The burden of influenza among Kenyan pregnant and postpartum women and their infants, 2015–2020

Background: In tropical Africa, data about influenza-associated illness burden are needed to assess potential benefits of influenza vaccination among pregnant women. We estimated the incidence of influenza among pregnant women and their infants in Siaya County, Kenya. Methods: We enrolled women at <31 weeks of gestation and conducted weekly follow-up until 6-month postpartum to identify acute respiratory illnesses (ARIs). We defined ARI among mothers as reported cough, rhinorrhoea or sore throat and among infants as maternal-reported cough, difficulty breathing, rhinorrhoea or clinician diagnosis of respiratory illness. We collected nasal/nasopharyngeal and oropharyngeal swabs from mothers/infants with ARI and tested for influenza A and B using molecular assays. We calculated antenatal incidence of laboratory-confirmed influenza among mothers and postnatal incidence among mothers and infants. Results: During June 2015 to May 2020, we analysed data from 3,026 pregnant women at a median gestational age of 16 weeks (interquartile range [IQR], 13, 18) and followed 2,550 infants. Incidence of laboratory-confirmed influenza during pregnancy (10.3 episodes per 1,000 person-months [95% confidence interval {CI} 8.6–11.8]) was twofold higher than in the postpartum period (4.0 [95% CI 2.6–5.5]; p < 0.01). Incidence was significantly higher among human immunodeficiency virus (HIV)-infected pregnant women (15.6 [95% CI 11.0–20.6] vs. 9.1 [95% CI 7.5–10.8]; p < 0.01). Incidence among young infants was 4.4 (95% CI 3.0–5.9) and similar among HIV-exposed and HIV-unexposed infants. Conclusion: Our findings suggest a substantial burden of influenza illnesses during pregnancy, with a higher burden among HIV-infected mothers. Kenyan authorities should consider the value of vaccinating pregnant women, especially if HIV infected. In 2015, the Kenya Medical Research Institute (KEMRI) in collaboration with the U.S. Centers for Disease Control and Prevention (CDC) initiated a prospective cohort study to estimate the burden of influenza disease in pregnancy and its impact on birth outcomes in western Kenya. The study was conducted in two public hospitals in Siaya County: Siaya County Referral Hospital and Bondo sub‐County Hospital. Siaya County has one of Kenya's highest burdens of maternal and infant mortality; 25 in 2014, maternal mortality was 692 per 100,000 (compared with the national average of 362 per 100,000) and infant mortality was 50 per 1,000 live births (national average, 39 per 1,000). 26 Among women aged 15–49 years, HIV prevalence was 22%, compared with the national average of 5%. 27 Malaria is endemic in the region with an overall prevalence of 37%, 28 and routine surveillance suggests that approximately 20% of pregnant women test positive for malaria during their first antenatal care visit (unpublished KEMRI data). An earlier study in the same region documented 18% parasite prevalence among pregnant women attending first antenatal care visit. 29 Study participants were recruited during home visits or when they came to study hospitals for routine antenatal care visits. For home‐based enrolment, trained community health volunteers (CHVs) administered rapid urine pregnancy tests at home and referred women who tested positive for human chorionic gonadotropin hormone to the nearest study facility for further screening. Pregnant women were eligible for participation if they (i) were under 31 weeks of gestation (established by ultrasound or fundal height), (ii) aged 15–49 years, (iii) resided within 10 km of study facilities and planned to remain in the study area for the next 12 months, (iv) consented to HIV counselling and testing, (v) agreed to all follow‐up visits, and (vi) were willing to deliver at the study facility. Enrolment was restricted to consenting, women with singleton pregnancies (because of likelihood of delivering low birth weight babies among women with twin pregnancies) and those without leg or spinal deformity or history of fistula repair (because of risks for complicated delivery). Before enrolment, study staff obtained written informed consent from women who were willing to participate in the study. Nurses and clinical officers then obtained detailed medical and obstetric histories from enrolled participants and provided HIV counselling and rapid diagnostic testing. The staff also collected demographics, participant contact information for follow‐up, current and past smoking history, use of medications such as anti‐malarial medication (including sulfadoxine–pyrimethamine for intermittent preventive treatment in pregnancy) and other medications, and hospitalizations during the current pregnancy. Health screening included vital signs, physical and obstetric examination (fundal height and presentation, fetal heart sounds and vaginal examination). Mothers were screened for high blood pressure and oedema to evaluate risk of pregnancy‐induced hypertension or preeclampsia. Laboratory examinations included blood grouping (ABO and Rhesus factor), haemoglobin count, urinalysis, venereal disease research laboratory tests, blood smear examination and rapid diagnostic tests for malaria. Medical history included history of TB or active TB on treatment, asthma, chronic obstructive pulmonary disease (COPD)/chronic bronchitis, diabetes, hypertension, epilepsy or other chronic illness. For HIV‐infected women, we documented information about the use of highly active antiretroviral therapy (HAART) and daily use of cotrimoxazole. We conducted weekly surveillance among participants and their infants to identify acute respiratory illnesses (ARIs), using participants' preferred contact method (telephone or home visits by CHV or study staff), until delivery and for 24‐week postpartum for both mother and infant. Participants not reachable after three consecutive weeks were declared lost to follow‐up at the time of last contact. We defined ARIs among pregnant and postpartum mothers as reported cough, runny nose or sore throat and among infants as reported cough, difficulty breathing, runny nose or clinician‐diagnosed respiratory illnesses in the past 7 days, during weekly follow up, and within the past 10 days during clinic visits for mothers and infants. We also inquired about any non‐respiratory illnesses among pregnant women, mothers and infants. Patients were tested for malaria if they were symptomatic or if clinicians/nurses suspected malaria infection. Mothers nearing their expected date of delivery were reminded to deliver at study hospitals. At delivery, study staff examined mothers and newborns and documented birth outcomes. For deliveries that occurred outside study facilities, maternal and newborn examinations were conducted within 72 h of birth. Mothers reporting ARI symptoms or symptoms in their infants during weekly surveillance were asked to come to study clinics for further assessment and management by a study clinician. Respiratory specimens (nasopharyngeal [NP]/nasal [NS] and oropharyngeal [OP]/throat swabs) were collected at study clinics from mothers or/and infants who met criteria for ARI. As a benefit of participation, additional specimens including blood smear for malaria tests, and urine for urinalysis was collected for diagnostics and patient management as per Ministry of Health guidelines. Episodes occurring 14 or more days after a previous ARI episode were considered new episodes. Swabs collected (NS/NP and OP) from a patient presenting with ARI were combined and kept between 2°C and 8°C in cryovials with viral transport medium at field sites, then transported at the end of the day to KEMRI central laboratories located at the main field station in Kisian–Kisumu for testing. The respiratory specimens were tested with real‐time reverse transcription polymerase chain reaction (RT‐PCR) for influenza A and B viruses, using primers and probes provided by CDC's Influenza Division, USA. 30 Assays were considered positive at cycle thresholds of <40.0. We describe demographic and clinical characteristics of pregnant women and pregnancy outcomes, including their infants using counts, percentages, medians, ranges and interquartile ranges (IQRs). We defined the gestational trimesters as first, at ≤13 weeks; second, from 14 to 27 weeks; and third, ≥28 weeks. Periods of increased influenza activity during the year were marked out as months where more specimens were testing positive for influenza than the national average of 7%. We calculated influenza incidence per 1,000 person‐months stratified by maternal HIV status or presence of any chronic condition. Chronic conditions were defined as asthma, TB, diabetes, COPD/chronic bronchitis, epilepsy or hypertension (including essential or pregnancy‐induced hypertension and preeclampsia/eclampsia). We had no access to HIV testing data for infants; we therefore stratified our analysis by HIV exposure for the infants. In calculating rates, we divided the number of laboratory‐confirmed influenza episodes by person‐months of follow‐up and adjusted for the proportion of ARI episodes for which specimens were not tested and for episodes reported during weekly follow‐up but not sampled. To estimate the 95% uncertainty interval (confidence interval [CI]), we ran 1,000 iterations allowing for the proportion sampled (tested) and the proportion that tested positive for influenza to vary assuming a binomial distribution defined by the actual observed proportions. We used the 2.5th and 97.5th values to estimate the lower and upper limits of the 95% CI. Antenatal person‐time was calculated from enrolment to pregnancy outcome (delivery or miscarriage), maternal death or loss to follow‐up; postpartum person‐time was calculated from delivery to maternal death, loss to follow‐up or study completion at 24 weeks for mothers, and postnatal person‐time from birth to infant death, loss to follow‐up or study completion at 24 weeks for infants. We performed analyses using Stata version 13.0 (Stata Corp., College Station, TX). Statistical significance was considered at p < 0.05.