G. Malinger

Zika virus intrauterine infection causes fetal brain abnormality and microcephaly: tip of the iceberg?

An unexpected upsurge in diagnosis of fetal and pediatric microcephaly has been reported in the Brazilian press recently. Cases have been diagnosed in nine Brazilian states so far. By 28 November 2015, 646 cases had been reported in Pernambuco state alone. Although reports have circulated regarding the declaration of a state of national health emergency, there is no information on the imaging and clinical findings of affected cases. Authorities are considering different theories behind the ‘microcephaly outbreak’, including a possible association with the emergence of Zika virus disease within the region, the first case of which was detected in May 20151. Zika virus is a mosquito-borne disease closely related to yellow fever, dengue, West Nile and Japanese encephalitis viruses2. It was first identified in 1947 in the Zika Valley in Uganda and causes a mild disease with fever, erythema and arthralgia. Interestingly, vertical transmission to the fetus has not been reported previously, although two cases of perinatal transmission, occurring around the time of delivery and causing mild disease in the newborns, have been described3. We have examined recently two pregnant women from the state of Paraiba who were diagnosed with fetal microcephaly and were considered part of the ‘microcephaly cluster’ as both women suffered from symptoms related to Zika virus infection. Although both patients had negative blood results for Zika virus, amniocentesis and subsequent quantitative real-time polymerase chain reaction4, performed after ultrasound diagnosis of fetal microcephaly and analyzed at the Oswaldo Cruz Foundation, Rio de Janeiro, Brazil, was positive for Zika virus in both patients, most likely representing the first diagnoses of intrauterine transmission of the virus. The sequencing analysis identified in both cases a genotype of Asian origin. In Case 1, fetal ultrasound examination was performed at 30.1 weeks’ gestation. Head circumference (HC) was 246 mm (2.6 SD below expected value) and weight was estimated as 1179 g (21st percentile). Abdominal circumference (AC), femur length (FL) and transcranial Doppler were normal for gestational age as was the width of the lateral ventricles. Anomalies were limited to the brain and included brain atrophy with coarse calcifications involving the white matter of the frontal lobes, including the caudate, lentostriatal vessels and cerebellum. Corpus callosal and vermian dysgenesis and enlarged cisterna magna were observed (Figure 1). In Case 2, fetal ultrasound examination was performed at 29.2 weeks’ gestation. HC was 229 mm (3.1 SD below Figure 1 Case 1: (a) Transabdominal axial ultrasound image shows cerebral calcifications with failure of visualization of a normal vermis (large arrow). Calcifications are also present in the brain parenchyma (small arrow). (b) Transvaginal sagittal image shows dysgenesis of the corpus callosum (small arrow) and vermis (large arrow). (c) Coronal plane shows a wide interhemispheric fissure (large arrow) due to brain atrophy and bilateral parenchymatic coarse calcifications (small arrows). (d) Calcifications are visible in this more posterior coronal view and can be seen to involve the caudate (arrows).

Congenital Zika Virus Infection: Beyond Neonatal Microcephaly

ImportancenRecent studies have reported an increase in the number of fetuses and neonates with microcephaly whose mothers were infected with the Zika virus (ZIKV) during pregnancy. To our knowledge, most reports to date have focused on select aspects of the maternal or fetal infection and fetal effects.nnnObjectivenTo describe the prenatal evolution and perinatal outcomes of 11 neonates who had developmental abnormalities and neurological damage associated with ZIKV infection in Brazil.nnnDesign, Setting, and ParticipantsnWe observed 11 infants with congenital ZIKV infection from gestation to 6 months in the state of Paraíba, Brazil. Ten of 11 women included in this study presented with symptoms of ZIKV infection during the first half of pregnancy, and all 11 had laboratory evidence of the infection in several tissues by serology or polymerase chain reaction. Brain damage was confirmed through intrauterine ultrasonography and was complemented by magnetic resonance imaging. Histopathological analysis was performed on the placenta and brain tissue from infants who died. The ZIKV genome was investigated in several tissues and sequenced for further phylogenetic analysis.nnnMain Outcomes and MeasuresnDescription of the major lesions caused by ZIKV congenital infection.nnnResultsnOf the 11 infants, 7 (63.6%) were female, and the median (SD) maternal age at delivery was 25 (6) years. Three of 11 neonates died, giving a perinatal mortality rate of 27.3%. The median (SD) cephalic perimeter at birth was 31 (3) cm, a value lower than the limit to consider a microcephaly case. In all patients, neurological impairments were identified, including microcephaly, a reduction in cerebral volume, ventriculomegaly, cerebellar hypoplasia, lissencephaly with hydrocephalus, and fetal akinesia deformation sequence (ie, arthrogryposis). Results of limited testing for other causes of microcephaly, such as genetic disorders and viral and bacterial infections, were negative, and the ZIKV genome was found in both maternal and neonatal tissues (eg, amniotic fluid, cord blood, placenta, and brain). Phylogenetic analyses showed an intrahost virus variation with some polymorphisms in envelope genes associated with different tissues.nnnConclusions and RelevancenCombined findings from clinical, laboratory, imaging, and pathological examinations provided a more complete picture of the severe damage and developmental abnormalities caused by ZIKV infection than has been previously reported. The term congenital Zika syndrome is preferable to refer to these cases, as microcephaly is just one of the clinical signs of this congenital malformation disorder.

ISUOG Interim Guidance on ultrasound for Zika virus infection in pregnancy: information for healthcare professionals

In response to the World Health Organization (WHO) statements and international concerns regarding the Zika virus (ZIKV) outbreak, ISUOG is publishing the following guidance for ultrasound during pregnancy. With the current uncertainty regarding many aspects of the diagnosis and clinical course of ZIKV infection in pregnancy, potentially valuable information may be obtained by ultrasound practitioners that may help in counseling pregnant women and further improve our understanding of the pathophysiology of ZIKV infection in pregnancy. This statement is not intended to replace previously published interim guidance on evaluation and management of ZIKV-exposed pregnant women. It should therefore be considered in conjunction with other relevant advice from organizations such as:

Association between Zika virus and fetopathy: a prospective cohort study in French Guiana

To establish the incidence of fetal central nervous system (CNS) anomalies (including microcephaly), signs of congenital infection and fetal loss in pregnant women infected with Zika virus (ZIKV) and non‐infected pregnant women in western French Guiana.

Prenatal counseling for neurodevelopmental delay in congenital heart disease: results of a worldwide survey of experts' attitudes advise caution

†Fetal Medicine and Surgery Unit– Istituto G.Gaslini, Genoa, Italy; ‡Department of Women’s and Children’s Health, Institute of Translational Medicine, University of Liverpool, Liverpool, UK; §Fetal Medicine Unit, St George’s University of London; and Brompton Centre for Fetal Cardiology, Royal Brompton Hospital, London, UK; ¶Fetal Medicine Unit, Department of Obstetrics and Gynaecology, St George’s Hospital, London, UK; **Ob-Gyn Ultrasound Unit, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; ††Fetal Medicine, Barcelona Center for Maternal Fetal and Neonatal Medicine, Hospital Clı́nic and Sant Joan de Déu, University of Barcelona, Barcelona, Spain; ‡‡Fetal Heart Program, Children’s Hospital of Philadelphia, PA, USA; §§The Fetal Center, University of Texas Health Science Center at Houston, Houston, TX, USA *Correspondence. (e-mail: dpaladini49@gmail.com)

Assessment of fetal midbrain and hindbrain in mid‐sagittal cranial plane by three‐dimensional multiplanar sonography. Part 1: comparison of new and established nomograms

To construct nomograms for fetal midbrain (MB) and hindbrain (HB) dimensions, assessed in the mid‐sagittal cranial plane by three‐dimensional multiplanar sonographic reconstruction (3D‐MPR).

Assessment of fetal midbrain and hindbrain in mid‐sagittal cranial plane by three‐dimensional multiplanar sonography. Part 2: application of nomograms to fetuses with posterior fossa malformations

To apply fetal midbrain (MB) and hindbrain (HB) nomograms, developed using three‐dimensional multiplanar sonographic reconstruction (3D‐MPR) in the mid‐sagittal cranial plane, to fetuses with known posterior fossa malformations.

Fetal posterior fossa dimensions: normal and anomalous development assessed in mid‐sagittal cranial plane by three‐dimensional multiplanar sonography

To construct nomograms of the dimensions of the fetal posterior fossa (PF), assessed in the mid‐sagittal plane in the second and third trimesters, and to assess how measurements from fetuses with PF abnormalities deviate from our normal ranges.

ISUOG consensus statement on current understanding of the association of neurodevelopmental delay and congenital heart disease: impact on prenatal counseling

An association between congenital heart disease (CHD) and neurodevelopmental delay (NDD) has long been recognized, but remains poorly understood. It is almost certainly multifactorial1–8. A number of abnormal magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS) or sonographic findings, specifically abnormal or delayed sulcation, reduced brain biometry and volumes and abnormal brain biochemistry, have been described in fetuses and neonates with some forms of CHD9–17. This suggests that genetic factors3 and the prenatal environment play an important role in the determination of postnatal neurodevelopmental function, in contrast to traditional concepts attributing adverse neurodevelopmental outcomes to postnatal events such as perinatal hypoxia and perisurgical damage. Furthermore, some large cohort trials have demonstrated an increased risk of NDD mainly – but not only – in children and young adults with univentricular circulation and, to a lesser extent, in those with transposition of the great arteries (TGA)14,18–21. The increasing supportive evidence in this field has led to the publication of an official scientific statement by the American Heart Association22, in which the conclusions are that: ‘Children with CHD are at increased risk of developmental disorder or disabilities or developmental delay’ and, therefore, ‘ . . . surveillance, screening evaluation and re-evaluation during childhood’ are recommended to diagnose and, if possible, treat the various aspects of these disabilities. Experience in the interpretation of any prenatal imaging modality is paramount in assessing its ability to detect real disease and, hence, its true clinical importance. This can be gained only in the setting of well-designed studies. Furthermore, the full extent of clinically important NDD cannot be determined during the first years of a child’s life; thus, these studies also require adequate follow-up. The deficiencies in current published studies have raised genuine and widespread concerns that a discussion of possible adverse neurodevelopmental outcomes linked to CHD may lead couples to opt for termination of pregnancy in those cases of isolated CHD that are usually associated with low mortality and low long-term morbidity, such as TGA. However, the available evidence would suggest that it is neither possible nor ethical to ignore this risk during prenatal counseling14,17,23. A recent survey, conducted by an ISUOG (International Society of Ultrasound in Obstetrics and Gynecology) Task Force to gauge the attitudes and perceptions of health professionals from leading referral units for CHD worldwide found significant differences in the way in which prenatal counseling is conducted, particularly between North American and European centers24. ISUOG has compiled the following Consensus Statement, which will be updated on a regular basis to take into account new studies in this field.

Application of a novel prenatal vertical cranial biometric measurement can improve accuracy of microcephaly diagnosis in utero

To construct a reference range for a new vertical measurement of the fetal head and to assess whether its combination with fetal head circumference (HC) can prevent the misdiagnosis of microcephaly in fetuses with an acrocephalic‐like head deformation.