key: cord-0262878-s2swcmcm authors: Avolio, L. N.; Smith, T. J. S.; Navas-Acien, A.; Kruczynski, K.; Pisanic, N.; Randad, P. R.; Detrick, B.; Fry, R. C.; van Geen, A.; Goessler, W.; Karron, R. A.; Klein, S. L.; Ogburn, E. L.; Wills-Karp, M.; Alland, K.; Ayesha, K.; Dyer, B.; Islam, M. T.; Oguntade, H. A.; Rahman, M. H.; Ali, H.; Haque, R.; Shaikh, S.; Schulze, K.; Muraduzzaman, A. K. M.; Alamgir, A. S. M.; Flora, M. S.; West, K. P.; Labrique, A. B.; Heaney, C. D.; Project, JiVitA Maternal and Child Health and Nutrition Research title: Cohort profile: The Pregnancy, Arsenic, and Immune Response (PAIR) Study, a longitudinal pregnancy and birth cohort in rural northern Bangladesh date: 2022-04-05 journal: nan DOI: 10.1101/2022.03.31.22273265 sha: 39da32530dc5f272a2e2c2fb1b304b4ff7c22041 doc_id: 262878 cord_uid: s2swcmcm Purpose: Arsenic exposure and micronutrient deficiencies may alter immune reactivity to influenza vaccination in pregnant women, transplacental transfer of maternal antibodies to the fetus, and maternal and infant acute morbidity. The Pregnancy, Arsenic, and Immune Response (PAIR) Study is a longitudinal pregnancy and birth cohort designed to assess whether arsenic exposure and micronutrient deficiencies alter maternal or newborn immunity and acute morbidity following maternal seasonal influenza vaccination during pregnancy. Participants: We enrolled 784 pregnant women in rural Gaibandha District in northern Bangladesh between October 2018 and March 2019. Women received a quadrivalent seasonal inactivated influenza vaccine at enrollment in the late first or early second trimester between 11 and 17 weeks of gestational age. Follow-up included up to 13 visits between enrollment and three months postpartum as well as weekly telephone surveillance to ascertain influenza-like illness and other acute morbidity symptoms in women and infants. Tube well drinking water and urine specimens were collected to assess arsenic exposure. Of 784 women who enrolled, 736 (93.9%) delivered live births and 551 (70.3%) completed follow-up visit to three months postpartum. Findings to Date: Arsenic was [≥]0.02 g/L in 97.9% of water specimens collected from participants at enrollment. The medians (interquartile ranges) of water and urinary arsenic were 5.1 (0.5-25.1) g/L and 33.1 (19.6-56.5) g/L, respectively. Water and urinary arsenic were strongly correlated (Spearman's {rho}=0.72) among women with water arsenic [≥] median but weakly correlated ({rho}=0.18) among women with water arsenic < median. Future Plans: The PAIR Study is well positioned to examine the effects of low-moderate arsenic exposure and micronutrient deficiencies on immune outcomes in women and infants. Registration: NCT03930017 . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 5, 2022. ; https://doi.org/10.1101/2022.03.31.22273265 doi: medRxiv preprint In-person Visits 169 We completed up to 13 in-person visits to implement questionnaires and collect biological and 170 environmental specimens, beginning at enrollment and continuing to three months postpartum, 171 for a follow-up period of roughly 10-11 months, depending on the timing and duration of each 172 pregnancy (Tables 2 and 3) . These included up to eight visits to the woman during pregnancy 173 and up to five visits to mother-infant pairs after live birth. At three visits (enrollment and 174 vaccination, 28 days post-vaccination, and three months postpartum), the CHRW brought 175 participants (the mother in pregnancy, the mother-infant pair after live birth) to a local clinical 176 center for detailed questionnaire and biospecimen collection. To minimize burden on mothers and 177 infants in the neonatal period, two home visits were conducted shortly after any live birth and 178 again within the first month postpartum for further questionnaire and biospecimen collection. Of 179 784 women who enrolled, 744 (94.9%) completed the 28-day post-vaccination visit, 598 (76.3%) 180 completed a visit within the first month postpartum, and 551 (70.3%) completed the three-month 181 postpartum visit (Table 4 ). In total, 736 (93.9%) enrolled women had 750 live births. Age, 182 gestational age, parity, education, living standards index, household size (number of people), 183 house size (number of rooms), height (cm), body mass index (kg/m 2 ), and urinary arsenic were 184 similar among the women who enrolled and the subset of women who completed follow-up at 185 three months postpartum ( surveillance to ascertain acute morbidities in women (enrollment to three months postpartum) and 191 infants (birth to three months of age). In women, we ascertained high fever with cough, high fever 192 . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 5, 2022. We collected a water specimen from the tube well that each participant indicated was her primary 204 source of drinking water before each center visit and at the home visit conducted within one month 205 postpartum ( Table 2) . Just prior to collection, the well was flushed for approximately five minutes. Up to 22 mL of venous blood was collected from mothers at each of the three center visits: 216 enrollment/vaccination, 28 days post-vaccination, and three months postpartum ( Table 2) . Up to 217 1 mL of capillary blood was collected from infants by heel stick during the center visit at three 218 . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 5, 2022. ; https://doi.org/10.1101/2022.03.31.22273265 doi: medRxiv preprint months postpartum (Table 3) . At the home visit within approximately one month of live birth, blood 219 was collected from mothers and infants using the methods described for the center visits. Blood 220 specimens were transported in temperature-controlled and -monitored coolers to a JiVitA 221 laboratory. Laboratory technicians processed maternal blood to serum, plasma, and peripheral 222 blood mononuclear cells (PBMCs), and processed infant blood to serum, on the day of collection. Micronutrients relevant to one-carbon metabolism will be measured in maternal plasma. 232 Urine was collected from all mothers at the three center visits and during the home visit 233 within one month of birth, and from a subset of mothers (n=468) during a home visit in late 234 pregnancy ( Table 2) . Mothers were asked to provide a urine specimen in a collection cup. A 235 CHRW immediately transferred the specimen to a container certified by the manufacturer as 236 trace-metal free (<1 µg/L for 20 metals, including As) and the specimens were transported to the 237 JiVitA laboratory. Urine specimens were aliquoted and stored at -20°C prior to analysis. Urinary (Tables 2 and 3) . ILI was defined as high fever with cough or sore throat in women and 261 high fever with cough in infants [49] . Severity was determined by calculating the sum of acute 262 morbidity symptoms reported during surveillance. Given limited capacity, women or infants with 263 the highest sum score were prioritized for the collection of a nasal swab. After collection by a 264 CHRW, swabs were placed in universal transport medium. The transport medium was intended 265 for the preservation of viruses (Puritan UniTranz-RT, Guilford, ME, USA). Samples were 266 transported to the local JiVitA lab and stored at -80°C. Nasal swabs were periodically batch-267 transported to IEDCR in Dhaka, Bangladesh, in liquid nitrogen, where RNA will be extracted and 268 tested by RT-qPCR for influenza A and B virus, including sub-types, according to WHO protocols 269 to assess laboratory-confirmed ILI [50] . 270 . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 5, 2022. Blood pressure, hemoglobin, and body temperature of mothers were measured by a local nurse 282 each time a mother had blood drawn ( Table 2) . Systolic and diastolic blood pressure were 283 measured twice, in the left arm, with the woman in a relaxed and seated position using a 284 WelchAllyn DuraShock DS66 Trigger Aneroid Sphygmomanometer (Skaneateles Falls, New 285 York, USA). Hemoglobin was measured in capillary blood by real-time assay using a HemoCue 286 Hb 301 analyzer (Ängelholm, Sweden). Body temperature of infants was measured at the birth 287 assessment and three months postpartum, and hemoglobin was measured at three months 288 postpartum by a local nurse (Table 3) . Vitals were recorded and provided to the mother after each 289 collection. Pregnant women and infants who were severely anemic (hemoglobin <7 g/dL)[53] 290 were given iron tablets and iron syrup, respectively, consistent with the study protocol and as 291 approved by the IRB. Blood type was determined using anti-A, anti-B, and anti-D blood grouping 292 reagents (Cromatest, LiNEAR, Montgat, Spain). 293 294 Questionnaires 295 . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 5, 2022. ; https://doi.org/10.1101/2022.03.31.22273265 doi: medRxiv preprint Questionnaires conducted at multiple visits between enrollment/vaccination and three months 296 postpartum covered a variety of topics (Table 2) , including questions related to the intentionality 297 of pregnancy, seven-and thirty-day morbidity including influenza-like illness, seven-day food 298 frequency, mental health, seven-day strenuous work activity, six-month pesticide storage and 299 use, poultry farming and exposures, handwashing practices, tobacco use and smoke exposure, 300 medical and vaccination history, household food security, and more. Additional questionnaires 301 asked about the birth and delivery of infants, including characteristics of labor and delivery, 302 micronutrient supplement consumption, and health crisis events. Answers to questionnaires for 303 infants were most often provided by the mother, and included morbidity, breastfeeding practices, 304 early feeding practices, infant injury and bleeding, immunization and supplementation, and 305 hospitalization history and medication use ( Table 3) . Topics related to arsenic exposure included 306 drinking water, rice products, and tobacco products and smoke exposure in the previous week. 307 308 JiVitA was established and operates in consultation with local community stakeholders, many of 310 whom are hired as JiVitA staff. JiVitA has benefited from their continued support for nearly two 311 decades. Participants were not directly involved in the design of the PAIR Study. 312 . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 5, 2022. ; https://doi.org/10.1101/2022.03.31.22273265 doi: medRxiv preprint reported during weekly telephone surveillance, based on severity. . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 5, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 5, 2022. Research (IEDCR/IRB/2017/07). All participants gave informed consent prior to enrollment. 424 . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 5, 2022. CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 5, 2022. ; https://doi.org/10.1101/2022.03.31.22273265 doi: medRxiv preprint . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 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Eligibility and enrollment in the Pregnancy, Arsenic, and Immune Response (PAIR) *Initially, pregnant women were eligible at 13-14 weeks of gestational age (GW)