The main findings of this cohort study are twofold. First, we found a 7.0% overall risk of neurologic and ocular defects possibly associated with ZIKV infection that were evident at birth in the offspring of women in French territories in the Americas who had acute, symptomatic, PCR-confirmed ZIKV infection during pregnancy. The overall risk of evident birth defects included in the current definition of the congenital Zika syndrome was 3.1%, and the overall risk of severe microcephaly was 1.6%. Second, although birth defects could be observed as a consequence of ZIKV infection in any trimester of pregnancy, our data showed that the risk of birth defects and the risk of the congenital Zika syndrome were higher when ZIKV infection occurred early in pregnancy — a finding consistent with previous reports.5,15 The risk of birth defects was 12.7% when ZIKV infection occurred in the first trimester, 3.6% when it occurred in the second trimester, and 5.3% when it occurred in the third trimester, and the risk of the congenital Zika syndrome was 6.9%, 1.2%, and 0.9%, respectively.

The percentage of fetuses and infants with neurologic birth defects (7%) in this study is similar to the 6% observed in the cohort of women in the United States5 and the 5% reported more recently in the U.S. territories,15 but it is much lower than the 42% observed in the Brazilian cohort.3 The difference is not attributable to the percentage of infants and fetuses with microcephaly — which is similar in the current study in French territories in the Americas, in the study in the United States, and in the study in Brazil (5.8%, 4.1%, and 3.4%, respectively) — but rather to the percentage with wider neurologic birth defects. The percentage of infants who were small for gestational age was similar in French territories in the Americas and in the Brazilian cohort (13.1% and 9%, respectively), but differences between those two cohorts are apparent when we examine the percentage of infants who were admitted to neonatal intensive care immediately after birth (1.3% in the French territories and 21% in Brazil) and the percentage of infants with abnormal neurologic findings from the clinical examination at birth (0.6% and 26.5%, respectively). The termination of 10 pregnancies for medical reasons in the French territories (as compared with none in Brazil) may have resulted in fewer neurologic abnormalities being detected at birth in the French territories than in Brazil, but this cannot explain the entire difference between the two cohorts. In addition, the extensive use of MRI in the Brazilian cohort may have resulted in isolated abnormal imaging findings that have not been observed in other studies in which the use of MRI has been less frequent. The clinical implications of these findings in Brazil are not yet known and will be determined only through longer-term follow-up of infants.

The strengths of our study include the size and homogeneity of the cohort of pregnant women who were living in a region in which an outbreak of ZIKV occurred and who were prospectively followed from the time that acute symptoms developed and ZIKV infection was confirmed by PCR until the pregnancy outcome. The diagnosis of ZIKV infection was made on the basis of PCR testing of specimens of blood or urine or both, and the date of infection could be ascertained because the date of symptom onset was close to the date of ZIKV PCR testing. The study was conducted in well-defined geographic areas, and high standards of care were available to all pregnant women living in these territories. Linkage to care of pregnant women with ZIKV infection was effective, with a low rate of loss to follow-up (1.6%). In addition, the results were consistent across the two territories in which the largest numbers of women were recruited (Martinique and Guadeloupe).

We acknowledge that our study has limitations. First, it focused only on pregnant women who had acute, symptomatic ZIKV infection. Although the rate of complications would be expected to be higher among women with symptomatic infection than among those who were asymptomatic, an observational study involving U.S. women did not show any significant difference in the rate of birth defects between the offspring of women who had symptomatic ZIKV infection and the offspring of women who had asymptomatic ZIKV infection during pregnancy.5 A recent study also showed no significant association between disease severity or viral load and adverse outcomes.16 Second, we were not able to fully assess the presence of birth defects possibly associated with ZIKV infection in the case of the 11 miscarriages, 2 of the 6 stillbirths, and the 1 voluntary abortion, as well as in the 96 live-born infants (18.2% of the 527 live-born infants) who did not undergo prenatal ultrasonography after ZIKV infection. Although missing ultrasonographic data may have led to underdiagnosis of ZIKV-related birth defects, it should be noted that in our cohort, only 1 live-born baby had an isolated brain abnormality (ventriculomegaly), detected by MRI, in the absence of clinical abnormalities, after infection during the second trimester of pregnancy. All other live-born babies with ZIKV-related defects had at least one abnormality that would have been detected during the clinical examination at birth (e.g., microcephaly, clubfoot, or a neural-tube defect such as spina bifida). Also, the majority of missing ultrasonographic data involved pregnancies in which infection occurred during the third trimester, and the consequences of infection during the third trimester were found to be limited in the other infants of the same cohort. Third, our end point was based on fetal ultrasonography and on neonatal clinical examinations and did not include postnatal ultrasonography or specialized hearing and ophthalmologic examinations. We believe that this aspect of the study design had a limited effect on the rate of birth defects that could have been identified if all neonates had undergone brain imaging soon after birth. Indeed, it has been reported that when ZIKV infection occurs during the first trimester or early second trimester, all brain abnormalities can be detected with ultrasonography before 28 weeks of gestation.10 Another study showed that none of 103 infants with normal prenatal ultrasonographic findings and normal clinical examinations at birth had anomalies attributable to ZIKV when MRI of the head was performed after birth.17 Still, the absence of microcephaly at birth does not exclude the possibility of delayed development of microcephaly or other ZIKV-related brain and other abnormalities.18 This information is now being collected as part of a cohort study of the infants (ClinicalTrials.gov number, NCT02810210); the study includes regular clinical examinations with specialized hearing and ophthalmologic testing. Only the longer-term follow-up of the children born to the women in the current study will help identify the full spectrum of ZIKV-related complications.

In conclusion, among pregnant women with PCR-confirmed, symptomatic ZIKV infection, birth defects possibly associated with ZIKV infection were present in 7% of fetuses and infants. Defects were more common among fetuses and infants whose mothers had been infected early in pregnancy. Longer-term follow-up of infants is required to assess for late-onset manifestations not detected at birth.