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Ultrasound screening for fetal microcephaly following Zika virus exposure

  • Society for Maternal-Fetal Medicine (SMFM) Publications Committee
Published:February 18, 2016DOI:https://doi.org/10.1016/j.ajog.2016.02.043
      The practice of medicine continues to evolve, and individual circumstances will vary. This publication reflects information available at the time of its submission for publication and is neither designed nor intended to establish an exclusive standard of perinatal care. This publication is not expected to reflect the opinions of all members of the Society for Maternal-Fetal Medicine.
      Microcephaly is a condition in which the size of the head is smaller than expected for age. This condition in fetuses and infants has been associated with the recent outbreak of Zika virus. Due to this association, the Centers for Disease Control and Prevention (CDC), American Congress of Obstetricians and Gynecologists (ACOG), and Society for Maternal-Fetal Medicine (SMFM) have suggested prenatal ultrasound evaluation for fetal microcephaly in pregnant women who have been infected or potentially exposed.
      • Oduyebo T.
      • Petersen E.E.
      • Rasmussen S.A.
      • et al.
      Update: interim guidelines for health care providers caring for pregnant women and women of reproductive age with possible Zika virus exposure–United States, 2016.

      ACOG and SMFM. Practice advisory: updated interim guidance for care of obstetric patients and women of reproductive age during a Zika virus outbreak. Available at: http://www.acog.org/About-ACOG/News-Room/Practice-Advisories/Practice-Advisory-Interim-Guidance-for-Care-of-Obstetric-Patients-During-a-Zika-Virus-Outbreak. Accessed Feb. 12, 2016.

      However, the diagnosis of microcephaly by prenatal sonography is not always straightforward. Given the complexity of prenatal diagnosis of microcephaly, the purpose of this document is to review the ultrasound criteria for the diagnosis following exposure to the Zika virus.
      Various national and international agencies have recommended prenatal ultrasound for evaluation for fetal microcephaly in women who have travelled to any of the high-risk areas for Zika exposure during pregnancy.
      • Oduyebo T.
      • Petersen E.E.
      • Rasmussen S.A.
      • et al.
      Update: interim guidelines for health care providers caring for pregnant women and women of reproductive age with possible Zika virus exposure–United States, 2016.

      ACOG and SMFM. Practice advisory: updated interim guidance for care of obstetric patients and women of reproductive age during a Zika virus outbreak. Available at: http://www.acog.org/About-ACOG/News-Room/Practice-Advisories/Practice-Advisory-Interim-Guidance-for-Care-of-Obstetric-Patients-During-a-Zika-Virus-Outbreak. Accessed Feb. 12, 2016.

      World Health Organization. Zika situation report: neurological syndrome and congenital anomalies. Available at: http://apps.who.int/iris/bitstream/10665/204348/1/zikasitrep_5Feb2016_eng.pdf?ua=1. Accessed Feb. 11, 2106.

      At present, however, there are limited data available regarding criteria for diagnosis of fetal microcephaly in the setting of Zika infection or exposure. In addition, the natural history of fetal microcephaly associated with Zika virus is unknown; although recent reports describe cases of microcephaly after maternal infection.
      • Mlakar J.
      • Korva M.
      • Tul N.
      • et al.
      Zika virus associated with microcephaly.
      • Oliveira Melo A.S.
      • Malinger G.
      • Ximenes R.
      • Szejnfeld P.O.
      • Alves Sampaio S.
      • Bispo de Filippis A.M.
      Zika virus intrauterine infection causes fetal brain abnormality and microcephaly: tip of the iceberg?.
      In most cases, it is difficult to differentiate between constitutionally small head size vs pathologic microcephaly, and available data regarding prenatal diagnosis of microcephaly are based on small numbers of cases of varying etiologies.
      In cases in which the fetal head circumference (HC) measures >2SD below the mean, we recommend that a detailed neurosonographic examination be performed,
      International Society of Ultrasound in Obstetrics and Gynecology Education Committee
      Sonographic examination of the fetal central nervous system: guidelines for performing the “basic examination” and the “fetal neurosonogram”.
      as some fetuses with HC >2SD below the mean due to in utero infection will have findings such as periventricular and intraparenchymal echogenic foci, ventriculomegaly, cerebellar hypoplasia, microcephaly, and cortical abnormalities.
      • Mlakar J.
      • Korva M.
      • Tul N.
      • et al.
      Zika virus associated with microcephaly.
      • Oliveira Melo A.S.
      • Malinger G.
      • Ximenes R.
      • Szejnfeld P.O.
      • Alves Sampaio S.
      • Bispo de Filippis A.M.
      Zika virus intrauterine infection causes fetal brain abnormality and microcephaly: tip of the iceberg?.
      In addition, assessment of the profile can be helpful as the forehead is often sloping in pathologic microcephaly, and demonstration of this finding should increase the index of suspicion. We recommend that isolated fetal microcephaly should be defined as fetal HC ≥3SD below the mean for gestational age (Table), and the diagnosis of pathologic microcephaly is considered certain when the fetal HC is ≥5SD.
      • Chervenak F.A.
      • Rosenberg J.
      • Brightman R.C.
      • Chitkara U.
      • Jeanty P.
      A prospective study of the accuracy of ultrasound in predicting fetal microcephaly.
      • Persutte W.H.
      Microcephaly–no small deal.
      If the HC by prenatal ultrasound is >2SD below the mean, a careful evaluation of the fetal intracranial anatomy is indicated. If the intracranial anatomy is normal, we recommend follow-up ultrasound in 3-4 weeks.
      TableMeans and SD of head circumference as function of gestational age
      Adapted from: Chervenak FA, Jeanty P, Cantraine F, et al. The diagnosis of fetal microcephaly. Am J Obstet Gynecol 1984;149:512-7.
      Gestational age, wkMean, mmHead circumference, mm: SD below mean
      –1–2–3–4–5
      20175160145131116101
      21187172157143128113
      22198184169154140125
      23210195180166151136
      24221206191177162147
      25232217202188173158
      26242227213198183169
      27252238223208194179
      28262247233218203189
      29271257242227213198
      30281266251236222207
      31289274260245230216
      32297283268253239224
      33305290276261246232
      34312297283268253239
      35319304289275260245
      36325310295281266251
      37330316301286272257
      38335320306291276262
      39339325310295281266
      40343328314299284270
      41346331316302287272
      42348333319304289275
      SMFM. Ultrasound screening for fetal microcephaly following Zika virus exposure. Am J Obstet Gynecol 2016.
      Data regarding the neonatal outcomes of fetal microcephaly are limited to small case series,
      • Stoler-Poria S.
      • Lev D.
      • Schweiger A.
      • Lerman-Sagie T.
      • Malinger G.
      Developmental outcome of isolated fetal microcephaly.
      • Leibovitz Z.
      • Daniel-Spiegel E.
      • Malinger G.
      • et al.
      Microcephaly at birth–the accuracy of three references for fetal head circumference. How can we improve prediction?.
      and specific to Zika infection only as case reports.
      • Mlakar J.
      • Korva M.
      • Tul N.
      • et al.
      Zika virus associated with microcephaly.
      • Oliveira Melo A.S.
      • Malinger G.
      • Ximenes R.
      • Szejnfeld P.O.
      • Alves Sampaio S.
      • Bispo de Filippis A.M.
      Zika virus intrauterine infection causes fetal brain abnormality and microcephaly: tip of the iceberg?.
      A recent report presented 1 case of ultrasound-diagnosed microcephaly also with intracranial findings correlated with postmortem pathology.
      • Mlakar J.
      • Korva M.
      • Tul N.
      • et al.
      Zika virus associated with microcephaly.
      Another reported 2 cases of prenatal microcephaly associated with Zika infection and both had intracranial findings.
      • Oliveira Melo A.S.
      • Malinger G.
      • Ximenes R.
      • Szejnfeld P.O.
      • Alves Sampaio S.
      • Bispo de Filippis A.M.
      Zika virus intrauterine infection causes fetal brain abnormality and microcephaly: tip of the iceberg?.
      In a case series of 20 fetuses with prenatal diagnosis of microcephaly, HC between 2SD and 3SD below the mean was associated with a normal HC at birth in 90% of cases.
      • Stoler-Poria S.
      • Lev D.
      • Schweiger A.
      • Lerman-Sagie T.
      • Malinger G.
      Developmental outcome of isolated fetal microcephaly.
      In another study of 42 cases of fetal microcephaly with HC >3SD below the mean, 40% of infants were found to a have normal HC at birth.
      • Leibovitz Z.
      • Daniel-Spiegel E.
      • Malinger G.
      • et al.
      Microcephaly at birth–the accuracy of three references for fetal head circumference. How can we improve prediction?.
      Of note, many ultrasound reporting packages report HC percentiles and not SD and often the lowest reported is <5th percentile. In such cases, use of the Table is suggested to determine the number of SD below the mean for gestational age, as this is the most validated reference standard for the diagnosis of microcephaly.
      In summary, this statement outlines the prenatal ultrasound diagnostic criteria for microcephaly and what is currently known about the predictive value for microcephaly at birth. The current guidance recommends serial ultrasounds, every 3-4 weeks, with evidence of maternal infection. These recommendations further suggest that serial ultrasounds can be considered for women who have traveled to endemic areas but have no evidence of infection, as Zika infection can be asymptomatic. At present, there are very limited data with respect to the natural history and outcomes of fetal microcephaly in the setting of Zika infection or exposure. As new data emerge, these recommendations may change. In addition, diagnostic testing, surveillance, and management of suspected prenatal Zika exposure and infection is evolving and will continue to change as new data become available. For additional information, go to www.smfm.org/education/zika, www.acog.org/About-ACOG/ACOG-Departments/Zika-Virus, or www.cdc.gov/zika/pregnancy/index for Zika virus infection during pregnancy.

      Recommendations

      • 1.
        If the HC by prenatal ultrasound is >2SD below the mean, a careful evaluation of the fetal intracranial anatomy is indicated. If the intracranial anatomy is normal, we recommend follow-up ultrasound in 3-4 weeks.
      • 2.
        We recommend that isolated fetal microcephaly should be defined as fetal HC ≥3SD below the mean for gestational age. The diagnosis of pathologic microcephaly is considered certain when the fetal HC is ≥5SD. A detailed neurosonographic examination should be performed and follow-up ultrasound done in 3-4 weeks.
      • 3.
        If a reporting package for fetal biometry provides HC measurements as a percentile, the Table can be used to determine the SD, which is necessary in most cases to identify true microcephaly.

      References

        • Oduyebo T.
        • Petersen E.E.
        • Rasmussen S.A.
        • et al.
        Update: interim guidelines for health care providers caring for pregnant women and women of reproductive age with possible Zika virus exposure–United States, 2016.
        MMWR Morb Mortal Wkly Rep. 2016; 65: 1-6
      1. ACOG and SMFM. Practice advisory: updated interim guidance for care of obstetric patients and women of reproductive age during a Zika virus outbreak. Available at: http://www.acog.org/About-ACOG/News-Room/Practice-Advisories/Practice-Advisory-Interim-Guidance-for-Care-of-Obstetric-Patients-During-a-Zika-Virus-Outbreak. Accessed Feb. 12, 2016.

      2. World Health Organization. Zika situation report: neurological syndrome and congenital anomalies. Available at: http://apps.who.int/iris/bitstream/10665/204348/1/zikasitrep_5Feb2016_eng.pdf?ua=1. Accessed Feb. 11, 2106.

        • Mlakar J.
        • Korva M.
        • Tul N.
        • et al.
        Zika virus associated with microcephaly.
        N Engl J Med. 2016; 374: 951-958
        • Oliveira Melo A.S.
        • Malinger G.
        • Ximenes R.
        • Szejnfeld P.O.
        • Alves Sampaio S.
        • Bispo de Filippis A.M.
        Zika virus intrauterine infection causes fetal brain abnormality and microcephaly: tip of the iceberg?.
        Ultrasound Obstet Gynecol. 2016; 47: 6-7
        • International Society of Ultrasound in Obstetrics and Gynecology Education Committee
        Sonographic examination of the fetal central nervous system: guidelines for performing the “basic examination” and the “fetal neurosonogram”.
        Ultrasound Obstet Gynecol. 2007; 29: 109-116
        • Chervenak F.A.
        • Rosenberg J.
        • Brightman R.C.
        • Chitkara U.
        • Jeanty P.
        A prospective study of the accuracy of ultrasound in predicting fetal microcephaly.
        Obstet Gynecol. 1987; 69: 908-910
        • Persutte W.H.
        Microcephaly–no small deal.
        Ultrasound Obstet Gynecol. 1998; 11: 317-318
        • Stoler-Poria S.
        • Lev D.
        • Schweiger A.
        • Lerman-Sagie T.
        • Malinger G.
        Developmental outcome of isolated fetal microcephaly.
        Ultrasound Obstet Gynecol. 2010; 36: 154-158
        • Leibovitz Z.
        • Daniel-Spiegel E.
        • Malinger G.
        • et al.
        Microcephaly at birth–the accuracy of three references for fetal head circumference. How can we improve prediction?.
        Ultrasound Obstet Gynecol. 2015; ([Epub ahead of print])