Zika Virus and Birth Defects: How Strong is the Correlation?

BACKGROUND AND PURPOSE:

  • Risk of congenital neurologic defects related to Zika virus (ZIKV) infection has ranged from 6 to 42% in contrasting reports
  • The magnitude of risk is still unclear
  • Hoen et al. (N Eng j Med, 2018) aimed to assess risk among pregnant women with symptomatic ZIKV infection in French territories (Guadeloupe, Martinique, Guyane) in the Americas

METHODS:

  • Prospective cohort study
  • Participants: Pregnant women with
    • Symptomatic ZIKV infection, confirmed by polymerase-chain-reaction (PCR) assay (blood, urine or both)
    • Symptomatic: At least one of the following consistent with acute ZIKV infection
      • Pruritic rash, fever, conjunctival hyperemia, arthralgia, or myalgia
    • Microcephaly: Head circumference >2 SD below the mean for sex and gestational age
      • Severe microcephaly: Head circumference >3 SD below the mean
    • The data was collected up until the last delivery in the cohort

RESULTS:

  • Data was collected from 555 fetuses and infants among the 546 pregnancies that were included in the analysis
    • 28 (5.0%) were not carried to term
    • 527 were born alive
  • Neurologic and ocular defects possibly associated with ZIKV infection were seen in 7% of fetuses and infants (95% CI, 5.0 to 9.5); of these
    • 10 were not carried to term because of termination of pregnancy for medical reasons
    • 1 was stillborn
    • 28 were live-born
  • Microcephaly was detected in
    • 5.8% fetuses and infants and of those
      • 1.6% had severe microcephaly
    • Neurologic and ocular defects were more common when ZIKV infection occurred during the first trimester (P=0.001)
      • First trimester 12.7%
      • Second trimester 3.6%
      • Third trimester 5.3%

CONCLUSION:

  • Defects associated with ZIKV were found in 7% of fetuses and infants from mothers with ZIKV
  • Overall risk of evident birth defects included in the current definition of the congenital Zika syndrome was 3.1% (see ‘Related ObG Topics’ below)
  • There was an increased risk of birth defects when infection occurs earlier in pregnancy

Learn More – Primary Sources:

Pregnancy Outcomes after ZIKV Infection in French Territories in the Americas

Zika virus: transmission, symptoms and management

Zika virus disease is a nationally notifiable condition:

Healthcare providers should report suspected Zika virus disease cases to their state, local, or territorial health department, who will report to the CDC.

WHAT IS IT?

  • The Zika virus (ZIKV) was first discovered in 1947, but has only become a global public health threat in the last decade with marked geographic spread in the last 5 years
  • The Zika virus is named after the Zika forest in Uganda where it was first found, is a Flavivirus and is related to similar viruses such as dengue, West Nile and Japanese encephalitis
  • The infectious viral particle (virion) is primarily composed of a single strand of RNA which is released into the infected cell’s cytoplasm, overtakes the infected cell’s genetic and cellular machinery, leading to replication and release of additional Zika virus
  • ZIKV, typical for a Flavirus, is predominantly spread via mosquito vectors, however transmission via blood transfusion and sexual contact can occur

KEY POINTS:

  • Clinical symptoms appear 3 to 14 days after a mosquito bite and should resolve within 2 to 7 days
  • Most people will be asymptomatic
  • 20% will have typical viral signs and symptoms, usually of a mild nature
    • Fever
    • Maculopaular rash
    • Conjunctivitis
    • Arthralgias
    • Headache
  • Management is that of typical viral illness and includes:
    • Rest
    • Antipyretics
      • Note: current drug labels state that NSAIDs should not be used by pregnant women in their third trimester of pregnancy because of the risk of premature closure of the ductus arteriosus in the fetus
    • Nutrition and adequate fluids
    • Monitor for signs and symptoms of severe infection such as coagulopathies and organ damage – ICU care is rare but any concern should be escalated
    • Guillain-Barré syndrome, an autoimmune neurological disorder, has been reported and while uncommon should generate a referral for diagnosis and management

Learn More – Primary Sources:

CDC: Zika Virus For Healthcare Providers

CDC: Areas with Risk of  Zika

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

ACOG Zika Tool Kit 

FDA Drug Safety Communication: FDA has reviewed possible risks of pain medicine use during pregnancy

Zika Virus Disease: How to Counsel Your Patient About Prevention

Zika virus disease is a nationally notifiable condition

Healthcare providers should report suspected Zika virus disease cases to their state, local, or territorial health department, who will report to the CDC. The ACOG Committee Opinion (August 2019 | Endorsed by SMFM) has updated recommendations, including guidance on prevention that are aligned with CDC.

  • Pregnant women should avoid travel to areas with active outbreaks (see CDC maps in ‘Learn More – Primary Sources’ below)
  • “Pregnant women and those planning pregnancy should talk to their health care providers about potential risks before traveling to an area where current or past Zika virus transmission has occurred”
  • If a pregnant woman opts to travel to these higher risk areas, counseling should focus on preventing mosquito bites

CLINICAL ACTIONS:

Zika virus can be transmitted via mosquito bite or more infrequently, through sexual (vaginal, anal or oral) contact, with blood transfusion now also reported. When counseling women, especially those of reproductive age, there are key points to review relating to exposure, prevention and fetal transmission:

Prevent exposure to infected mosquitoes (Aedes species) if traveling to areas where Zika virus has been reported

  • Mosquitoes lay eggs near standing water – avoid areas with standing water; once a week empty, scrub, turn over, cover or throw out items that hold still water
  • Use screens and air conditioning when available – alternative is mosquito bed netting, especially if sleeping outdoors
  • Wear long-sleeved shirts and pants and consider permethrin-treated clothing and gear
  • Insect repellent (EPA registered) – DEET and permethrin can be used if pregnant and reapplication instructions should be carefully followed
  • Protect against mosquitoes during the day and night, including dusk and dawn

Use appropriate barrier contraception if not planning pregnancy or already pregnant

  • Barrier contraception includes male and female condoms and dental dams
  • Pregnant : If a patient’s sex partner (male or female) either lives or has traveled to an active Zika virus transmission area, the use of barriers or abstention from sex for the duration of the pregnancy is recommended
  • Does Not Desire Pregnancy : Determine the best contraceptive method for your patient that will be used correctly and consistently. To prevent transmission, barrier use or abstention is recommended for the following length of time if exposed to Zika virus
    • Men : for at least 3 months after onset of symptoms or exposure (if asymptomatic)
    • Women : for at least 8 weeks after onset of symptoms or exposure (if asymptomatic)
    • If a couple resides in an active Zika virus transmission area: for the time that active mosquito-borne transmission persists

Delay attempting desired pregnancy for the following length of time, if diagnosed or exposed to Zika virus

  • Men : for at least 3 months after onset of symptoms or exposure (if asymptomatic)
  • Women : for at least 8 weeks after onset of symptoms or exposure (if asymptomatic)
  • If a couple lives in a high risk area: Provide counseling regarding risk of microcephaly and other birth defects
    • For couples who desire to conceive, mosquito bite prevention strategies are imperative

SYNOPSIS:

While first reported in Africa decades ago, the initial reported case of Zika virus disease in South America was in 2015.  The CDC maintains world maps (open access) to identify active areas. 20% of those infected will be symptomatic. Incubation period has been reported to be between 3 to 14 days. Zika virus became an international health emergency due to the risk of severe birth defects, in particular microcephaly, through maternal transmission.

KEY POINTS:

  • CDC recommends that pregnant women not travel to areas where there have been reports of local transmission (color code red on map)
  • CDC keeps an updated map of both international and national active transmission area (See ‘Learn More – Primary Sources’ for CDC maps)
  • CDC advises that healthcare providers discuss travel plans in preconception counseling, and both women and men should consider avoiding nonessential travel to active transmission areas
    • CDC states that for areas with current or past transmission (as opposed to known outbreak regions and coded purple)

These countries have a potential risk of Zika, but we do not have accurate information on the current level of risk 

As a result, detection and reporting of new outbreaks may be delayed

  • CDC defines ‘exposure’ to Zika virus as either of the following:
    • Travel or residency in an area of active Zika virus transmission
    • Sex without a condom with a partner who has lived or traveled to such an area
  • Routine Zika virus testing is not currently recommended for women or men with exposure, but who are asymptomatic
  • No transmission via ART has been identified, but is possible in theory
  • No cases of transmission via breastfeeding have been reported
    • Currently, opinion suggests benefits of breastfeeding outweigh risks
  • The most current public health recommendations can be found on the CDC website, which is continuously updating and revising guidance as new evidence becomes available

Learn More – Primary Sources:

ACOG Zika Toolkit

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

CDC: Zika Travel Information (color coded map) 

CDC: Zika in the US

CDC: Zika Virus For Healthcare Providers

Update: Interim Guidance for Preconception Counseling and Prevention of Sexual Transmission of Zika Virus for Men with Possible Zika Virus Exposure — United States, August 2018

WHO Emergencies Preparedness, Response (July 2019): Information for travellers visiting countries with Zika virus transmission 

WHO Zika epidemiology update (July 2019) 

Practical obstetrics info for your women's healthcare practice

Microcephaly – Beyond the Zika Virus

WHAT IS IT? 

  • Microcephaly means “small head”, and can be used interchangeably in some instances with microencephaly, “small brain”
    • Consider abnormal development (primary microcephaly) if detected prior to 32 weeks gestation, as opposed to a degenerative condition in which normal head size becomes smaller (secondary microcephaly)

SYNOPSIS:

Microcephaly has an incidence of 2-12 in 10,000 births in the USA, and can be diagnosed prenatally via ultrasound (in second or early third trimester) or postnatally via measurement of head circumference (HC).  Microcephaly has been linked to developmental delay, seizures, as well as feeding, vision and hearing problems.  Prognosis depends on the severity of the microcephaly and whether it is associated with other anomalies.

KEY POINTS:

Definitions

SMFM – Fetal Microcephaly

  • HC ≥ 3 SD below the mean for gestational age is the recommended definition
  • HC ≥ 5 SD below the mean is a certain diagnosis

CDC – Postnatal Congenital Microcephaly

  • Definite Congenital Microcephaly
    • HC at birth < 3rd percentile for gestational age and sex
    • If HC not available at birth, HC < 3rd percentile for age and sex within the first 2 weeks of life
    • For Stillbirths and elective terminations, CDC definition based on HC at delivery < 3rd percentile for gestational age and sex
  • Possible Congenital Microcephaly
    • For Live Births: If earlier HC is not available, HC < 3rd percentile for age and sex beyond 6 weeks of life
    • For All Pregnancy Outcomes: Microcephaly diagnosed or suspected on prenatal ultrasound in the absence of available postnatal HC measurements

Management

  • If fetal HC by ultrasound is > 2 SD below the mean for gestational age, a careful evaluation of the fetal intracranial anatomy is indicated
    • If the intracranial anatomy is normal, consider follow-up in 3-4 weeks
  • When evaluating the finding of fetal microcephaly, assess for the following
    • Infectious exposures including
      • Zika virus
      • Maternal syphilis, herpes, HIV, rubella, toxoplasmosis, cytomegalovirus
    • Alcohol consumption, exposure to certain medications and/or smoking during pregnancy
    • Genetic conditions, including aneuploidy or single gene disorders
  • Many ultrasound packages report HC percentiles and not standard deviations (SD) and often the lowest reported HC measurement is <5th percentile
    • In such cases, SMFM suggests using head circumference (in millimeters) to determine SD below the mean
    • SMFM provides a table (see ‘Learn More – Primary Sources’ below) to determine the number of SD below the mean as a function of gestational age
  • Role of MRI: The SOGC Guideline states (III-A evidence)

Once fetal microcephaly is identified by ultrasound, fetal magnetic resonance imaging, when available and if potential findings are likely to alter pregnancy management, may be considered.

Fetal magnetic resonance imaging images should be reviewed by a radiologist with expertise in fetal magnetic resonance imaging.

  • Consider referral to a Fetal Maternal Medicine Specialist
  • Consider referral to Genetic Counseling, especially if microcephaly is associated with other findings
  • Consider referral to Pediatric Neurologist for review of short and long term potential outcomes for the newborn and child with microcephaly
Microcephaly

Image credit: Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities

Learn More – Primary Sources:

Microcephaly: An Epidemiologic Analysis 

SMFM Statement- Ultrasound Screening for Fetal Microcephaly Following Zika virus Exposure

SOGC Guideline 380: Investigation and Management of Prenatally Identified Microcephaly

CDC: Zika Virus For Healthcare Providers

CDC: Areas with Risk of  Zika in the US

Serial Head and Brain Imaging of 17 Fetuses With Confirmed Zika Virus Infection in Colombia, South America

US Zika Pregnancy Registry Collaboration: Birth Defects Among Fetuses and Infants of US Women With Evidence of Possible Zika Virus Infection During Pregnancy

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

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