ACOG Addresses Use of Oxygen for Fetal Indications During Labor

SUMMARY:

ACOG has released a Practice Advisory regarding the use of oxygen supplementation in the setting of category II or III fetal heart tracings. The Advisory supplements the Practice Bulletin regarding intrapartum fetal heart rate monitoring and recommends against supplemental oxygen. The Advisory is based on recent literature, and focuses on a key paper by Raghuraman et al.

Maternal Oxygen Supplementation Compared With Room Air for Intrauterine Resuscitation (JAMA Pediatrics, 2021)

Background

  • The research team assessed whether there was an association between umbilical artery (UA) gas measures and neonatal outcomes with peripartum maternal oxygen administration vs room air

Methods

  • Systematic review and meta-analysis 
  • Study inclusion criteria
    • RCTs
    • Studies that compared oxygen with room air at the time of scheduled cesarean delivery or labor
    • Participants were patients with singleton, nonanomalous pregnancies

Primary outcome

  • Umbilical artery (UA) pH

Secondary outcomes

  • UA pH <7.2 | UA PaO2 | UA base excess | Apgar scores (1 and 5 min) | NICU

Conclusion

  • Supplemental oxygen therapy at delivery was not associated with improvement in umbilical artery pH or other neonatal outcomes

KEY POINTS:

  • An associated editorial to the above study concludes

While maternal oxygen administration to the normally oxygenated mother in labor is likely as innocuous as it is useless, concern for the practice of evidence-based medicine would seem to suggest that recommendations for its use in 2 million to 3 million women annually may be inappropriate

  • The ACOG Practice Advisory states

Based on this body of research, routine use of oxygen supplementation in individuals with normal oxygen saturation is not recommended for fetal intrauterine resuscitation

Learn More – Primary Sources:

ACOG Practice Advisory: Oxygen Supplementation in the Setting of Category II or III Fetal Heart Tracings

ACOG Update: Thyroid Disease in Pregnancy

SUMMARY:

Thyroid disease, both thyrotoxicosis and hypothyroidism, are associated with adverse pregnancy outcomes and poor fetal development, including neurocognitive outcomes.  Given the importance of understanding physiology, changes during pregnancy, and management, ACOG has published recommendations to guide clinical decision-making. Universal TSH screening for thyroid disease in pregnancy is not recommended. Subclinical thyroid disease (abnormal TSH but normal free T4) does not require treatment. However, overt hyperthyroidism and hypothyroidism warrant further management

Physiologic Changes in Pregnancy

  • Maternal thyroid volume increases 10-30% in pregnancy, especially in 3rd trimester, as a result of increased blood volume and extracellular fluid
    • An enlarged thyroid gland in isolation is not an indication for screening for thyroid disease if no other clinically relevant history, symptoms, or signs are present
  • TSH (thyroid stimulating hormone, or ‘thyrotropin’)
    • Decreased in early pregnancy
      • β-hCG weakly stimulates TSH receptors causing increased T4 (thyroxine) levels | Estrogen stimulates higher levels of thyroid-binding globulin that transport thyroid hormone in the blood
      • American Thyroid Association recommends the following in the late first trimester if local reference ranges for TSH are unavailable: Reduce lower reference range by 0.4mU/L | Reduce upper reference range by 0.5mU/L
    • After first trimester: Use non-pregnant reference ranges as TSH increases due to increased production of placental deiodinase
  • Maternal transfer of T4 to fetus
    • Necessary for fetal brain development
    • 30% of umbilical cord T4 is maternally derived
  • Maternal iodine requirements
    • Pregnant women: 220 micrograms
    • Lactating women: 290 micrograms
    • Majority of women in US have sufficient intake

Workup of Thyroid Abnormalities (Clinically Indicated Testing)

  • Test TSH first
    • TSH high or low (abnormal): Reflex to free T4 (plus total T3 for hyperthyroidism)
    • Free T4 is normal: Thyroid disease is subclinical and does not warrant further workup
  • Anti-thyroid peroxidase antibodies
    • Testing for these anti-bodies (without history and normal thyroid tests) does not improve pregnancy outcomes, therefore is not recommended

Hyperthyroidism

Low TSH and Increased free T4

  • Universal screening not recommended | Diagnosis based on clinical symptoms | 95% will be due to Graves disease
  • Symptoms
    • Nervousness | Tremors | Heat intolerance | Sweating | Weight loss |Goiter | Insomnia | Hypertension | Tachycardia
    • Associated with Graves Disease
      • Graves ophthalmopathy: Upper eyelid retraction | Edema | Erythema of the periorbital tissues and conjunctivae | Proptosis (see ‘Learn More, Primary Sources’ for additional reference including pictures)
      • Dermopathy: For example pretibial myxedema
  • Potential outcomes if left untreated 
    • Iatrogenic preterm deliveries | LBW | Stillbirth
    • Fetal thyrotoxicosis
      • Caution: Not necessarily related maternal clinical thyroid status
      • Signs: Fetal hydrops | FGR | Fetal goiter | Persistent fetal tachycardia
      • MFM consultation recommended
  • Treatment: Follow free T4 and total T3 every 2 to 4 weeks until titrated to high normal range
    • First trimester
      • PTU: 100 to 600mg divided TID
    • After first trimester
      • PTU: 100 to 600mg divided TID or
      • Methimazole 5 to 30mg divided into BID
    • Adverse events
      • Do not use methimazole in first trimester due to association with birth defects including esophageal/choanal atresia and aplasia cutis
      • Due to (rare) association of PTU with hepatotoxicity, option to transition to methimazole or continue PTU after first trimester
      • Both PTU and methimazole have risk of leukopenia (10% patients) but does not require therapy termination
      • Agranulocytosis: Rare side effect | Remain alert for sore throat or fever which does require CBC and cessation of medication
    • Symptom control: Propranolol 10 to 40mg TID/QID

Note: Maternal antibodies found in Graves disease cross the placenta and are cleared slowly | Notify neonatology of maternal diagnosis as neonatal Graves disease may not present immediately following delivery

Hypothyroidism

High TSH, Low Free T4

  • Diagnosis based on history (personal or family), clinical symptoms or type 1 diabetes, other autoimmune disorders
  • Symptoms
    • Cold intolerance | Muscle cramps | Weight gain | Edema | Dry skin | Hair loss
    • Prolonged relaxation of deep tendon reflexes is a notable feature
  • Most common: Hashimoto thyroiditis
    • Anti-thyroid peroxidase antibodies destroy thyroid gland
  • Potential outcomes if left untreated 
    • Miscarrriage | Preeclampsia | Preterm birth | Abruptio placentae | Stillbirth | Abnormal neuropsychological development in offspring
  • Fetal hypothyroidism: Maternal antibodies rarely cross placenta (unlike Graves)
  • Treatment (follow TSH every 4 to 6 weeks and titrate to lower reference limit)
    • Levothyroxine: 1 to 2 micrograms/kg daily | Typically 100 micrograms daily
    • Avoid T3 compounds (fetal CNS development dependent on maternal T4)
    • Pre-pregnancy diagnosis: Medication requirement will likely increase 25%

KEY POINTS:

Hyperemesis Gravidarum And Hyperthyroidism

  • Hyperthyroidism presents in 3-11% of women in early pregnancy
    • TSH receptor stimulation due to high β-hCG levels | Considered to be physiologic
    • ‘Gestational transient hyperthyroidism’ also seen with multiple gestation and molar pregnancies
    • TSH may remain suppressed for weeks after free T4 returns to normal
  • Hyperemesis gravidarum: Measurements of thyroid function not recommended without other clinical indications for testing
    • Does not require treatment | Not associated with poor pregnancy outcomes

Thyroid Storm

  • Medical emergency due to hypermetabolic state
    • Elevated thyroid hormone levels can lead to heart failure
  • Clinical features
    • Fever | Tachycardia | Cardiac arrhythmia | CNS abnormalities
    • Cardiac myopathy leading to heart failure and pulmonary hypertension | More common in pregnancy | Reversible if treated
  • Other clinical associations
    •  Preeclampsia | Anemia |Sepsis
  • Treatment
    • PTU: 1,000mg loading PO then 200mg q6 hours
    • Iodine: Initiate 1 to 2 hours after PTU via sodium iodide (500-1,000mg IV q8h) or potassium iodide (5 drops by mouth q8 hours) or lugol solution (10 drops by mouth q8h) or lithium carbonate (iodine anaphylaxis history, 300mg PO q6h)
    • Dexamethasone:  2mg IV q6h x4 doses or hydrocortisone 100mg IV q8h x3 doses
  • Propranolol, labetalol, and esmolol
    • Have been used to treat tachycardia, but caution warranted in setting of heart failure

Postpartum Thyroiditis 

  • Thyroid dysfunction within 12 months of delivery
    • Diagnosis: New-onset abnormal TSH and free T4
  • First phase
    • Initially thyrotoxicosis as thyroid gland is destroyed and T4 released
    • Mild symptoms controlled with beta-blockers rather than PTU or methimazole
  • Second phase (4 to 8 months postpartum)
    • Overt hypothyroidism with typical symptoms and thyromegaly
  • Depression
    • Order TSH screen for new onset postpartum depression or any new diagnosis of depression
  • Risk of permanent overt hypothyroidism
    • Majority of cases will spontaneously resolve
    • Approximately a third will not resolve (highest risk associated with higher antibody titers)

Thyroid Nodules Detected During Pregnancy

  • Prevalence: 1-2% | 90-95% of solitary nodules are benign
  • Aside from history and physical examination, order
    • TSH
    • Neck ultrasound
  • Radioiodine scanning not recommended due to theoretical risk with fetal irradiation
    • However, if patient inadvertently receives radioiodine in the first trimester, risk of fetal thyroid damage low because fetal thyroid is not active until after the first trimester
  • If cancer identified
    • Surgical treatment in first and second trimesters with thyroidectomy “may be performed” but usually delayed to avoid possible damage to parathyroid glands
    • Management is multidisciplinary and should include possibility of familial cancer syndrome (uncommon)

Learn More – Primary Sources:

ACOG Practice Bulletin 233: Thyroid Disease in Pregnancy

Graves’ Ophthalmopathy (NEJM)

The Measles Outbreak: CDC Recommendations and ACOG Practice Advisory

SUMMARY:

  • Measles (Rubeola)
    • Caused by an RNA virus with 1 serotype
    • Humans are the only natural hosts of measles virus
    • Average of 10 to 12 days from exposure to the appearance of the first symptom (usually fever)
    • Healthcare providers should report suspected measles cases to their local health department within 24 hours
  • Groups at high risk for severe illness include
    • Infants and children aged <5 years
    • Adults aged >20 years
    • Pregnant women
    • People with compromised immune systems, such as from leukemia and HIV infection

KEY POINTS:

Clinical Features

  • Typical presenting features
    • Prodrome of fever (as high as 105°F) and malaise
    • The 3 ‘C’s: Cough | Coryza (runny nose) Conjunctivitis
  • 2 to 3 days: Pathognomonic enanthema: Koplik spots within 2 to 3 days
    • white spots with red areola on buccal mucosa across from lower molars
Koplik Spots on Buccal Mucosa: Credit CDC
  • 3 to 5 days: Maculopapular rash
    • Appears 14 days after a person is exposed
    • Spreads from the head to the trunk to the lower extremities
    • Patients contagious from 4 days before to 4 days after the rash appears
    • Note: Immunocompromised patients may not develop rash
Measles Rash on Back: Credit CDC

Measles Transmission

  • Individuals are contagious from 4 days before to 4 days after the rash appears
  • Considered an ‘highly contagious virus’ according to CDC
    • “…if one person has it, up to 90% of the people close to that person who are not immune will also become infected”
  • Virus lives in nose and throat mucus of an infected person
  • Spread via
    • Breathing contaminated air: Virus can live in an airspace where the infected person coughed or sneezed for up to 2 hours
    • Touching infected surface: Followed by touching eyes, nose or mouth

Complications

  • Common complications include
    • Bronchopneumonia | Laryngotracheobronchitis | Diarrhea
    • Otitis Media: 1/10 children and may result in permanent hearing loss
  • Severe complications in children requiring hospitalization
    • Acute encephalitis: 1/1,000 children, resulting in permanent brain damage
    • Respiratory and neurologic: 1/1,000 children will die from these complications
    • Subacute sclerosing panencephalitis (SSPE): Rare, fatal degenerative disease of CNS, resulting in deterioration and seizures 7 to 10 years after measles infection

Diagnosis and Testing

  • Clinical suspicion
    • Signs and symptoms detailed above
    • Special concern for those traveling internationally or exposed to someone with a febrile rash illness
  • Laboratory confirmation
    • Essential for all sporadic measles cases and all outbreaks
    • A capture IgM EIA (non-quantitative) that incorporates a recombinant measles nucleocapsid protein as the antigen is used to detect measles IgM
    • A commercial, indirect EIA (non-quantitative) assay is used to detect IgG
    • Viral detection methods: Includes real time RT-PCR to detect measles viral RNA (available at many state public health laboratories and though the APHL/CDC Vaccine Preventable Disease Reference Centers)
    • Detection of measles-specific IgM antibody in serum and measles RNA by RT-PCR in a respiratory specimen are the most common methods for confirming measles infection
    • Obtain both a serum sample and a throat swab (or nasopharyngeal swab) from patients suspected to have measles at first contact
    • Urine samples may also contain virus: If possible collect both respiratory and urine samples
    • Public Health: Molecular analysis (genotyping) can map transmission pathways of measles viruses

Evidence of Immunity

Note: Do not accept verbal reports of immunity

Acceptable presumptive evidence of immunity against measles includes ≥1 of the following

  • Written documentation of adequate vaccination
  • Laboratory evidence of immunity *
  • Laboratory confirmation of measles
  • Birth before 1957

*Note: CDC addresses laboratory evidence of immunity and states the following

*People who have negative or equivocal results for measles IgG should be vaccinated or revaccinated. In some cases it is not possible to vaccinate a patient, and you may need to test them with a second line diagnostic assay to determine whether they are immune to measles. Because the sensitivity and specificity of commercial measles IgG assays vary, state public health departments can provide information on appropriate second line assays.

NOTE FOR HEALTHCARE PERSONNEL (HCP): CDC has interim guidance that states

Consider vaccinating HCP born before 1957 who do not have other evidence of immunity to measles

During a measles outbreak, 2 doses of measles virus-containing vaccine are recommended for all HCP, regardless of year of birth

See more HCP interim guidance using the CDC link below in ‘Learn More – Primary Sources’

Measles Vaccine Recommendations (CDC)

  • Children – MMR vaccine
    • First dose: 12 through 15 months of age
    • Second dose: 4 through 6 years of age no earlier than 28 days following the first dose
  • Students at post-high school educational institutions without evidence of measles immunity
    • 2 doses of MMR vaccine
    • Second dose administered no earlier than 28 days after the first dose
  • Adults born ≥1957 who do not have evidence of measles immunity
    • Should get at least one dose of MMR vaccine
  • International travelers ≥6 months of age
    • Infants 6 through 11 months: one dose of MMR vaccine
      • One dose at 12 through 15 months of age and another dose at 4 through 6 years of age or at least 28 days later
      • Infants who get one dose of MMR vaccine before their first birthday should get two more doses according to the routinely recommended schedule
    • Children ≥12 months: Documentation of two doses of MMR vaccine (the first dose of MMR vaccine should be administered at age 12 months or older; the second dose no earlier than 28 days after the first dose)
    • Teenagers and adults born ≥1957 (no immunity): Documentation of two doses of MMR vaccine, with the second dose administered no earlier than 28 days after the first dose

Post-exposure Prophylaxis

Cannot Readily Show Evidence of Immunity Following Exposure to Measles

  • Offer post-exposure prophylaxis (PEP) or be excluded from the setting (school, hospital, childcare)
  • Unvaccinated individuals who receive their first dose of MMR vaccine within 72 hours after exposure may return to childcare, school, or work except healthcare workers
  • PEP: Administer MMR vaccine within 72 hours of initial measles exposure or immunoglobulin (IG) within six days of exposure
  • Monitor for signs and symptoms consistent with measles for at least one incubation period following PEP
  • Note: “Do not administer MMR vaccine and IG simultaneously, as this practice invalidates the vaccine”

MMR vaccine for PEP

  • Should still offer MMR vaccine even if beyond 72 hours to protect from future exposures
  • Outbreak control measure for infants <12 months of age: Measles vaccination of infants as young as 6 months of age may be used (revaccinate when they are 12 through 15 months old and again when they are 4 through 6 years of age)

Immunoglobulin (IG) for PEP

  • IG dosing
    • IGIM dose: 0.5 mL/kg of body weight (maximum dose = 15 mL)
    • IGIV dose: 400 mg/kg
  • IG used for high risk populations
    • Infants younger <12 months
      • Intramuscular IG (IGIM) for all
      • However, if 6 through 11 months, MMR vaccine can be given in place of IG, if administered within 72 hours of exposure
    • Pregnant women without evidence of measles immunity
      • Intravenous IG (IGIV)
    • Severely compromised immune systems
      • Administer IGIV regardless of immunologic or vaccination status
    • Note: People cannot return to healthcare settings following receipt of IG | For other settings, such as childcare, school, or work “factors such as immune status, intense or prolonged contact, and presence of populations at risk, should be taken into consideration before allowing people to return”
  • PEP for healthcare personnel
    • MMR vaccine should be given within 72 hours or IG should be given within 6 days
    • “Exclude healthcare personnel without evidence of immunity from duty from day 5 after first exposure to day 21 after last exposure, regardless of post-exposure vaccine”

Isolation

  • Isolate for four days after they develop a rash
  • Use airborne precautions in healthcare settings
    • All healthcare staff entering the room should use respiratory protection consistent with airborne infection control precautions (use of an N95 respirator or a respirator with similar effectiveness in preventing airborne transmission)
    • Use single-patient airborne infection isolation room (AIIR) for patient with measles
  • People without evidence of immunity who have been exempted from measles vaccination for medical, religious and now PEP within appropriate timeframe
    • Exclude from affected institutions in the outbreak area until 21 days after the onset of rash in the last case of measles

Treatment

  • There is no specific antiviral therapy for measles
  • Supportive care to address symptoms and complications
  • Severe measles in children: Administer Vitamin A (a substrate for preserving epithelial cell integrity and involved in immune modulation) immediately on diagnosis and repeated the next day with following dosing
    • <6 months: 50,000 IU
    • 6–11 months: 100,000 IU
    • ≥12 months: 200,000 IU

Measles and Pregnancy

  • ACOG has released a practice advisory on measles in pregnancy, and endorses the University of Washington Consensus document (see ‘Learn More – Primary Sources’)
    • Consensus document provides helpful infographics and algorithms
  • ACOG emphasizes that parents will start making decisions about vaccinating their children before or during pregnancy
    • Therefore, obstetric providers can have an impact on decision making by providing facts around importance of MMR
  • Pregnant women are considered a ‘high risk’ category due to increased risk for adverse maternal, fetal and newborn events
    • Maternal: Increased risk of hospitalization and severe respiratory complications including pneumonia
    • Fetal: Miscarriage | Stillbirth | LBW | Preterm birth

Prior to Pregnancy

  • Ensure vaccinations are up to date
  • Wait 4 weeks following MMR to conceive
    • Theoretical risk, not proven and should not be used as an indication for termination of pregnancy (if vaccine received inadvertently)

During Pregnancy

  • Documentation of immunity (see ‘Evidence of Immunity’ section above)
    • Low risk of exposure: Documentation of one dose is adequate
    • Hi risk of exposure: Two doses should be documented
    • Note: ObGyns should contact local heath department officials to confirm correct number of doses
  • If immunity not documented: Consider IgG serologic testing
    • False negatives are possible – ideally send negative result for confirmation to a specialized lab
    • Positive IgG result confirms immunity and no further testing is necessary (University of Washington Consensus Statement)
  • PEP in pregnancy: IGIV within 6 days of measles exposure if
    • Non-immune and exposed (including if serologic testing not readily available)

Postpartum

  • Give MMR postpartum if no evidence of immunity
    • Breastfeeding is safe and does not impact vaccine

Contraindications and Precautions to MMR Vaccine

Contraindication – Greatly Increases Chance of Serious Adverse Reaction

The following individuals should not receive MMR vaccine

  • History of severe allergic reaction (e.g., anaphylaxis) following previous dose or to a vaccine component
  • Known severe immunodeficiency
  • Pregnancy (see above re: theoretical risk)
  • History of anaphylactic reactions to neomycin

Precaution – Might increase the chance or severity of a serious adverse reaction or might compromise the ability of the vaccine to produce immunity

Precautions for MMR vaccine include the following

  • Moderate or severe acute illness with or without fever
  • Recent (within 11 months) receipt of antibody-containing blood product (timing depends on product)
  • History of thrombocytopenia or thrombocytopenic purpura
  • Need for tuberculin skin testing
  • Personal or family history of seizures

Learn More – Primary Sources:

ACOG: Practice Advisory: Management of Pregnant and Reproductive-Aged Women during a Measles Outbreak

CDC: Measles Cases and Outbreaks

CDC: Measles (Rubeola) for Healthcare Professionals  

CDC: About Measles

Measles & the MMR Vaccine: Recommendations Around Pregnancy, Including the Periconception and Postpartum Periods (University of Washington) 

CDC: Routine Measles, Mumps, and Rubella Vaccination

CDC: Interim Infection Prevention and Control Recommendations for Measles in Healthcare Settings

Chronic Hypertension in Pregnancy – Evaluation and Management

CLINICAL ACTIONS:

ACOG has released recommendations on chronic hypertension in pregnancy. Management of chronic hypertension in pregnancy depends on gestational age and symptoms. Initial assessment, including identification of end-organ damage and evaluation of medications will drive treatment and delivery planning.

Evaluation

  • Ideally preconception or the first prenatal visit is the optimal time to establish a diagnosis (primary vs. secondary hypertension) and assess for end-organ damage, based on a thorough history and physical

Laboratory tests

  • Complete blood count
  • Liver function tests
  • Serum electrolytes (esp. potassium)
  • Renal Function Tests
    • Serum creatinine
      • Mild renal impairment: Cr 0.9-1.4
      • Moderate renal impairment: Cr 1.4-2.4
      • Severe renal impairment: Cr 2.4-2.8
    • Blood urea nitrogen
    • Spot urine protein/creatinine to screen for proteinuria
      • <0.15 denotes patient spilling <300 mg for a 24-hour sample
      • If spot urine ratio elevated, do 24-hour urine
      • Note: 24-hour urine assessment not required if normal Cr and spot urine ratio <0.15
    • Order ECG if ≥1 of the following
      • Chronic hypertension present >4 years
      • Maternal age >30 years with long standing hypertension
      • History abnormal ECG
      • Additional risk factors (i.e. long-standing diabetes)

SYNOPSIS:

The benefits of treating mild to moderate chronic hypertension in pregnancy are not clear, thus a conversation with patients (i.e. shared decision-making) is warranted. Timing of delivery depends on severity of disease and gestational age. Women with chronic hypertension remain at risk for complications during the postpartum period so early follow-up is recommended.

KEY POINTS:

Medical Management

Choice of Antihypertensive

  • Most commonly used antihypertensives
    • Labetalol – ‘preferred’: 200 to 2,400 mg/d po (2 to 3 divided doses)
      • Initiate at 100 to 200 mg twice a day
      • Watch for potential bronchospasm
      • Avoid in women with asthma, heart disease, congestive heart failure, bradycardia and heart block
    • Nifedipine – ‘preferred’: 30 to 120 mg/d po (avoid sublingual)
      • Initiate at 30 to 60 mg daily (extended release)
      • Avoid in women with tachycardia
    • Methyldopa – ‘less favored’: 500 to 3,000 mg/d po (2 to 4 divided doses)
      • Initiate at 250 mg twice or 3 times/day
      • May not be as effective and limited by side-effects such as dizziness, depression or sedation
    • Second line therapy
      • HCTZ (considered a safe diuretic)
    • Other medications are available and may be used with MFM consultation
    • Note: The following medications are not recommended
      • Ace inhibitors | Angiotensin II receptor blockers | Renin inhibitors | Mineralocorticoid receptor antagonists | Atenolol (due to risk for FGR and LBW)

Threshold for Initiation of therapy  

  • Based on the CHAP Trial (see ‘Related ObG Entries’ below), ACOG and SMFM have revised guidance regarding initiation of therapy for women with mild chronic hypertension during pregnancy 
  • Start antihypertensive therapy at >140/90 

Patient on medications prior to pregnancy

  • In the absence of mitigating factors or side effects
    • Maintain on their medications
    • Do not discontinue and wait until blood pressures in the severe range to initiate therapy
    • Individualize decision whether to discontinue
  • Replace contraindicated medications and monitor therapy and BP targets accordingly

Target BP

  • ACOG
    • Notes that RCT (CHAP Trial) demonstrated benefit of using 140/90 as threshold but did not determine ideal target BP or if there is a BP at which growth restriction may be a concern
  • SMFM
    • “…recommends treatment with antihypertensive therapy for mild chronic hypertension in pregnancy to a goal BP <140/90 mm Hg”

Aspirin

  • Use aspirin for risk reduction (see ‘Related ObG Topics below)
    • Initiate daily low dose aspirin (81 mg) between 12 to 28 weeks gestation

Fetal Surveillance

  • Antepartum
    • Timing/interval of testing not well established
    • Assess fetal growth in the 3rd trimester
  • Intrapartum
    • Continuous fetal monitoring

Timing of Delivery

  • Chronic HTN and no medications
    • Delivery <38w0d not recommended
  • Chronic HTN well controlled on maintenance antihypertensive medication
    • Delivery <37w0d not recommended
  • Chronic HTN with superimposed preeclampsia without severe features
    • Expectant management with delivery at 37w0d
  • Chronic HTN with superimposed preeclampsia with severe features
    • Expectant management under certain circumstances until delivery at 34w0d (inpatient care only)
    • Initiation of antenatal steroids as per guidelines (see ‘Related ObG Topics below)
  • Note: When considering the latest time to deliver, ACOG states

…expectant management beyond 39 0/7 weeks of gestation should only be done after careful consideration of the risks and benefits and with appropriate surveillance

Postpartum

  • Early ambulatory visits (within 2 weeks) postpartum
    • Severe HTN or superimposed preeclampsia may develop for the first time in the postpartum period
  • Patient may return to prepregnancy regimen and managed appropriately, without fetal considerations
    • Note: Avoid methyldopa in postpartum period due to risk for depression
  • Careful medication titration to achieve BP no higher than 150/100 mm Hg
  • Analgesia
    • NSAIDs were not associated with BP elevation based on data from women with preeclampsia with severe features
  • Breastfeeding
    • Antihypertensives can be used in breastfeeding women
    • Propranolol and labetalol are preferred due to lower levels in breast milk compared to some other medications
    • ACE inhibitors can also be used safely unless high doses required
    • Calcium channel blockers are not associated with adverse outcomes
    • Note: Diuretics may reduce quantity of breast milk

Learn More – Primary Sources:

ACOG Practice Bulletin 203: Chronic Hypertension in Pregnancy

ACOG: Clinical Guidance for the Integration of the Findings of the Chronic Hypertension and Pregnancy (CHAP) Study

SMFM Statement: Antihypertensive therapy for mild chronic hypertension in pregnancy (The CHAP Trial)

ISUOG Recommendations for Preeclampsia Prevention: Combined Screening and the Role of Ultrasound

SUMMARY:

The ISUOG Clinical Standards Committee, based on the latest evidence, has released practice guidelines that provide recommendations regarding the role of ultrasound in screening for and follow-up of preeclampsia. Preventative strategies (such as low-dose aspirin) for preeclampsia are effective if started in the first trimester and should begin as soon as high-risk status is identified.  

Given the superiority of combined screening, the use of Doppler cut-offs as a standalone screening modality should be avoided if combined screening is available (GRADE OF RECOMMENDATION: B)

Note: Screening refers to identification of at risk cases that may lead to prevention | Prediction refers to ability to identify at risk cases, but no evidence available regarding improved outcomes  

Combined Screening
Ultrasound Only
Multifetal Pregnancies

KEY POINTS:

Combined Screening (10-13 weeks) – Preferred where available   

  • ASPRE trial results with a 10% FPR (see ASPRE summary in ‘Related ObG Topics’ below) 
    • 100% detection rate for preeclampsia <32 weeks 
    • 75% detection rate for preeclampsia <37 weeks 
    • 43% detection rate for preeclampsia ≥37 weeks 

Combined screening approach is preferred over ultrasound alone and includes the following (see summary of ASPRE algorithm details in ‘Related ObG Topics’ below)   

  • Maternal factors 
    • History | Demographics | CVD and metabolic profile  
  • Maternal arterial BP
  • Placental growth factor (PlGF) 
  • Pulsatility index (PI) should be used to assess uterine artery resistance  
    • Transabdominal approach preferred as used for most studies   
    • Transabdominal: Use color flow mapping on a mid-sagittal view of the uterus at the level of the cervical internal os (transabdominal approach)  
    • Transvaginal: Also obtain mid-sagittal view of the uterus, with lateral movement until paracervical vascular plexus is seen and uterine artery is also at the level of the internal cervical os  
    • Identify an ascending or descending branch of the uterine arteries 
      • Narrow Doppler sampling gate (2 mm) 
      • Insonation angle <30 degrees 
      • Peak systolic velocity of a uterine artery should be greater than 60 cm/s 
      • PI measurement obtained when 3 identical waveforms are captured  
    • 95th percentile uterine artery mean PI (11-13 weeks) 
      • Transabdominal: 2.35  
      • Transvaginal 3.10 for CRL up to 65 mm 
    • Uterine artery PI may be affected by  
      • Ethnicity: African origin has higher PI 
      • Obesity: Decreasing PI with increasing BMI 
      • History of preeclampsia: Increased PI 

Note: Placental volume and vascularization indices are not recommended | Combined screening in the second trimester compares favorably to first trimester, but aspirin intervention is ineffective if initiated >20 weeks

Ultrasound Screening Only  

First Trimester Ultrasound Screening (10-13 weeks) 

  • Due to maternal effects and lesser performance, uterine artery PI is not preferred as a stand-alone test based on cut-offs, but should preferably be incorporated into a combined, multifactorial screening model (see above) 
  • Uterine artery PI >90th percentile in the first trimester detects  
    • 47.8% of women who will develop early PE (7.9% FPR) 
    • 26.4% of women who will develop any PE (6.6% FPR) 
  • PI is superior to resistance index (RI) or uterine artery notching as a preeclampsia predictive tool 
    • PI is more stable than RI, and may still be used in cases of absent or reversed diastolic values 
    • Uterine artery notching is a subjective measure with low specificity
      • Associated with 22-fold increased risk for preeclampsia and 9-fold increased risk for an SGA neonate 
      • However, may be observed in up to 50% of patients at 11-13th weeks 

Second Trimester Ultrasound Screening  

  • Uterine artery PI may be performed at time of the second trimester scan (10% FPR) 
    • 85% detection of early-onset preeclampsia  
    • 48% detection of late-onset preeclampsia  
  • 95th percentile uterine artery mean PI (23 weeks) 
    • Transabdominal: 1.44  
    • Transvaginal: 1.58  

Third Trimester Ultrasound Screening  

  • Use of PI during this period is not recommended due to insufficient outcomes data

Multifetal Pregnancies 

  • Use twin-specific reference ranges  
    • Increased placental mass and lower mean uterine artery resistance seen in multiple gestation 
    • Combined screening approach 
      • >95% detection 
      • 75% screen positive rate

Learn More – Primary Sources:

ISUOG Practice Guidelines: role of ultrasound in screening for and follow up of pre-eclampsia

Fetal Alcohol Spectrum Disorders – CDC Summary and Updates

WHAT IS IT?

The current understanding of Fetal Alcohol Spectrum Disorder (FASD) is that there is no known safe amount of alcohol during pregnancy or when trying to get pregnant. All types of alcohol are equally harmful, including all wines and beer. Professional colleges recommend screening women in pregnancy. Fetal Alcohol Syndrome (FAS) is on the most severe end of the spectrum.

Fetal Alcohol Syndrome (FAS) – Diagnostic Criteria 

Abnormal facial features (see diagram below)

  • Smooth philtrum (ridge between nose and upper lip)   
  • Thin vermillion (upper lip)  
  • Small palpebral fissures (distance between inner and outer corners of the eyes) giving the eyes a wide-spaced appearance   

Growth problems (prenatal or postnatal) 

  • Height and/or weight ≤10th percentile 

CNS 

  •  Structural  
    • Head circumference ≤10th percentile  
    • Clinically significant brain abnormalities observable through imaging 
  • Neurological deficits unrelated to a postnatal insult or fever 
  • Functional Performance below expectations  
    • Global cognitive or intellectual deficits (Low IQ or developmental delay in younger children) or  
    • Problems in at least 3 of the following areas  
      • Cognitive or developmental deficits or discrepancies | Executive functioning deficits | Motor functioning delays | Attention deficit or hyperactivity | Social skills | Other problems such as sensory / language / memory  

Maternal Alcohol Exposure

  • Helpful if maternal alcohol use can be confirmed during pregnancy
  • Confirmation of maternal alcohol use is not needed if child meets the other, above criteria

Facial Features of FAS (Credit: NIAAA)


Alcohol-Related Neurodevelopmental Disorder (ARND) 

  • CNS, cognitive and behavioral effects without growth restriction and typical facial experience  
    • Intellectual disabilities | Behavior and Learning abnormalities  
    • Difficulties with math, memory, attention, judgment and impulse control 
    • Requires confirmation of prenatal alcohol exposure

Alcohol-Related Birth Defects (ARBD) 

  • Abnormal physical findings only (see more detail below in ‘Key Points’)  
    • Heart | Kidneys | Bones | Hearing  
    • Requires confirmation of prenatal alcohol exposure

Neurobehavioral Disorder Associated with Prenatal Alcohol Exposure (ND-PAE) 

  • ND-PAE was first included as a recognized condition in the Diagnostic and Statistical Manual 5 (DSM 5) of the American Psychiatric Association (APA) in 2013 
  • Problems identified  
    • Thinking and memory, where the child may have trouble planning or may forget material he or she has already learned 
    • Behavior problems, such as severe tantrums, mood issues (for example, irritability), and difficulty shifting attention from one task to another 
    • Trouble with day-to-day living, which can include problems with bathing, dressing for the weather, and playing with other children.  
  • Diagnosis requires  
    • >13 alcoholic drinks per month (30-day period) of pregnancy or 
    • > 2 alcoholic drinks in one sitting 

KEY POINTS:

  • Structural abnormalities associated with prenatal alcohol exposure include 
    • Facial abnormalities (described above plus short nose, cleft lip/palate)  
    • Cardiac anomalies (ASD, VSD, abnormal great vessels)  
    • Auditory (Chronic serous otitis media, conductive and/or neurosensory hearing loss) 
    • Renal anomalies (Aplastic/dysplastic/hypoplastic kidneys, horseshoe kidney, hydronephrosis, ureteral duplications) 
    • Microcephaly 
    • Meningomyelocele 
    • Hydrocephalus 
    • Short or webbed neck 
    • Vertebra and rib anomalies

Screening Tool  

T-ACE & TACER-3 (same questions with different cut-offs)

  • Tolerance: How many drinks does it take to make you feel high?  
    • Positive answer: ≥ 2 drinks  
      • One drink is the equivalent of 0.5 oz of absolute alcohol (approximately 12 oz of regular beer, 1.5 oz of liquor, or 4 oz of wine) 
    • Score: 2   
  • Annoyance:  Has anybody ever annoyed you by complaining about your drinking?  
    • Positive answer: Yes 
    • Score: 1  
  • Cut down:  Have you ever felt you ought to cut down on your drinking?  
    • Positive answer: Yes 
    • Score: 1  
  • Eye-opener:  Have you ever needed a drink first thing in the morning to get going? 
    • Positive answer: Yes  
    • Score: 1  

Note: T-ACE cut-off is 2; TACER-3 cut-off is 3, which results in fewer false positives

Learn More – Primary Sources:

CDC Fetal Alcohol Spectrum Disorders (FASD) – Basics

CDC: Fetal Alcohol Spectrum Disorders (FASD) – Training And Resources

Note: Includes guidelines and information for nurses, social workers, Family Medicine, ObGyns, Pediatricians and Medical Assistants

AAFP: Fetal Alcohol Syndrome and Fetal Alcohol Spectrum Disorders

ACOG: Fetal Alcohol Spectrum Disorders (FASD) Prevention Program 

Increased cut-point of the TACER-3 screen reduces false positives without losing sensitivity in predicting risk alcohol drinking in pregnancy 

ACOG Guidance Update: Diagnosis and Management of PROM (Prelabor Rupture of Membranes)

SUMMARY:  

ACOG guidance on Prelabor Rupture of Membranes (PROM) addresses current literature especially related to management of late preterm PROM (34w0d to 36w6d). Following appropriate counseling, expectant management or delivery is appropriate. The use of ‘prelabor’ is in keeping with reVITALize terminology (see ‘Related ObG Topics’ below) and is defined as the ‘spontaneous rupture of membranes that occurs before the onset of labor’.

Diagnosis

  • Most cases can be diagnosed based on history and physical examination 
  • Avoid digital examination due to infection risk, unless delivery appears to be immediate  
  • Speculum examination  
    • Visualization of amniotic fluid (AF) leaking through the cervix  
    • Vaginal pooling
    • Fern test of dried vaginal fluid seen under microscope
    • pH testing 
      • Normal: 3.8 to 4.5
      • AF: 7.1 to 7.3 
      • False positives: Blood or semen, alkaline antiseptics or BV  
      • False negatives: Minimal remaining AF following rupture 
  • If above inconclusive  
    • Ultrasound for AFV may be helpful but not diagnostic  
    • Fetal fibronectin is sensitive with high negative predictive value but positive result is not diagnostic
    • Amniotic protein tests have high sensitivity for PROM but false-positive rates may be as high as 19–30%
      • ACOG states that “These test kits should be considered ancillary to standard methods of diagnosis”

Note: In August 2018, the FDA sent a letter to health providers to be aware of rupture of membranes (ROM) test limitations, due to reports of adverse events. The FDA letter states that “health care providers may be over-relying on ROM test results when making critical patient management decisions, despite labeling instructions warning against this practice.” To promote awareness and aid in the proper use of the ROM test, the FDA letter states

The following limitations are typically stated in ROM device labeling

  • A negative result does not assure the absence of membrane rupture
  • False negatives may result if the amniotic sac has resealed or the position of the fetus has obstructed the rupture
  • The presence of blood, meconium, anti-fungal creams or suppositories, baby powder, baby oil, or the use of lubricant with a vaginal exam may interfere with the device
  • The test may not be accurate if sample collection and testing occurs after the timeframe recommended by the manufacturer
  • To help protect patients and reduce the chance of adverse events, ROM tests should be part of an overall clinical assessment, which may include physical examination of the patient and testing to detect leaking amniotic fluid
  • Conclusive test – dye instillation
    • Ultrasound guided dye with passage into the vagina and detected with tampon or pad stain  
    • Maternal urine may turn blue following instillation of indigo carmine
    • See ‘Related ObG Topics’ below for alternatives to indigo carmine  

PROM at < 24 Weeks

Clinical Considerations

  • Survival with PROM ≥ 22 weeks is significantly higher (57.7%) than <22 weeks (14.4%)
    • Survival rates are likely overestimated
    • Combination of birthweight, gestational age and sex will impact morbidity/mortality
      • Individualize risks
  • Maternal complications: infection | endometritis | abruption | retained placenta  
    • Maternal sepsis risk of 1%  
  • Latency  
    • 40-50% will deliver within 1 week and 70-80% will deliver within 2-5 weeks  
  • Pulmonary hypoplasia 
    • Will occur in approximately 10-20% of cases  
    • Insufficient data to recommend ultrasound for determination of lung volumes or function   
  • Oligohydramnios can result in Potter’s deformation sequence   
    • Low-set ears | recessed chin | prominent bilateral epicanthal folds  
    • Limb contractures 
    • Skeletal malformations   

Management 

  • Counsel regarding risks and benefits of expectant management vs immediate delivery  
    • Immediate delivery should be offered as an option
    • Consider MFM and neonatology consultation   
  • If patient chooses expectant management and no infection  
    • Outpatient surveillance is an option following inpatient assessment  
      • Give information to return to hospital immediately if signs or symptoms of bleeding, labor or infection (self-monitor temperature) 
      • Advise return to hospital at time of viability  
  • Corticosteroids and latency antibiotics: Data currently limited at <24 weeks  
    • Offering antibiotics as early as 20w0d is an option 
    • Consider offering a single course of corticosteroids as early as 23w0d of due to risk of delivery within 7 days   
    • Antenatal corticosteroids and latency antibiotics (see below for Preterm PROM) are recommended upon reaching viability
  • GBS prophylaxis not recommended prior to viability | May be considered as early as 23w0d 
  • Tocolysis is not recommended prior to viability | May be considered as early as 23w0d 
  • Neuroprotection (magnesium sulfate) is not recommended prior to viability | May be considered as early as 23w0d

Preterm PROM at 24w0d-33w6d

  • Expectant management is recommended and will usually include hospital admission with monitoring for
      • Infection | Hemorrhage (abruption) | Umbilical cord compression | Fetal assessment | Evidence of labor
    • If there are maternal and/or fetal contraindications to expectant management, delivery is recommended  
  • Antenatal (single course) corticosteroids are recommended | Insufficient evidence regarding rescue course  
  • Latency antibiotics are recommended
    • Eunice Kennedy Shriver NICHD MFMU Network trial regimen  
      • IV ampicillin [2 g every 6 hours] and erythromycin [250 mg every 6 hours] for 48 hours followed by oral amoxicillin [250 mg every 8 hours] and erythromycin base [333 mg every 8 hours] for an additional 5 days (7 days total) 
      • Azithromycin (e.g., 1 g single dose) “is a suitable alternative” to replace erythromycin if unavailable or poorly tolerated
    • Amoxicillin–clavulanic acid  
      • Not recommended due to increased risk for necrotizing enterocolitis 
    • Allergy to β-lactam antibiotics 
      • “May be reasonable to consider another agent against GBS” | Choice based on severity of allergic reaction and susceptibility profiling 
    • Unclear as to whether cerclage should be removed or retained but if retained, antibiotic therapy should not be extended beyond 7 days

Note: There are multiple regimens in use | There is no evidence to support a single optimal regimen for latency antibiotics    

  • Patients with PROM before 32w0d and imminent delivery are candidates for fetal neuroprotective treatment with magnesium sulfate (if no contraindications)
  • Obtain vaginal/rectal swab for GBS | Administer GBS prophylaxis as indicated
  • HSV infection and Preterm PROM
    • Risk of vertical transmission is 30-50% with primary HSV and 3% with recurrent HSV   
    • Recurrent active HSV  
      • Expectant management is recommended <34w0d
      • Initiate HSV therapy 
      • Corticosteroids | Antibiotics | Magnesium sulfate per indications
      • Cesarean section is indicated if active disease or prodromal symptoms are present at time of delivery   
    • Primary HSV
      • Management less clear due to high risk of vertical transmission  
      • HSV therapy is recommended  
      • Cesarean delivery recommended if active lesions are present  
  • HIV infection and Preterm PROM 
    • Optimal management is uncertain due to concern of vertical transmission with PROM 
    • Management should include a physician with expertise in the management of HIV in pregnancy and standard HIV guidelines should be followed   
    • Most recent data suggest that vertical transmission risk my not be increased if the patient is on highly active antiretroviral therapy with a low viral load and has received antepartum and intrapartum zidovudine 
    • Management should be individualized 
      • If gestational age is early, but patient is on appropriate therapy with a low viral load expectant management may be appropriate  

Late Preterm (34w0d to 36w6d)

  • “Either expectant management or immediate delivery is a reasonable option”
    • Data suggests when comparing these 2 options
      • No difference in neonatal sepsis
      • Newborn: Increased respiratory distress, mechanical ventilation, ICU stay in the immediate group
      • Maternal: Increased hemorrhage and infection in expectant management group
  • Administer single-course corticosteroids if
    • Not previously given
    • Delivery expected in >24 hours and ≤7 days
    • No chorioamnionitis
  • Screen for GBS and administer prophylaxis as indicated
  • Chorioamnionitis: Treat and plan for delivery
  • ACOG states (PB 831)

Care should be individualized through shred decision making, and expectant management should not extend beyond 37 0/7 weeks of gestation

Outside the scenario of unknown GBS status, latency antibiotics are not appropriate in this setting

Term (≥37w0d)

  • Induction is recommended vs expectant management | Short period of expectant management (12 to 24 hours) “may be appropriately offered”
    • If no spontaneous labor, induce labor with oxytocin 
      • Allow adequate time (12-18 hours) for latent phase to progress before performing a cesarean section for failed induction of labor  
    • Induction with prostaglandins equally as effective as oxytocin but may have higher rates of chorioamnionitis  
    • Insufficient data to recommend for or against cervical ripening with mechanical methods such as a Foley balloon 
    • Insufficient evidence to recommend antibiotic prophylaxis beyond GBS indications  
  • If a patient declines delivery and requests expectant management, counsel regarding risks and benefits 
    • If fetal and maternal status are reassuring, expectant management ‘may be acceptable’   
  • Screen for GBS and administer prophylaxis as indicated
  • Chorioamnionitis: Treat and plan for delivery

Key Points:

PROM-Related Risks 

  • Preterm birth 
    • 50% of patients will deliver within 1 week 
    • Risks associate with prematurity include RDS, sepsis, IVH and NEC  
  • Infection
    • Preterm PROM and intrauterine inflammation are associated with increased risk of neurologic injury   
    • Intraamniotic infection (15-25%) 
    • Postpartum infection (15-20%) 
  • Abruption (2-5%) 
  • Infection and umbilical cord accidents are associated with a 1 to 2% chance for fetal demise  

Additional Clinical Considerations

  • Membranes may reseal spontaneously leading to good outcomes   
  • Hospital admission is recommended if the fetus is viable to monitor for signs of infection, abruption and fetal compromise   
    • Acceptable strategy includes periodic ultrasound for fetal growth and FH monitoring (precise timing not established) 
    • No clinical utility evidence for the use of serial WBC counts or other infectious markers  
  • Use of tocolysis  
    • Tocolytic therapy is not recommended at 34w0d to 36w7d gestation
    • Can be considered for steroid benefit at earlier gestational age and during maternal transport
  • GBS as per standard protocol 
    • GBS prophylaxis should be given based on prior culture results or intrapartum risk factors if cultures not performed or unavailable 

PROM Following Amniocentesis 

  • Risk of PROM following amniocentesis is 1%   
  • Outpatient, expectant management  
  • Monitor regularly with ultrasound and counsel patients to watch for signs of infection, bleeding and/or miscarriage  
  • Contrary to spontaneous PROM, good outcomes have been reported   
    • AF fluid reaccumulated within 1 month in 72% of patients 
    • Perinatal survival rate was 91%  

Preterm PROM and Future Pregnancies  

  • Increased risk of recurrent PROM and preterm birth  
  • Offer progesterone supplementation starting at 16-24 weeks 
  • Consider cervical length screening  
  • Consider cerclage for women with the following  
    • Current singleton pregnancy 
    • Prior spontaneous preterm birth < 34 weeks  
    • Cervical length < 25 mm prior to 24 weeks  

Learn More – Primary Sources:  

ACOG Practice Bulletin 217: Prelabor Rupture of Membranes

ACOG Practice Bulletin 831: Medically Indicated Late-Preterm and Early-Term Deliveries

FDA: Risks Associated with Use of Rupture of Membranes Tests – Letter to Health Care Providers

FDA News Release: FDA alerts healthcare providers, women about risks associated with improper use of rupture of membranes tests

Potter’s Sequence

New CDC Interim Guidance on Infants with Possible Zika & Perinatal Review (Oct 2017)

SUMMARY:

On October 20th, the CDC released interim guidance for the diagnosis and management of infants with possible congenital Zika infection.  According to the guidance document,

All infants born to mothers with possible Zika virus exposure during pregnancy should receive a standard evaluation at birth and at each subsequent well-child visit including a comprehensive physical examination, age-appropriate vision screening and developmental monitoring and screening using validated tools and newborn hearing screen at birth, preferably using auditory brainstem response (ABR) methodology.

Jump to:

Definitions

  • Possible Zika virus exposure
    • Includes travel to, or residence in an area with mosquito borne Zika virus transmission OR
    • Sex without the use of condoms with a partner who has traveled to or resides in an area with mosquito borne Zika virus transmission 
  • Laboratory evidence of possible Zika virus infection during pregnancy: Defined as  
    • NAT: Zika virus infection detected by a Zika virus NAT on any maternal, placental, or fetal specimen (referred to as NAT-confirmed OR 
    • Serology: Positive/equivocal Zika virus IgM and Zika virus plaque reduction neutralization test (PRNT) titer ≥10, regardless of dengue virus PRNT value or negative Zika virus IgM, and positive or equivocal dengue virus IgM, and Zika virus PRNT titer ≥10, regardless of dengue virus PRNT titer 
    • Note: The use of PRNT for confirmation of Zika virus infection, including in pregnant women, is not routinely recommended in Puerto Rico
  • Assessment of visual acuity: Responses to teller or grating tests (if possible), pupillary response, external examination, anterior segment examination, intraocular pressure measurement if indicated, and dilated fundus examination 
    • After 3–4 months of age, also assess ocular motility, cycloplegia refraction and accommodation by dynamic retinoscopy 
    • If physical abnormalities are present, recommend photo documentation if resources are available

Updated Guidance for Testing of Pregnant Women with Possible Zika Virus Exposure  

  • Zika virus NAT testing should be offered as part of routine obstetric care to asymptomatic pregnant women with ongoing possible Zika virus exposure (residing in or frequently traveling to an area with risk for Zika virus transmission) 
  • Serologic testing is no longer routinely recommended because of the limitations of IgM tests  
  • Zika virus testing is not routinely recommended for asymptomatic pregnant women who have possible recent, but not ongoing, Zika virus exposure (however, guidance might vary among jurisdictions)  
  • Communication regarding possible maternal exposures between pediatric health care providers and obstetric care providers is critical 
  • For families of infants with possible congenital Zika virus infection health care providers should  
    • Ensure that psychosocial support is in place and that families have access to care 
    • Communicate that the long-term prognosis for infants with congenital Zika virus infection is not yet known 
    • Address families’ concerns, facilitate early identification of abnormal findings, and refer infants for neurodevelopmental follow-up and therapy when indicated

Special Considerations for the Prenatal Diagnosis of Congenital Zika Virus Infection

Ultrasound

  • Routine screening for fetal abnormalities is a component of prenatal care in the United States 
    • Comprehensive ultrasound examination to evaluate fetal anatomy is recommended for all women at 18–22 weeks’ gestation
    • If maternal testing does not suggest infection, patients should receive the same ultrasound screening as any other pregnant woman as part of standard routine prenatal care 
  • Prenatal ultrasound findings associated with congenital Zika virus infection include  
    • Intracranial calcifications at the gray-white matter junction 
    • Ventriculomegaly 
    • Abnormalities of the corpus callosum 
    • Microcephaly 
    • Limb anomalies  
  • Sensitivity, specificity, NPV and PPV of ultrasound findings for Zika virus unknown at this time  
  • Abnormalities have been detected anywhere from 2 to 29 weeks after symptom onset  
  • Brain abnormalities associated with congenital Zika syndrome have been identified by ultrasound in the second and third trimesters in published case reports  
  • Serial Ultrasound Monitoring  
    • CDC previously recommended serial ultrasounds every 3–4 weeks for women exposed during pregnancy with laboratory evidence of Zika virus infection 
    • No data specific to congenital Zika virus infection to guide these timing recommendations  
      • Clinicians may consider extending the time interval between ultrasounds in accordance with patient preferences and clinical judgment  
    • Women with possible exposure but without laboratory evidence of Zika virus infection during pregnancy should receive ultrasound screening as recommended for routine prenatal care 

Amniocentesis

  • The role of amniocentesis for the detection of congenital Zika virus infection is unknown 
  • PPV, NPV and optimal timing are unknown  
  • Positive Zika test results in amniotic fluid  
    • Zika virus RNA has been detected in amniotic fluid specimens 
    • Serial amniocenteses have demonstrated that Zika virus RNA might only be present transiently 
    • A negative test result on amniotic fluid cannot rule out congenital Zika virus infection 
    • If amniocentesis is indicated as part of the evaluation for abnormal prenatal findings, NAT testing for Zika virus should be considered to assist with the diagnosis of fetal infection 

Summary of prenatal diagnosis of congenital Zika virus infection

  • A shared decision-making model is essential to ensure that pregnant women and their families understand the risks and benefits of screening in the context of the patient’s preferences and values 
  • Decisions should be individualized 

Congenital Zika Virus Infection

  • Microcephaly  
  • Brain anomalies 
    • Thin cerebral cortices with enlarged ventricles and increased extra-axial fluid collections 
    • Intracranial calcifications  
    • Absent or hypoplastic corpus callosum 
    • Hypoplasia of the cerebellum or cerebellar vermis 
    • Hypoplasia of the ventral cord  
  • Eye anomalies (both anterior and posterior) 
    • Microphthalmia 
    • Coloboma 
    • Intraocular calcifications 
    • Optic nerve hypoplasia and atrophy 
    • Macular scarring with focal pigmentary retinal mottling
    • Even in absence of structural eye lesions, cortical visual impairment may be present due to anomalies in visual system of the brain  
  • Other neurologic sequelae  
    • Congenital limb contractures, dysphagia, sensorineural hearing loss, epilepsy, and abnormalities of tone or movement, including marked hypertonia and signs of extrapyramidal involvement  
  • Additional findings since last update 
    • Eye findings in infants without microcephaly or other brain anomalies  
    • Postnatal-onset microcephaly in infants born with normal head circumferences 
    • Postnatal-onset hydrocephalus in infants born with microcephaly
    • Abnormalities on sleep electroencephalogram (EEG) in some infants with microcephaly who did not have recognized seizures
    • Diaphragmatic paralysis in infants born with microcephaly and arthrogryposis 

Infants with Clinical Findings Consistent with Congenital Zika Syndrome and Mothers with Possible Zika Virus Exposure in Pregnancy

  • Laboratory Testing 
    • Zika virus testing is recommended, regardless of maternal testing results 
    • Testing CSF for Zika virus RNA and Zika virus IgM antibodies should be considered, especially if serum and urine testing are negative and another etiology has not been identified 
  • Clinical Evaluation and Management in addition to standard evaluation 
    • 1 month 
      • Head ultrasound 
      • Comprehensive ophthalmologic exam 
      • Automated ABR if the newborn hearing screen was passed using only otoacoustic emissions methodology  
    • Referral to a developmental specialist and early intervention service programs are recommended 
    • Consider the following referrals  
      • Infectious disease  
      • Clinical genetics for confirmation of the clinical phenotype and evaluation for other causes of microcephaly or congenital anomalies 
      • Neurology by age 1 month  
      • Other consultations based on clinical findings 
    • Note change from previous guidance: Diagnostic ABR is no longer recommended at age 4–6 months for infants who passed the initial hearing screen with automated ABR because of the absence of data suggesting delayed-onset hearing loss in infants with congenital Zika virus infection 

Infants without Clinical Findings Consistent with Congenital Zika Syndrome and Mothers with Laboratory Evidence of Possible Zika Virus Infection During Pregnancy

  • Laboratory Testing 
    • Zika virus testing is recommended
  • Clinical Evaluation and Management in addition to standard evaluation 
    • 1 month 
      • Head ultrasound 
      • Comprehensive ophthalmologic exam 
      • Automated ABR if the newborn hearing screen was passed using only otoacoustic emissions methodology  
    • Health care providers should perform  
      • Standard evaluation along with routine preventive pediatric care and immunizations at each subsequent well-child visit 
      • Remain vigilant for signs that might be associated with congenital Zika virus infection 
      • Refer if suspicious findings identified at any time 
  • Infants with Laboratory Evidence of Congenital Zika Virus Infection 
    • Laboratory evidence of congenital Zika virus infection includes  
      • Positive Zika virus NAT or  
      • A nonnegative Zika virus IgM with confirmatory neutralizing antibody testing, if PRNT confirmation is performed 
    • Follow recommendations for infants with clinical findings even in the absence of clinically apparent abnormalities 
  • Infants without laboratory evidence of congenital Zika virus infection 
    • If laboratory and clinical findings are both negative, infection is unlikely  
    • Infants should continue to receive routine pediatric care, and health care providers should remain alert for any new findings 

Infants without Clinical Findings Consistent with Congenital Zika Syndrome and Mothers with Possible Zika Virus Exposure in Pregnancy but No Laboratory Evidence

  • This category refers to mothers who were never tested or results could be negative related to timing or test related issues  
  • Laboratory Testing 
    • Not routinely recommended for infants born to mothers in this category  
    • If abnormal findings are identified, these infants should receive further evaluation, including evaluation and testing for congenital Zika virus infection 
  • Clinical Evaluation and Management 
    • Infants should have a standard evaluation performed at birth and at each subsequent well-child visit along with routine preventive pediatric care and immunizations 
    • Further clinical evaluation for congenital Zika virus infection beyond a standard evaluation and routine pediatric care is not routinely indicated 
    • Health care providers can consider additional evaluation in consultation with families, including
      • possible risks of screening (e.g., identification of incidental findings)
      • Maternal factors, such as the presence and timing of symptoms
      • Type, location, and length of possible Zika virus exposure 
    • Older infants in whom maternal Zika virus exposure was not assessed at birth and who are evaluated later might also have more clinical data  
    • If findings consistent with congenital Zika syndrome are identified at any time, referral as needed consistent with recommendations above for children with suspected Zika virus 

Learn More – Primary Sources:

Update: Interim Guidance for the Diagnosis, Evaluation, and Management of Infants with Possible Congenital Zika Virus Infection — United States, October 2017

ACOG Committee Opinion 784: Management of Patients in the Context of Zika Virus

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 – Seizure Prophylaxis  

  • 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 

Prenatal & Preconception Carrier Screening for Fragile X: Clinical and Genetic Essentials

WHAT IS IT?

Fragile X is a serious X-linked dominant genetic disorder that is strongly associated with significant developmental and CNS manifestations. Prevalence approximately 1/4000 males and 1/8000 females.

When to Offer Prenatal/Preconception Screening for Fragile X?

ACOG

  • ACOG does not recommend universal screening for this disorder but rather the test should be offered based on clinical context
  • Fragile X screening is indicated for the following
    • Family or personal history of unexplained autism, intellectual disability or fragile X related disorders (see below)
      • Family history: obtain a 3 generation pedigree and pay particular attention to male relatives
    • Unexplained ovarian insufficiency or failure
    • Elevated follicle-stimulating hormone (FSH) level before age 40 years
    • If patient does not meet above criteria but requests screening
      • May offer following informed consent

ACMG

  • ACMG does recommend universal screening for Fragile X as part of it’s recommended ‘tier 3 panel’ (see, ‘Related ObG Topics Below) that includes
    • 97 autosomal recessive genes
    • 16 X-linked genes, including DMD and Fragile X

Note: Genetic Counseling and informed consent are key components of screening and diagnostic testing

KEY CLINICAL FINDINGS:

  • NEUROLOGIC
    • Intellectual disability
      • Males: Mild to moderate
      • Females: Seen in approximately 1/3
    • Features of autism spectrum disorder (approximately 1/3)
    • Attention Deficit Disorder (ADD)
    • Anxiety and hyperactive behaviors
    • Language delay
    • Seizures
      • Males: 15%
      • Females: 5%
  • HEAD AND NECK
    • Macrocephaly
    • Coarse facies
    • Large forehead
    • Prominent jaw
  • CARDIOVASCULAR
    • Mitral valve prolapse
  • CHEST
    • Pectus excavatum
  • GENITOURINARY
    • External Genitalia (Male)
    • Macroorchidism

KEY POINTS:

Genetics

Most cases (98%) caused by expanded trinucleotide repeat (CGG)n in the FMR1 gene

  • Unaffected: < 45 repeats
  • Intermediate: 45-54 repeats
    • Approximately 14% of intermediate alleles are unstable and may expand into the premutation range when transmitted by the mother
    • Does not incur risk to offspring for fragile X
  • Premutation: 55 to 200 repeats
    • Some boys with premutations show milder features, including large ears, autistic features, anxiety or depression
    • Females are at increased risk for fragile X-associated primary ovarian insufficiency (FXPOI)
      • May be overt with premature ovarian failure (POF) before age 40 or occult (reduced fertility)
      • 1/200 women have premutation but only 25% will be affected
    • Primarily males are at increased risk for fragile X-associated tremor/ataxia syndrome (FXTAS)
      • Movement disorder (intention tremor and ataxia) that also affects cognition
      • Late-onset progressive disorder > 50 years, and its signs and symptoms worsen with age
      • 1/450 males have premutation but only 40% will be affected
      • 1/200 females have the premutation but only 16% will be affected
  • Symptomatic: > 200 repeats due to silencing (methylation) of the FMR1 gene located on the X chromosome

Complexity Related to Inheritance Pattern

  • Females: premutation can expand to > 200 CGG repeats during oogenesis
  • Males: premutation does not expand during spermatogenesis
    • Men pass the premutation only to daughters

Premutation Expansion Risk Based on Number of Repeats

  • More CGG repeats increase the risk of full mutation expansion to fragile X (>200 repeats)
  • AGG ‘interruptions’
    • Located in the FMR1 repeat regions
    • Most individuals have 1 or 2 AGG interruptions
    • AGG interruptions stabilize FMR1 to prevent premutation expansion
      • More AGGs, decreased risk to full expansion
    • Being used by some clinical laboratories to refine fragile X risk to offspring in maternal permutation carriers
      • >90 repeats very high risk and >90% will expand to full mutation regardless of AGG
Maternal Repeat Size %Full Mutation #AGG – %Full Mutation
45 – 49 0% 0%
50 – 54 0 0%
55 – 59 0.5 0 AGG – 3%
>1 AGG – 0%
60 – 64 1.7 0 AGG – 5%
>1 AGG – 0%
65 – 69 7 0 AGG – 17%
>1 AGG – 0%
70 – 74 21 0 AGG – 52%
1 AGG – 7%
2 AGG – 0%
75 – 79 47 0 AGG – 73%
1 AGG – 33%
2 AGG – 7%
80-84 62 0 AGG – 87%
1 AGG – 67%
2 AGG – 15%
85 – 89 81 0 AGG – 88%
1 AGG – 83%
2 AGG – 50%
90 – 99 94
≥100 – 200 98
>200 100

Adapted from Nolin et al., 2011 and 2015

Learn More – Primary Sources:

Fragile X analysis of 1112 prenatal samples from 1991 to 2010

Fragile X full mutation expansions are inhibited by one or more AGG interruptions in premutation carriers

GeneReviews: FMR1-Related Disorders

ACOG Committee Opinion 691: Carrier Screening for Genetic Conditions

ACMG: Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics

GHR: Fragile X Syndrome

Joint SOGC–CCMG Opinion for Reproductive Genetic Carrier Screening: An Update for All Canadian Providers of Maternity and Reproductive Healthcare in the Era of Direct-to-Consumer Testing

Locate a genetic counselor or genetics services:

Genetic Services Locator-ACMG

Genetic Services Locator-NSGC

Genetic Services Locator-CAGC

Locate a Maternal Fetal Medicine Specialist

Maternal Fetal Medicine Specialist Locator-SMFM

Spinal Muscular Atrophy: Genetic Concepts and Carrier Screening 

WHAT IS IT?

ACOG recommends that screening for spinal muscular atrophy (SMA) be offered to all women who are considering or who are currently pregnant. SMA is a severe progressive neuromuscular disorder caused by loss of alpha motor neurons in the spinal cord, with the loss of muscle strength, leading to paralysis.

This disorder is common, with carrier frequencies in one study of 1/47 in Caucasians; 1/67 in Ashkenazi Jewish; 1/59 in Asian; 1/68 Hispanic; 1/52 Asian Indian; and 1/72 African American. In the overall US panethnic population, the carrier frequency was 1/54 with a detection rate of over 90%.  SMA affects all population groups and is only second to cystic fibrosis as a cause of death from an autosomal recessive condition.

Childhood SMA is divided into 4 clinical groups but span a continuum without clear delineation

  • Type 0: Congenital SMA
    • Presents at birth
    • Death by 6 months of age
  • Type I: Severe SMA (Werdnig-Hoffmann disease)
    • Onset < 6 months
    • Median survival 2 years of age
  • Type II: Intermediate SMA (Dubowitz disease)
    • Onset 6-18 months
    • Children can sit but not stand unaided but lose ability by mid-teens
    • Life expectancy not known with certainty – adolescence to 3rd or 4th decade
  • Type III: Juvenile SMA (Kugelberg-Welander disease)
    • Onset > 18 months
    • Patients learn to walk unaided but most will lose ability with age
    • Life expectancy that of normal population

KEY POINTS:

Genetics

  • There are two related, almost identical genes on the long arm of chromosome 5, SMN1 and SMN2
    • SMN1 is the SMA-determining gene
    • Exon 7 in SMN1 is absent in both gene copies (maternal and paternal) in over 95% of affected individuals
    • In a few individuals, exon 7 is absent in one gene copy and there is a smaller mutation in the other gene copy
    • Some individuals have additional copies of SMN2 and their presence seem to lessen the severity of SMA

Limitations to Carrier Testing – False Negatives

  • De novo mutation: In 2% of cases, SMA results from a de novo mutation and therefore in this particular situation, screening parents will not detect the pathogenic variant (usually paternal)
  • Silent Carrier (2 + 0): Healthy individuals can carry 2 copies of SMN1 on a single chromosome and no copies on their other chromosome
    • The % of ‘silent carriers’ varies from approximately 30% in African Americans to 5% in Caucasians
    • The standard carrier screening tests are based on gene dosage and result in a false negative because 2 normal copies will be detected and therefore total amount of SMN1 will be interpreted as ‘normal’
    • The (2+0) individual is a carrier because there is a 50% chance he/she will pass the abnormal (missing SMN1) chromosome to the fetus
    • There are variants that track with silent carriers (i.e., found on chromosomes with duplications and not single-copy alleles) that can be incorporated into clinical carrier screening tests to improve residual risk estimates

Medication now available for SMA

Nusinersen

  • The FDA approved the first medication (nusinersen) in 2016, to treat children and adults with spinal muscular atrophy (SMA)
  • The FDA approval was based on a clinical trial in 121 patients with infantile-onset SMA who were diagnosed before 6 months of age and who were less than 7 months old at the time of their first dose
    • Patients were randomized to receive an injection of nusinersen into the fluid surrounding the spinal cord, or undergo a mock procedure without drug injection (a skin prick)
    • Forty percent of patients treated with nusinersen achieved improvement in motor milestones as defined in the study, whereas none of the control patients did

Onasemnogene abeparvovec-xioi

  • Indicated for the treatment of children with SMA <2 years
  • Gene therapy
    • Adeno-associated virus vector-based gene therapy
    • Vector delivers a fully functional copy of human SMN gene into the target motor neuron cells
    • One-time IV administration
  • Studies
    • Primary evidence of effectiveness from ongoing clinical trial
    • Compared to the natural history of patients with infantile-onset SMA patients in treatment arm demonstrated significant improvement in their ability to reach developmental motor milestones (e.g., head control and the ability to sit without support)

Learn More – Primary Sources:

ACOG Committee Opinion 691: Carrier Screening for Genetic Conditions

FDA approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality

GeneReviews: Spinal Muscular Atrophy

FDA approves first drug for spinal muscular atrophy

ACMG: Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics

ACMG: Carrier screening for spinal muscular atrophy

Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens

An Ashkenazi Jewish SMN1 haplotype specific to duplication alleles improves pan-ethnic carrier screening for spinal muscular atrophy