cold) and improve specificity
• Types of Antibody Testing
  • Binding antibody detection that use purified SARS-CoV-2 (not live virus)
    • Point-of-care (POC) tests
    • Laboratory tests that usually require skilled personnel and specialized equipment
  • Neutralizing antibody detection (none currently FDA authorized)
    • Serum or plasma is incubated with live virus followed by infection and incubation of cells
    • Can take up to 5 days to complete the study

When Can Antibody Testing be Helpful?

Antibody testing may be helpful in the following situations

• Seroconversion: In a patient who did not receive a positive viral test
  • A positive antibody test at least 7 days following acute illness onset but a previous negative antibody test may indicate new onset SARS-CoV-2 infection
• To support a diagnosis in the presence of a complex clinical situation, such as patients who present with COVID-19 complications (e.g., multisystem inflammatory syndrome and other post-acute sequelae of COVID-19)
  • Note: Due to antibody persistence, a single positive antibody test result may reflect previous SARS-CoV-2 infection and not a recent illness
• Clinical, occupational health, and public health purposes, such as serologic surveys

Vaccination and Test Interpretation

• In a person never vaccinated
  • testing positive for antibody against either N, S, or RBD indicates prior natural infection
• In a vaccinated person
  • Testing positive for antibody against the vaccine antigen target, such as the S protein, and negative for other antigen: Suggests vaccine-induced antibody and not SARS-CoV-2 infection
  • Testing positive for any antibody other than the vaccine-induced antibody, such as the N protein: Indicates resolving or resolved SARS-CoV-2 infection that could have occurred before or after vaccination
• The CDC states that

SARS-CoV-2 antibodies, particularly IgG antibodies, might persist for months and possibly years

Therefore, when antibody tests are used to support diagnosis of recent COVID-19, a single positive antibody test result could reflect previous SARS-CoV-2 infection or vaccination rather than the most recent illness

Learn More – Primary Sources:

CDC: Interim Guidelines for Collecting, Handling, and Testing Clinical Specimens from Persons for Coronavirus Disease 2019 (COVID-19)

Interim Guidelines for COVID-19 Antibody Testing in Clinical and Public Health Settings

CDC: Overview of Testing for SARS-CoV-2

Interpreting SARS-CoV-2 Test Results

The Promise and Peril of Antibody Testing for COVID-19

EUA Authorized Serology Test Performance