Diagnostic accuracy of prenatal imaging for the diagnosis of congenital Zika syndrome: Systematic review and meta-analysis

Objective The aim of this study was to assess the accuracy of prenatal imaging for the diagnosis of congenital Zika syndrome. Data sources Medline (via Pubmed), PubMed, Scopus, Web of Science, and Google Scholar from inception to March 2022. Two researchers independently screened study titles and abstracts for eligibility. Study eligibility criteria Observational studies with Zika virus-infected pregnant women were included. The index tests included ultrasound and/or magnetic resonance imaging. The reference standard included (1) Zika infection-related perinatal death, stillbirth, and neonatal death within the first 48 h of birth, (2) neonatal intensive care unit admission, and (3) clinically defined adverse perinatal outcomes. Synthesis methods We extracted 2 × 2 contingency tables. Pooled sensitivity and specificity were estimated using the random-effects bivariate model and assessed the summary receiver operating characteristic (ROC) curve. Risk of bias was assessed using QUADAS 2 tool. The certainty of the evidence was evaluated with grading of recommendations. Results We screened 1,459 references and included 18 studies (2359 pregnant women, 347 fetuses with confirmed Zika virus infection). Twelve studies (67%) were prospective cohorts/case series, and six (37%) were retrospective cohort/case series investigations. Fourteen studies (78%) were performed in endemic regions. Ten studies (56%) used prenatal ultrasound only, six (33%) employed ultrasound and fetal MRI, and two studies (11%) used prenatal ultrasound and postnatal fetal MRI. A total of six studies (ultrasound only) encompassing 780 pregnant women (122 fetuses with confirmed Zika virus infection) reported relevant data for meta-analysis (gestation age at which ultrasound imagining was captured ranged from 16 to 34 weeks). There was large heterogeneity across studies regarding sensitivity (range: 12 to 100%) and specificity (range: 50 to 100%). Under a random-effects model, the summary sensitivity of ultrasound was 82% (95% CI, 19 to 99%), and the summary specificity was 97% (71 to 100%). The area under the ROC curve was 97% (95% CI, 72 to 100%), and the summary diagnostic odds ratio was 140 (95% CI, 3 to 7564, P < 0.001). The overall certainty of the evidence was “very low”. Conclusion Ultrasound may be useful in improving the diagnostic accuracy of Zika virus infection in pregnancy. However, the evidence is still substantially uncertain due to the methodological limitations of the available studies. Larger, properly conducted diagnostic accuracy studies of prenatal imaging for the diagnosis of congenital Zika syndrome are warranted. Systematic review registration Identifier [CRD42020162914].


Besnard 2016
Population assessed in the study was comprised by 19 cases of congenital cerebral malformations. CZS was not examined for every case "For some cases with of non-microcephalic, congenital abnormalities we were not able to prove or exclude ZIKV infection retrospectively". Data extracted took into account malformation and report of ZIKV infection, based on PCR evaluation or mother reporting symptoms during pregnancy.

N Source
TP (abnormal prenatal imaging + zika confirmation) 7 According to figure 4, cases with abnormal prenatal US and confirmation of ZIKV infection (4) and abnormal prenatal US+ mother experiencing symptoms of ZIKV infection + medical termination of pregnancy (3).
FN (normal prenatal imaging + abnormal postnatal outcome) 0 There is no report of normal prenatal US and brain abnormalities related to ZIKV infection.

TN (normal prenatal and mothers reporting no ZIKV infection symptoms/no
ZIKVneutralising antibodies) 6 According to figure 4, prenatal US did not show brain abnormalities in 6 cases, 5 cases reported under group 3 and 1 under group 1b. It is mentioned that cases on group 3 had no ZIKV neutralising antibodies and no symptoms during pregnancy and laboratory tests were normal for the 1 case on group 1b, and the mother was asymtomatic.

N Source
TP (abnormal prenatal imaging + zika confirmation or exclusion of other congenital infections)

19
The study reported 19 cases of microcephaly, ALL detected by prenatal US. Thus, FN and TN = zero.
According to the study:  Second-trimester ultrasound was normal in all except three cases: two cases of brain malformations in the confirmed group (2/8, 25%), both consistent with CZS (case 1 and 8,

Definitions of fetal brain anomalies
Definitions of the anomalies in fetal brain reported: Three studies classify fetal brain findings in major and minor anomalies (37,43,46). Major anomalies associated to CZS included: major CNS abnormality, like agenesia of corpus callosum, brainstem dysgenesis and migration disorders. Minor findings included: abnormal doppler, umbilical artery and middle cerebral artery; fetal growth restriction (FGR), amniotic fluid anomalies, oligohydramnios, and polyhydramnios; choroid plexus cyst. One of the studies did not report any brain abnormalities definitions at all (35).
Fetal microcephaly: Mild to moderate microcephaly was determined based on the head circumference, but the criterion varied across studies. Of the 18 included studies, 6 (33.3%) used a head circumference smaller than three standard deviations below the mean to define microcephaly. One study defined severe microcephaly as a head circumference smaller than three standard deviations below the mean of the gestational age or smaller than two standard deviations below the mean, along with some other CNS findings. Five studies used the CDC definition of microcephaly as a head circumference smaller than the 3rd percentile for gestational age ( Fetal ventriculomegaly: Fetal ventriculomegaly definition varied across the studies. Majority of the studies classified ventriculomegaly as severe, above 15mm (4, 36-40). Other studies classified as a mild ventriculomegaly when the level of the atria measures between 10-12mm; Sarno et al (33), classified a mild anomaly when atria <15mm.One study used to cut off >10mm to describe ventriculomegaly (42).

Growth abnormalities:
Pires et al estimated fetal weight (EFW) with the Hadlock 3 formula (39); Pereira, Mulkey defined FGR as fetal weight <10 percentile with Hadlock formula (35,42) ; IG-21 was used by (4,36) . One study reported femur sparring pattern of fetal growth restriction using fetal body ratios and IG-21 and did not use EFW to make the definition (47). Pereira small for gestational age neonate (SGA) was defined by IG-21 standards-Doppler studies. The pulsatility index of the umbilical artery and middle cerebral artery (MCA) were defined as abnormal if 1) greater than the 95 th percentile or 2) if the peak systolic velocity of the MCA was greater than 1.5 multiples of the median