Original Research
Obstetrics
Femur-sparing pattern of abnormal fetal growth in pregnant women from New York City after maternal Zika virus infection

https://doi.org/10.1016/j.ajog.2018.04.047Get rights and content

Background

Zika virus is a mosquito-transmitted flavivirus, which can induce fetal brain injury and growth restriction following maternal infection during pregnancy. Prenatal diagnosis of Zika virus–associated fetal injury in the absence of microcephaly is challenging due to an incomplete understanding of how maternal Zika virus infection affects fetal growth and the use of different sonographic reference standards around the world. We hypothesized that skeletal growth is unaffected by Zika virus 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

We sought to determine if maternal Zika virus infection is associated with a femur-sparing pattern of intrauterine growth restriction through analysis of fetal biometric measures and/or body ratios using the 2014 International Fetal and Newborn Growth Consortium for the 21st Century Project and World Health Organization Fetal Growth Chart sonographic references.

Study Design

Pregnant women diagnosed with a possible recent Zika virus infection at Columbia University Medical Center after traveling to an endemic area were retrospectively identified and included if a fetal ultrasound was performed. Data were collected regarding Zika virus testing, fetal biometry, pregnancy, and neonatal outcomes. The 2014 International Fetal and Newborn Growth Consortium for the 21st Century Project and World Health Organization Fetal Growth Chart sonographic standards were applied to obtain Z-scores and/or percentiles for fetal head circumference, abdominal circumference, and femur length specific for each gestational week. A novel 2014 International Fetal and Newborn Growth Consortium for the 21st Century Project standard was also developed to generate Z-scores for fetal body ratios with respect to femur length (head circumference:femur length, abdominal circumference:femur length). Data were then grouped within clinically relevant gestational age strata (<24, 24–27 6/7, 28–33 6/7, >34 weeks) to analyze time-dependent effects of Zika virus infection on fetal size. Statistical analysis was performed using Wilcoxon signed-rank test on paired data, comparing either abdominal circumference or head circumference to femur length.

Results

A total of 56 pregnant women were included in the study with laboratory evidence of a confirmed or possible recent Zika virus infection. Based on the Centers for Disease Control and Prevention definition for microcephaly after congenital Zika virus exposure, microcephaly was diagnosed in 5% (3/56) by both the 2014 International Fetal and Newborn Growth Consortium for the 21st Century Project and World Health Organization Fetal Growth Chart standards (head circumference Z-score ≤–2 or ≤2.3%). Using 2014 International Fetal and Newborn Growth Consortium for the 21st Century Project, intrauterine fetal growth restriction was diagnosed in 18% of pregnancies (10/56; abdominal circumference 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 abdominal circumference vs femur length by either 2014 International Fetal and Newborn Growth Consortium for the 21st Century Project or World Health Organization Fetal Growth Chart (P < .001 for both). A difference in distribution of fetal abdominal circumference compared to femur length was first apparent in the 24–27 6/7 week strata (2014 International Fetal and Newborn Growth Consortium for the 21st Century Project, P = .002; World Health Organization Fetal Growth Chart, P = .001). A significantly smaller head circumference compared to femur length was also observed by 2014 International Fetal and Newborn Growth Consortium for the 21st Century Project as early as the 28–33 6/7 week strata (2014 International Fetal and Newborn Growth Consortium for the 21st Century Project, P = .007). Overall, a femur-sparing pattern of growth restriction was detected in 52% of pregnancies with either head circumference:femur length or abdominal circumference:femur length fetal body ratio <10th percentile (2014 International Fetal and Newborn Growth Consortium for the 21st Century Project Z-score ≤–1.3).

Conclusion

An unusual femur-sparing pattern of fetal growth restriction was detected in the majority of fetuses with congenital Zika virus 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 Zika virus infection.

Introduction

Zika virus (ZIKV) is a mosquito-transmitted flavivirus, recently linked to microcephaly following a maternal infection during pregnancy.1 Vertical transmission of ZIKV has been associated with fetal microcephaly and development of the congenital ZIKV syndrome, a condition encompassing a spectrum of fetal neurologic injury including cortical malformations, ventriculomegaly, ocular injury, and arthrogryposis.2, 3, 4 A maternal ZIKV infection has been associated with a rate of birth defects between 5–8%, but may be as high as 13% when infection occurs in the first trimester.5, 6 Recently, reports of children with a normal head circumference (HC) at birth who were later found to have abnormal brain imaging, ocular injury, and postnatal development of microcephaly, has led to the concept that microcephaly does not capture the broader spectrum of ZIKV-associated brain injury.3, 7, 8, 9, 10 Identification of fetuses with a normal head size that are at risk for long-term adverse outcomes remains limited due to the incomplete knowledge of how a less overt spectrum of ZIKV-associated fetal injury may be detected prenatally. This limitation is further compounded by weaknesses related to diagnostic testing including: (1) inadequate availability of ZIKV testing in regions at risk, (2) lower sensitivity of real-time polymerase chain reaction testing due to the transient nature of ZIKV viremia, and (3) lower positive predictive value of serologic testing due to cross-reactivity between ZIKV and related flaviviruses.

AJOG at a Glance

  • To determine if Zika virus infection during pregnancy is associated with a femur-sparing pattern of fetal growth restriction, similar to observations in a nonhuman primate model of decelerating growth of the fetal head and abdomen with respect to femur length.

  • An unusual femur-sparing pattern of fetal growth restriction was detected in the majority of fetuses with congenital Zika virus exposure using 2014 International Fetal and Newborn Growth Consortium for the 21st Century Project fetal body ratios comparing head or abdominal circumference to femur length.

  • Fetal body ratios may provide a new screening tool to detect Zika virus-associated fetal injury in pregnancies without overt microcephaly.

In a nonhuman primate model, ZIKV-associated fetal brain injury was associated with an unusual femur-sparing profile of intrauterine growth restriction (IUGR) notable for a growth arrest in ultrasound biometric measures of the fetal head (biparietal diameter [BPD]) and abdomen (abdominal circumference [AC]) with continued growth of the femur (femur length [FL]).11, 12 This profile of IUGR has been noted as “femur-sparing,”13 but has not been characterized in a clinical study nor is it part of the mainstream categories for IUGR; typically, IUGR has been defined as asymmetric (conserved head growth with lagging growth of the abdomen) or symmetric (equal growth restriction of the head, abdomen, and femur).14

There is a paucity of data to link aberrant fetal growth in the context of a maternal ZIKV infection to long-term adverse outcomes in the neonate, but IUGR may represent a sensitive indicator of viral injury to the placenta or fetus itself. Whether fetuses exposed to ZIKV with abnormal growth patterns, without microcephaly, may be more susceptible to eye injury or late-onset microcephaly is unknown and represents an important knowledge gap.15 Although IUGR has been reported in pregnant women with a possible ZIKV infection, the profile of IUGR has not been described.2, 10 Our objective was to determine if maternal ZIKV infection was associated with a femur-sparing profile of growth restriction, similar to observations in a nonhuman primate model of congenital ZIKV infection.11, 12 Such an observation may be a first step in identifying nonmicrocephalic fetuses at risk for long-term morbidity.

Section snippets

Study population and ethics statement

All pregnant women presenting to Columbia University Medical Center from Jan. 1, 2016, through Feb. 1, 2017, from an area with known ZIKV local transmission were offered screening per Centers for Disease Control and Prevention (CDC) recommendations. The Columbia University Institutional Review Board approved the study (IRB-AAAQ9686) as a retrospective chart review and informed consent was not required. Cases were excluded if no ultrasound for fetal size or anatomy was completed prior to

ZIKV diagnosis and timing of exposure

Study participants were pregnant women diagnosed with ZIKV infection after travel to countries with local transmission, who received obstetrical care from Columbia University Medical Center (New York, NY) from Jan. 1, 2016, through Feb. 1, 2017. A total of 66 pregnant women were retrospectively identified with a recent ZIKV infection and 56 were included based on availability of ultrasound data within the Columbia University health care system. The cohort was of mixed race/ethnicity: 12

Principal findings of the study

Our study is the first to demonstrate a femur-sparing pattern of IUGR in late gestation of women with a possible ZIKV infection. This unusual fetal growth profile was found by application of the IG-21 and WHO-FGC standards and differs from prior models of IUGR (Figure 2). We found a significant skewing of fetal biometrics with a smaller AC vs FL, which was first apparent in the 24–27 6/7 week strata. Fetal body ratios (HC:FL and AC:FL, by IG-21) were consistent with a femur-sparing pattern of

Acknowledgment

We would like to acknowledge Jan Hamanishi for technical assistance with preparation of the figures. We thank Dr Torvid Kiserud for consultation and advice related to the WHO-FGC. Aris T. Papageorghiou is supported by the National Institute for Health Research Oxford Biomedical Research Centre.

Data Availability

Fetal biometric measures from de-identified cases will be made available upon request.

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      Postnatal testing, as recommended by the CDC, is more likely to detect lesser viral injuries through cranial ultrasound imaging (and/or MRI, if feasible), eye examination, auditory screening (ie, automated auditory brainstem response), longitudinal developmental assessments, and close monitoring of growth.38 A maternal ZIKV infection is estimated to result in birth defects in 5–13% of cases, with higher rates of anomalies when infection occurs earlier in pregnancy;22,35,39–43 however, these rates should be taken only as an estimate, given the clinical difficulty in detection of lesser injuries during pregnancy and in the neonatal period. Although the long-term risk for developing ocular and subtle brain injuries after ZIKV exposure in utero is unknown,44 a few case series have reported rates of abnormalities detected in the prenatal and neonatal periods (Table).

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    This work was primarily supported by generous private philanthropic gifts mainly from 5 donors in Florida, who wish to remain anonymous. Further support was obtained from the University of Washington Department of Obstetrics and Gynecology; Seattle Children’s Research Institute; and the National Institutes of Health (NIH), grants R01AI100989 (L.R. and K.M.A.W), AI083019 (M.G.), and AI104002 (M.G.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or other funders. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

    The authors report no conflict of interest.

    Cite this article as: Walker CL, Merriam AA, Ohuma EO, et al. Femur-sparing pattern of abnormal fetal growth in pregnant women from New York City after maternal Zika virus infection. Am J Obstet Gynecol 2018;219:187.e1-20.

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