Abstract

BACKGROUND: Zika virus (ZIKV) is a mosquito-transmitted flavivirus, which can induce fetal brain injury and growth restriction following maternal infection during pregnancy. Prenatal diagnosis of ZIKV-associated fetal injury in the absence of microcephaly is challenging due to an incomplete understanding of how maternal ZIKV infection affects fetal growth and the use of different sonographic reference standards around the world. We hypothesized that skeletal growth is unaffected by ZIKV infection and that the femur length can represent an internal standard to detect growth deceleration of the fetal head and/or abdomen by ultrasound. OBJECTIVE: To determine if maternal ZIKV infection is associated with a femur-sparing pattern of intrauterine growth restriction (IUGR) through analysis of fetal biometric measures and/or body ratios using the INTERGROWTH-21st Project (IG-21) and World Health Organization Fetal Growth Chart (WHO-FGC) sonographic references. STUDY DESIGN: Pregnant women diagnosed with a possible recent ZIKV infection at Columbia University Medical Center after traveling to an endemic area were retrospectively identified and included if a fetal ultrasound was performed. Data was collected regarding ZIKV testing, fetal biometry, pregnancy and neonatal outcomes. The IG-21 and WHO-FGC sonographic standards were applied to obtain Z-scores and/or percentiles for fetal head, abdominal circumference (HC, AC) and femur length (FL) specific for each gestational week. A novel IG-21 standard was also developed to generate Z-scores for fetal body ratios with respect to femur length (HC:FL, AC:FL). Data was then grouped within clinically relevant gestational age strata (<24 weeks, 24-27 6/7, 28-33 6/7, >34 weeks) to analyze time-dependent effects of ZIKV infection on fetal size. Statistical analysis was performed using Wilcoxon signed-rank test on paired data, comparing either AC or HC to FL. RESULTS: A total of 56 pregnant women were included in the study with laboratory evidence of a confirmed or possible recent ZIKV infection. Based on the CDC definition for microcephaly after congenital ZIKV exposure, microcephaly was diagnosed in 5% (3/56) by both the IG-21 and WHO-FGC standards (HC Z-score ≤ -2 or ≤ 2.3%). Using IG-21, IUGR was diagnosed in 18% of pregnancies (10/56; AC Z-score ≤-1.3, <10%). Analysis of fetal size using the last ultrasound scan for all subjects revealed a significantly abnormal skewing of fetal biometrics with a smaller AC versus FL by either IG-21 or WHO-FGC (p<0.001 for both). A difference in distribution of fetal AC compared to FL was first apparent in the 24-27 6/7 week strata (IG-21, p=0.002; WHO-FGC, p=0.001). A significantly smaller HC compared to FL was also observed by IG-21 as early as the 28-33 6/7 week strata (IG-21, p=0.007). Overall, a femur-sparing pattern of growth restriction was detected in 52% of pregnancies with either an HC:FL or AC:FL fetal body ratio less than the 10th percentile (IG-21 Z-score ≤-1.3). CONCLUSIONS: An unusual femur-sparing pattern of fetal growth restriction was detected in the majority of fetuses with congenital ZIKV exposure. Fetal body ratios may represent a more sensitive ultrasound biomarker to detect viral injury in nonmicrocephalic fetuses that could impart long-term risk for complications of congenital ZIKV infection.