International pregnancy cohort study to evaluate the effect of influenza virus infection on pregnancy and perinatal outcomes and estimate the vaccine-preventable incidence of influenza during pregnancy among women in low- and middle-income countries

Data from both influenza pandemics and seasonal epidemics indicate that pregnant women are at increased risk of severe illness due to influenza virus infection compared to non-pregnant women of childbearing age or the general population.[1-3] In 2012, the Strategic Advisory Group of Experts (SAGE) on Immunization of the World Health Organization (WHO) identified pregnant women as the highest priority target group for influenza vaccination.  While influenza vaccines are safe [4, 5] and effective [6-9] at preventing influenza among pregnant women, recent data have also suggested that influenza vaccination of pregnant women might have broader effects such as prevention of premature and small for gestational age births.[10-13]  While clinical trials and observational studies have evaluated the effect of influenza vaccination on pregnancy course and outcomes, few data are available on the effect of influenza virus infection on these outcomes to support the plausibility that influenza vaccination might have benefits beyond prevention of influenza during pregnancy.  Further, data on the incidence and effect of influenza virus infection in pregnant women have been largely limited to high-income countries but are needed to inform decisions about introduction of influenza vaccines for pregnant women in low- and middle-income countries where use of influenza vaccines will likelybe weighed against introduction of other public health prevention programs.

This prospective, longitudinal cohort study of pregnant women in low- and middle-income countries will be conducted during two influenza seasons in each country with three primary objectives:  1) to evaluate the effect of laboratory-confirmed influenza virus infection on pregnancy and perinatal outcomes among women in low- and middle-income countries; 2) to estimate the incidences of all-cause acute respiratory illness (ARI), febrile ARI, and laboratory-confirmed influenza virus infection during pregnancy; and 3) to examine the clinical spectrum of illness due to influenza viruses, including duration and severity of illness.

At least 13,200 women who are pregnant with an estimated delivery date at least 8 weeks after the anticipated start date of the influenza season (as predicted by influenza surveillance data from previous years) will be enrolled into the study at up to six study sites over the course of two influenza seasons (i.e. approximately 1,000-2,000 women per site per year).  Efforts will be made to recruit pregnant women who are in any of theall three trimesters of pregnancy for study participation during the enrollment period, so that women in each trimester of pregnancy are represented in the cohort during the influenza season.  At enrollment, participants will complete an enrollment interview and participants who have not already had an ultrasound at <28 weeks gestation with pregnancy dating results that can be verified by medical record will have a transabdominal ultrasound done for pregnancy dating. Up to 700 participants per site during each season may also have blood collected for baseline influenza serologic testing at sites that opt to participate in an optional serology sub-study.

For the purposes of this study, the case definition used for identification of participants with laboratory-confirmed influenza is influenza-like symptoms (ILS) defined as new onset or sudden worsening of one or more of the following symptoms within the past 7 days: myalgia, cough, runny nose or nasal congestion, sore throat, or difficulty breathing.  Definitions for acute respiratory illness and febrile ARI will be applied during data analysis to address study objectives related to these syndromes.  For analytic purposes, ARI is defined as acute illness with new or worsened cough, runny nose, sore throat, or difficulty breathing with symptom onset within the past 7 days (where duration since symptom onset is calculated as the date of reporting minus the date of symptom onset). Febrile ARI is defined as illness meeting the criteria for ARI with measured or reported (subjective) fever or chills.

Throughout cohort participation, participants will be instructed to contact study staff if they experienceinfluenza-like symptoms (ILS), and active surveillance for ILS will be conducted via one or more contact methods, including twice weekly telephone calls, mobile telephone text messaging, or home visits by local health workers depending upon site capabilities and preferences.  Participants with illness episodes meeting the ILS case definition will be asked to complete acute illness and illness follow-up interviews, and during the influenza season, participants will have mid-turbinate nasal swab specimens collected by trained study staff or through self-collection procedures for influenza virus testing by real- time reverse transcription polymerase chain reaction.

Participants will be contacted within 7 days of the end of the pregnancy (i.e. delivery, spontaneous abortion, elective abortion, or stillbirth) to complete a survey on the pregnancy course and perinatal outcomes.  Women who had blood collected at study enrollment as part of the serology sub-study will also have blood specimens collected within 14 days of end of pregnancy for influenza serologic testing.   If women deliver in a study hospital or clinic, infants will be weighed on the day of delivery using standardized digital scales designed to measure weight with accuracy to the nearest 10 grams.  If infants are delivered at a non-study hospital or outside the hospital setting, study staff will attempt to visit the woman on the day of delivery (but no later than 48 hours after delivery) to measure the infant’s birth weight using standardized digital scales designed to measure weight with accuracy to the nearest 10 grams.Other than collecting infant weight, study staff will not provide medical care to the mothers. If medical attention is needed, study staff will refer the mother to medical care per healthcare standard protocol for that site. If medical records of the end of pregnancy are available, data will also be abstracted on select pregnancy and perinatal outcomes.  Women will be contacted again 6-8 weeks postpartum to complete a survey on postpartum and neonatal course.