Incidence of influenza during pregnancy and association with pregnancy and perinatal outcomes in three middle-income countries: a multisite prospective longitudinal cohort study

Abstract

Background: Influenza vaccination during pregnancy prevents influenza among women and their infants but remains underused among pregnant women. We aimed to quantify the risk of antenatal influenza and examine its association with perinatal outcomes.

Methods: We did a prospective cohort study in pregnant women in India, Peru, and Thailand. Before the 2017 and 2018 influenza seasons, we enrolled pregnant women aged 18 years or older with expected delivery dates 8 weeks or more after the season started. We contacted women twice weekly until the end of pregnancy to identify illnesses with symptoms of myalgia, cough, runny nose or nasal congestion, sore throat, or difficulty breathing and collected mid-turbinate nasal swabs from symptomatic women for influenza real-time RT-PCR testing. We assessed the association of antenatal influenza with preterm birth, late pregnancy loss (≥13 weeks gestation), small for gestational age (SGA), and birthweight of term singleton infants using Cox proportional hazards models or generalised linear models to adjust for potential confounders.

Findings: Between March 13, 2017, and Aug 3, 2018, we enrolled 11 277 women with a median age of 26 years (IQR 23-31) and gestational age of 19 weeks (14-24). 1474 (13%) received influenza vaccines. 310 participants (3%) had influenza (270 [87%] influenza A and 40 [13%] influenza B). Influenza incidences weighted by the population of women of childbearing age in each study country were 88·7 per 10 000 pregnant woman-months (95% CI 68·6 to 114·8) during the 2017 season and 69·6 per 10 000 pregnant woman-months (53·8 to 90·2) during the 2018 season. Antenatal influenza was not associated with preterm birth (adjusted hazard ratio [aHR] 1·4, 95% CI 0·9 to 2·0; p=0·096) or having an SGA infant (adjusted relative risk 1·0, 95% CI 0·8 to 1·3, p=0·97), but was associated with late pregnancy loss (aHR 10·7, 95% CI 4·3 to 27·0; p<0·0001) and reduction in mean birthweight of term, singleton infants (-55·3 g, 95% CI -109·3 to -1·4; p=0·0445).

Interpretation: Women had a 0·7-0·9% risk of influenza per month of pregnancy during the influenza season, and antenatal influenza was associated with increased risk for some adverse pregnancy outcomes. These findings support the added value of antenatal influenza vaccination to improve perinatal outcomes.

Funding: US Centers for Disease Control and Prevention.

Translations: For the Thai, Hindi, Marathi and Spanish translations of the abstract see Supplementary Materials section.

Figure 1:. Study profile

*Includes all women who presented to the antenatal clinics for antenatal care during the enrolment period. †Includes all women who study staff screened for selected eligibility criteria, such as age, before formal eligibility screening. ‡If participants did not have ultrasounds for gestational dating that met study protocol standards, ultrasounds were done as part of the study. If participants were found to be at gestational age of more than 28 weeks by ultrasound, they were withdrawn due to ineligibility. §Met gestational age criteria by ultrasound and completion of an enrolment interview and at least one surveillance contact. ¶Excluded women who had missing data on gestational age dating by ultrasound at less than 28 weeks or pregnancy outcome (pregnancy loss or livebirth) and women who had elective terminations.

Figure 2:. Incidence of confirmed influenza in pregnant women (N=11 108)

Error bars represent 95% CI. 169 women who were not pregnant for at least 2 weeks during the influenza season were excluded. Influenza season was defined as starting and ending on the date of collection of the first and last nasal swabs that were positive for influenza virus by real-time RT-PCR.