nutrients Article Association of Hemoglobin and Hematocrit Levels during Pregnancy and Maternal Dietary Iron Intake with Allergic Diseases in Children: The Japan Environment and Children’s Study (JECS) Limin Yang 1,2,* , Miori Sato 1,2, Mayako Saito-Abe 1,2, Makoto Irahara 1,2, Minaho Nishizato 1,2, Hatoko Sasaki 1,2, Mizuho Konishi 1,2, Kazue Ishitsuka 1,2 , Hidetoshi Mezawa 1,2, Kiwako Yamamoto-Hanada 1,2 , Kenji Matsumoto 1,2, Yukihiro Ohya 1,2 and on behalf of the Japan Environment and Children’s Study (JECS) Group † 1 Allergy Center, National Center for Child Health and Development, Tokyo 157-8535, Japan; [email protected] (M.S.); [email protected] (M.S.-A.); [email protected] (M.I.); [email protected] (M.N.); [email protected] (H.S.); [email protected] (M.K.); [email protected] (K.I.); [email protected] (H.M.); [email protected] (K.Y.-H.); [email protected] (K.M.); [email protected] (Y.O.) 2 Medical Support Center for the Japan Environment and Children’s Study, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan * Correspondence: [email protected]; Tel.: +81-3-3416-0181; Fax: +81-3-3416-2222 Citation: Yang, L.; Sato, M.; † Membership of the Japan Environment and Children’s Study (JECS) Group is provided in Saito-Abe, M.; Irahara, M.; Nishizato, the Acknowledgments. M.; Sasaki, H.; Konishi, M.; Ishitsuka, K.; Mezawa, H.; Yamamoto-Hanada, Abstract: Few epidemiologic studies have examined the role of maternal iron status in allergic K.; et al. Association of Hemoglobin diseases in offspring and findings have been inconsistent. We used a large birth cohort in Japan to and Hematocrit Levels during explore the association of the markers for maternal iron status (maternal hemoglobin, hematocrit and Pregnancy and Maternal Dietary Iron dietary iron intake during pregnancy) with allergy development in offspring during early childhood. Intake with Allergic Diseases in We analyzed information on children age 0–3 years from the Japan Environment and Children’s Children: The Japan Environment Study (JECS). We used logistic models and generalized estimating equation models to evaluate the and Children’s Study (JECS). effect of maternal hemoglobin and hematocrit levels and dietary iron intake on allergies in children. Nutrients 2021, 13, 810. https:// Models were also fitted with propensity score-matched datasets. Data were collected for a total doi.org/10.3390/nu13030810 of 91,247 mother–child pairs. The prevalence (95% confidence interval) of low hemoglobin and Academic Editor: James H. Swain hematocrit was 14.0% (13.7–14.2%) and 12.5% (12.3–12.8%), respectively. After adjusting confounders, low hemoglobin and hematocrit during pregnancy were not associated with childhood allergic Received: 30 January 2021 outcomes. Findings from models with propensity score-matched datasets also indicated that children Accepted: 24 February 2021 born to mothers with low hemoglobin or hematocrit levels during pregnancy did not have a higher Published: 1 March 2021 risk of developing allergic conditions at 3 years old. We found no meaningful associations between low energy adjusted maternal dietary iron intake and allergies in children. In conclusion, using Publisher’s Note: MDPI stays neutral birth cohort data, we found no evidence supporting an association of low maternal hemoglobin, with regard to jurisdictional claims in hematocrit and low dietary iron intake with allergy symptoms during early childhood. Further published maps and institutional affil- studies with more suitable proxy markers for blood iron status are needed. iations. Keywords: hemoglobin; hematocrit; iron intake; allergy; pregnancy Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. 1. Introduction This article is an open access article Anemia is one of the most common complications in young women, especially during distributed under the terms and pregnancy. Anemia is considered a risk for many adverse maternal and perinatal outcomes, conditions of the Creative Commons such as prematurity and low size or birth weight, peripartum blood loss, maternal de- Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ pression, fetal impairment and maternal and fetal mortality. Anemia can be caused by 4.0/). genetic traits, inadequate food consumption, folate, or vitamin B12 and other diseases Nutrients 2021, 13, 810. https://doi.org/10.3390/nu13030810 https://www.mdpi.com/journal/nutrients Nutrients 2021, 13, 810 2 of 13 such as malaria, schistosomiasis, hookworm infection and HIV infection [1]. The most common cause of anemia is iron deficiency, which accounts for 50% of diagnoses [1]. In 2011, the prevalence of anemia during pregnancy was 38% worldwide [1], of whom about 75% were manifested with iron deficiency [2]. During pregnancy, the plasma volume increases disproportionately to the erythrocyte mass. As a result, pregnant women with a hemoglobin level less than 12 g/dL may experience “physiologic anemia of pregnancy”. It is generally considered that a hemoglobin concentration <11 g/dL in the late first trimester is abnormal [3]. Allergic conditions are common chronic conditions of immunologic dysfunction among children. A recent nationwide survey in Japan indicated that the prevalence among Japanese primary school students of wheeze, allergic rhino-conjunctivitis and eczema was 10.2%, 18.7% and 14.6%, respectively [4]. The prevalence rates have increased over the past decades [5]. Interactions between genetics and environmental exposures affect the development of allergy [6,7]. Iron deficiency anemia in pregnancy has been linked to an inadequate oxygen and nutrition supply to the fetus, which increases the risk of preterm birth and low birth weight [8–13]. Evidence suggests that preterm birth and low birth weight can affect the offspring’s lung function and development of allergic diseases in childhood [9,14–20]. In addition, a recent study demonstrated that low iron concentration interferes with interferon (IFN)-γ receptor signaling, which is a key factor for allergy prevention [21]. Given this situation, low maternal iron status might influence the development of adverse outcomes in children, including allergies. However, to date, few epidemiologic studies have examined the role of maternal iron status on allergic diseases in offspring and the findings have been inconsistent [18,22–24]. In this study, we used a large birth cohort in Japan to explore the association of indicator of maternal iron status (maternal hemoglobin, hematocrit concentration and dietary iron intake) during pregnancy with development of allergies in offspring during early childhood. 2. Methods 2.1. Study Design Our study population consisted of children between age 0 to 3 years participat- ing in the Japan Environment and Children’s Study (JECS), a nationwide birth cohort study with 104,062 fetal records [25]. The design of the JECS has been described in detail elsewhere [25–27]. The JECS was conducted in accordance with the Helsinki Declaration, and approved by the Ministry of the Environment’s Institutional Review Board on Epi- demiological Studies (No.100406001, 6 April 2010) and by the Ethics Committees of all participating units and institutions. All participants signed informed consent forms [28,29]. The jecs-ta-201901930-qsn dataset, released by the Program Office in October 2019 was used for this analysis. 2.2. Data Collection The processes of data selection in this study, are shown in Figure1. Abortion, stillbirth, unknown pregnancy outcomes, twins and triplets were excluded from the analysis. In the selected cohort, we used data from the following questionnaires: (1) Questionnaires completed by women during their first trimester (named MT1 in JECS) and second/third trimester (MT2). These questionnaires were used to collect information regarding maternal medical background, lifestyle and socioeconomic status; (2) questionnaires completed by the parents of children age 1 to 3 years. Hemoglobin and hematocrit were obtained from maternal blood samples collected during the first trimester. NutrientsNutrients 20212021, 13, 13, 810, 810 3 of 133 of 13 FigureFigure 1. 1. FlowFlow chart chart of data selection.selection. 2.3. Allergies in Children 2.3. Allergies in Children Data on allergic outcomes in children were obtained from the questionnaires com- pletedData by on the allergic caregiver outcomes of children in agechildren 1 to 3 we years.re obtained The outcome from variablesthe questionnaires in this study, com- pletedincluded by wheeze,the caregiver asthma, of atopicchildren dermatitis age 1 to (AD), 3 years. rhinitis, The hayoutcome fever andvariables food allergy. in this The study, includeddefinitions wheeze, of allergic asthma, outcomes atopic (wheeze, dermatitis asthma, (AD), atopic rhinitis, dermatitis hay fever (AD), and rhinitis food allergy. and hay The definitionsfever), using of aallergic modified outcomes Japanese-translated (wheeze, asthma, version atopic of International dermatitis Study (AD), of rhinitis Asthma and and hay fever),Allergies using in Childhood a modified (ISAAC) Japanese-translated [30–32], which ve wasrsion validated of International based on the Study ISAAC of Asthma protocol and Allergiesfor 6–7 years in Childhood children with (ISAAC) part of [30–32], modification, which arewas as validated follows: based on the ISAAC proto- col• forCurrent 6–7 years wheeze: children Caregiver’s with part report of modification, of wheeze in are the as past follows: 12 months. •• CurrentEver wheeze: wheeze: Caregiver’s Caregiver’s report report of wheeze of wheeze ever. in the past 12 months. •• EverEver wheeze: asthma: ACaregiver’s positive answer report to of the wheeze question ever. “Has your children ever had asthma?” • • EverEver rhinitis:asthma: Caregiver’sA positive report answer of sneezingto the question or runny or“Has congested your children nose ever ever when had the child did not have cold or flu. asthma?” • Current rhinitis: Sneezing or a runny or congested nose accompanied by itchy when • Ever rhinitis: Caregiver’s report of sneezing or runny or congested nose ever when the child did not have cold or flu in the past 12 months.