Twenty-eight (11.2%) women with antenatal Zika virus infection and 4,340 (5.8%) women without Zika virus infection gave birth to an SGA neonate; after adjustment, the risk of having an SGA neonate was 1.8 times higher for women with antenatal Zika virus infection (95% CI 1.3–2.6) (Table 2). For women with and without antenatal Zika virus infection, prevalence of preterm birth was 8.8% and 7.8%, respectively; there was no association between antenatal Zika virus infection and preterm birth in the adjusted model, however, CIs were wide (relative risk 1.0; 95% CI 0.69–1.6). Mean birth weight of the 228 neonates born at term to women with antenatal Zika virus infection was 3,256±479 g vs 3,303±447 g for the 68,861 term neonates born to women without Zika virus infection; this difference was not significant in crude or adjusted analyses.
Of the 250 neonates born to women with antenatal Zika virus infection, 202 (80.8%) had Zika virus testing after birth; 20 neonates (9.9%) had laboratory evidence of congenital Zika virus infection (Table 3). The proportion of neonates born SGA and preterm were similar for neonates with positive and negative Zika virus test results (10.0% vs 11.5%, and 5.0% vs 7.1%, respectively), and the difference in mean birth weight between these two groups was 133 g.
In the sensitivity analysis restricted to the 73 women (29.2% of Zika virus–positive women) with confirmed Zika virus infection (ie, excluding those with probable Zika virus infection), the adjusted risk ratio of SGA was 2.8 (95% CI 1.7–4.6) (Appendix 1, available online at http://links.lww.com/AOG/B624). Term neonates born to women with confirmed Zika virus infection had lower mean birth weight than those born to women with no Zika virus infection (adjusted difference, −110 g, 95% CI −204 to −16 g). Excluding 3,069 women in the unexposed group who had recently emigrated from a country with mosquito-borne Zika virus transmission gave similar results to the main analyses, as did analyses restricted to 24,323 New York City women who were born in these countries (Appendix 2, available online at http://links.lww.com/AOG/B624). When we defined SGA according to a U.S.-based growth reference,25 more neonates were classified as SGA (13.4% vs 5.8% using INTERGROWTH-21st). Using this reference, antenatal Zika virus infection was associated with 1.5 times higher risk of having an SGA neonate (95% CI 1.1–1.9) (Appendix 2, http://links.lww.com/AOG/B624).
Women with antenatal Zika virus infection were more likely to have an SGA neonate compared with women with no Zika virus infection in this cohort of nonwhite women in New York City. This difference remained significant after controlling for parity and region of origin and was robust across several sensitivity analyses. Prevalence of preterm delivery and birth weight of term neonates were similar in both groups. These findings provide supportive evidence for the hypothesis that antenatal Zika virus infection might be associated with SGA, but do not support an association with preterm birth or birth weight at term.
To date, few studies have compared birth outcomes for women with and without laboratory evidence of Zika virus during pregnancy. Brasil et al9 enrolled women with fever in pregnancy and compared those who tested positive for Zika virus with those with negative Zika virus test results, some of whom were diagnosed with chikungunya virus. Despite this morbidity in the comparison group, investigators found a not-statistically significant higher proportion of SGA in the Zika virus–positive group (8.6% vs 5.3%, P=.06). Similar to our findings, preterm birth risk in that study did not differ between the two groups. A smaller U.S. study26 compared 29 women with laboratory evidence of Zika virus infection with women with potential exposure to Zika virus but negative test results and found no difference in birth weight or risk of SGA or preterm birth.
In our cohort, antenatal Zika virus infection was associated with a higher risk of SGA, however only two neonates of 20 with congenital Zika virus infection were SGA. This raises several possible hypotheses. First, antenatal Zika virus infection may be associated with SGA even without congenital Zika virus infection. Studies of other viruses have suggested that maternal infection during pregnancy may impair placental function and affect fetal growth, even without transmission of the virus to the fetus.3,27,28 In mouse models, Zika virus shows tropism for placental tissue and induces pathologic changes that cause placental insufficiency resulting in fetal growth restriction.29 Thus, Zika virus might induce growth restriction in the absence of congenital infection, resulting in neonates who are SGA. A study of 66 pregnant women in New York City with possible Zika virus infection found a pattern of femur-sparing fetal growth restriction in the majority, whereas few neonates had laboratory evidence of congenital Zika virus infection when tested after birth.30 Second, congenital Zika virus infection may have been under-ascertained in our cohort. In our study, 20% of neonates born to mothers with probable or confirmed Zika virus were not themselves tested for Zika virus. Also, sensitivity of Zika virus testing in neonates is unknown. Though we found that very few SGA neonates born to women with antenatal Zika virus infection themselves had laboratory evidence of Zika virus infection, it is possible more SGA neonates were affected by congenital Zika virus infection than were detected by routine testing of neonate serum and urine.
Small-for-gestational-age can co-occur with microcephaly, the primary neonate outcome of antenatal Zika virus infection studied to date. For symmetrically small neonates with SGA, head circumference may meet criteria for microcephaly owing to growth restriction and not disrupted brain development, particularly if no abnormalities are detected on neuroimaging.31 Silva et al32 found fetal growth restriction was strongly associated with microcephaly. Understanding the association of antenatal Zika virus infection and fetal growth can inform the evaluation of neonates with congenital Zika virus exposure and microcephaly. Longitudinal studies of neurodevelopment for infants with congenital Zika virus exposure will be important for understanding whether risk of adverse outcomes differs between SGA and appropriate-for-gestational-age neonates.
Small-for-gestational-age is a relative measure dependent on a specific growth reference or standard. Using the INTERGROWTH-21st Growth Standard,16 recommended by the CDC for the evaluation of neonates with possible Zika virus exposure33 and commonly used in published studies about Zika virus,9,34 only 5.8% of neonates in this cohort were in the lowest 10th percentile of birth weight. Reasons for this may include the exclusion of women with diabetes and those with BMIs higher than 30 from the INTERGROWTH-21st derivation cohort, because these women typically give birth to larger neonates.16,35 Supporting this hypothesis, our sensitivity analysis using a U.S.-derived growth reference classified more than 13% of New York City neonates as SGA. However, the results of our analyses were not sensitive to the growth reference chosen.
Strengths of this study include the relatively large cohort of women with probable or confirmed Zika virus infection and use of birth record data; the latter enabled us to control for maternal nativity, because a high proportion of New York City women diagnosed with antenatal Zika virus infection were born outside the United States. However, the results are subject to several limitations. Some women may have had Zika virus infection but were misclassified as uninfected because they were tested after molecular and serologic evidence could be detected, they were not tested in New York City, or not tested at all. Next, because serologic testing for Zika virus is subject to cross-reactivity with other flaviviruses,36 some positive Zika virus results might reflect infection with another flavivirus (eg, dengue), and not Zika virus. However, sensitivity analyses addressing these possible forms of misclassification supported our findings.
Despite the larger size of our cohort, some analyses had sample sizes too small to analyze and CIs that did not allow us to rule out either protective or harmful effects of antenatal Zika virus infection. Although we were able to control for many important predictors of birth weight, residual confounding might have influenced our findings. Medical comorbidities and smoking during pregnancy often are poorly documented in birth certificate data,37,38 potentially explaining the very low estimates of smoking in this cohort. Information about maternal characteristics and medical conditions obtained from birth certificates may be inaccurate, therefore models adjusting for these variables may not fully remove confounding. Of note, because the self-reported variables used for the birth certificate are usually documented at the first obstetric visit, most women would have provided these data before receiving information on their Zika virus infection status, thereby diminishing potential recall bias related to Zika virus infection status.
Trimester of Zika virus infection during pregnancy may be associated with differential risk of adverse outcomes; however, given the large proportion of women who had an asymptomatic infection and whose laboratory evidence of Zika virus infection was serologic and not molecular in nature, we did not have sufficient data on timing of infection to address this question. Lastly, we only included live births in this analysis. Pregnancies affected by fetal growth restriction may result in miscarriage, stillbirth, or abortion. As such, an analysis of live births may underestimate the association between antenatal Zika virus infection and growth restriction.
In summary, among women who gave birth in New York City in 2016, we found Zika virus infection during pregnancy was associated with higher risk of SGA. Prospective studies of women with Zika virus infection during pregnancy are needed to validate this finding.
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