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

CDC: Areas with Risk of  Zika

ACOG Statement on Zika Virus

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

Microcephaly – Definitions and Key Points

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 to 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

American Academy of Neurology and Child Neurology Society

• At birth
  • HC >2 SD below the mean for age and gender
  • Severe would be considered >3 SD below the mean

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

Learn More – Primary Sources:

Microcephaly: An Epidemiologic Analysis 

CDC: Congenital Anomalies of the Nervous System: Microcephaly 

Prenatal gender-customized head circumference nomograms result in reclassification of microcephaly and macrocephaly

SMFM: Ultrasound screening for fetal microcephaly following Zika virus exposure

Practice Parameter: Evaluation of the child with microcephaly (an evidence-based review) 

SOGC Guideline 380: Investigation and Management of Prenatally Identified Microcephaly

CDC: Zika Virus For Healthcare Providers

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