Abstract
OBJECTIVE
Allergic disease is multifactorial in origin. Because iron nutrition affects immune responses and maternal pregnancy weight gain impairs fetal iron delivery while increasing fetal demands for growth, the study examined maternal pregnancy weight gain, newborn iron status and an index of atopic disease, infant eosinophilia.
STUDY DESIGN
Within a larger prospective study of healthy newborns at risk for developing iron deficiency anemia, umbilical cord iron indicators were compared to infant eosinophil counts.
RESULT
Infants who developed eosinophilia exhibited higher cord reticulocyte-enriched zinc protoporphyrin/heme ratio, P < 0.05 and fewer cord ferritin values in the highest (best) quartile, P < 0.05. If cord ferritin was in the upper three quartiles, the negative predictive value for infant eosinophilia was 90%. High maternal pregnancy weight gain predicted infant eosinophil counts, P < 0.04, and contributed to cord ferritin predicting eosinophilia, P < 0.003.
CONCLUSION
Poor fetal iron status may be an additional risk factor for infant eosinophilia.
INTRODUCTION
Risk for poor iron status and atopic disease may overlap in some infants, including those born to mothers with a history of gestational obesity.1,2 Obesity during pregnancy and higher pregnancy weight gain have been shown to lessen the placental transfer of maternal iron, increase iron needs for fetal growth and impair fetal erthyrocyte and tissue iron allotment.3,4 Maternal pregnancy weight gain is also associated with increased risk for childhood asthma5 and dysregulated cord blood immune responses,6 but the mechanism behind this association is unknown.
Persistent blood eosinophilia is a recognized hematological correlate of recurrent wheeze7–10 because it reflects inflammatory pathways involved in the pathogenesis of atopic disease.1,11,12 The maturation, recruitment and activation of eosinophils originates from a relative overproduction of certain cytokines from allergic T-helper (Th) type 2 (Th2) lymphocytes.11,12 Iron is essential for Th cell maturation2,13–15 and the relative amount of cellular iron needed for non-allergic Th type 1 (Th1) lymphocytes is greater than for Th2. In vitro work found compromised Th1 proliferation and cytokine production under iron-limited conditions,16 but unchanged clonal growth and cytokine production in Th2 cells. Poor iron availability during the development of the fetal immune system may consequently result in a pattern of persistent Th2 dominance. The finding of low umbilical cord iron content associated with wheezing in later infancy supports this connection between early iron status and future atopic disease.17 Although typically considered to be distinct pediatric outcomes, the goal of the current analysis was to investigate the linkage between the potential impact of higher maternal pregnancy weight gain, iron status at birth and eosinophilia in infancy. The conceptual framework for our hypothesis-generating investigation is that impaired fetal iron biology, influenced by maternal weight gain, can affect immune regulation and predispose for atopic airway disease in childhood.
METHODS
Eligibility and enrollment
This prospective, observational study examined newborns with prenatal risk factors for the development of infant iron deficiency anemia (IDA) and was approved by the institutional review boards at the University of Wisconsin, Madison and Meriter Hospital. Newborns with one or more of the following risk factors for infant IDA were recruited for enrollment: prenatally diagnosed maternal IDA, pre-gestational or gestational diabetes mellitus, small-for-gestational age or large-for-gestational age newborns, maternal ethnic minority (African American, Latina or Asian) or low socioeconomic status using the surrogate indicator of self-pay or Wisconsin Medicaid.3,4 English- and Spanish-speaking women 18 to 40 years of age delivering infants ≥ 35 weeks of gestation at the Meriter Hospital Birthing Center were approached for written consent. This study screened 210 enrollees with umbilical cord clamping occurring immediately (< 30 s) after birth, and not via delaying clamping ≥ 30 s, a method known to improve iron status. Although all 210 immediate clamped enrollees had cord blood iron assessments, 97 were used here due to availability of eosinophil counts by 12 months of age.
Electronic medical record examination
Electronic medical records were examined for newborn birth weight and length, gestational age, sex or delivery method. Maternal age, anemia, prenatal vitamin use, diabetes, pregnancy complications, body mass index (BMI), maternal pregnancy weight gain, insurance status, education, race/ethnicity and personal and/or family history of atopic disease or asthma were also recorded at delivery. During the first year of life, the infant’s physician performed physical assessments and determined characteristics known to be associated with atopic airway disease. Infant weight and length, duration of breastfeeding, daycare status, number of siblings, respiratory and total infections, wheezing episodes, ER/urgent care visits for wheezing and inhaled beta agonist and systemic steroid therapy were recorded at 6 and/or 12 months of age.
Sample collection and laboratory tests
Blood collected from the umbilical cord was stored at 4 °C and processed within 8 days of collection. Blood was also collected from older infants at 6 and 12 months. Cord and infant iron indices were determined, including hemoglobin (Hb) and mean cell volume by pocH-100i analyzer (Sysmex, Mundelein, IL, USA). Red blood cell iron incorporation was tested by zinc protoporphyrin/heme ratio (ZnPP/H) and reticulocyte-enriched ZnPP/H (RE-ZnPP/H), (Hemafluorometer, Aviv Biomedical, Lakewood, NJ, USA).18 Δ-ZnPP/H (ΔZnPP/H) was defined as the difference between RE-ZnPP/H and whole blood ZnPP/H.18 Storage iron was assessed by plasma ferritin test (Bio-Quant ELISA, San Diego, CA, USA). Infant blood was additionally tested for total white blood cell and lymphocyte counts (pocH-100i analyzer, Sysmex), and eosinophil percentages were determined by a blinded reviewer on Wright-Giemsa-stained smears. From these measures, absolute eosinophil counts were calculated. Cord blood eosinophils were not counted due to potential artifactual lowering of counts after 1 week of storage.
Data analysis
Demographic and laboratory data were initially analyzed by the presence and absence of eosinophilia in infancy. Absolute eosinophilia ≥ 470 × 106 l−1 was used as the criterion for eosinophilia because it more accurately represents eosinophilia than does a percentage,9,10 and was previously shown to predict persistent wheezing in infants.19 Low cord ferritin was defined as the lower 25th percentile (≤84 µg l−1) and upper 25th percentile (>200 µg l−1),20 and low infant ferritin as ≤11 µg l−1. Data were also dichotomized by maternal pregnancy weight gain, and dichotomized as < 18 kg (normal) or ≥ 18 kg (maximal recommended weight gain for any pregnancy).21 Unpaired t-tests were used for normally distributed data and log-converted plasma ferritin. Mann–Whitney U-tests, chi-square, simple linear regression, analysis of variance and multiple analysis of variance tests were also used. Values are portrayed in the tables as mean ± s.e. A P-value of < 0.05 was set for attaining statistical significance. The primary end point for ascertaining IDA during infancy was a composite outcome of lowest Hb at 6 or 12 months of age, because if abnormal iron status was found at 6 months, iron treatment was initiated at 6 months. Likewise, the lowest plasma ferritin or highest ZnPP/H values at 6 or 12 months were secondary study end points, because of the impact of treatment. The highest eosinophil count at 6 or 12 months and corresponding white blood cell and lymphocyte counts have been reported.
RESULTS
Maternal and neonatal demographics at birth
Eosinophil counts were determined by 12 months of age in 97 enrollees. Thirteen enrollees (13%) had eosinophilia during infancy. No differences in birth weight, Z-score, BMI, gestational age, gestational size (appropriate, small or large), sex or delivery method were found between those presenting or not presenting with eosinophilia (Table 1). Maternal age, weight, anemia, prenatal vitamin use, diabetes, pregnancy conditions, insurance status, education, race/ethnicity or personal and/or family history of atopic disease or asthma did not reveal a difference between those with and without eosinophilia (Table 1).
Table 1.
Demographic data at birth by the presence of eosinophilia
| Low eosinophils < 470 (1012 l−1), n = 84 | High eosinophils ≥ 470 (1012 l−1), n = 13 | P-value | |
|---|---|---|---|
| Neonatal demographic data | |||
| Birth weight (kg) | 3.422 ± 0.068 | 3.765 ± 0.20 | 0.08 |
| Birth weight Z-score | − 0.14 ± 0.19 | 0.77 ± 0.42 | 0.08 |
| Birth BMI (kg m−2) | 13.9 ± 0.2 | 14.8 ± 0.5 | 0.08 |
| Gestation (weeks) | 38.90 ± 0.13 | 39.32 ± 0.35 | 0.3 |
| SGA/AGA/LGA (%) | 19/54/27 | 16/30/54 | 0.16 |
| Male (%) | 50 | 61 | 0.4 |
| C/S (%) | 33 | 38 | 0.7 |
| Maternal demographic data | |||
| Age (years) | 30.1 ± 0.5 | 33.2 ± 3.2 | 0.09 |
| Anemia during pregnancy (%) | 55 | 31 | 0.11 |
| Prenatal vitamins (%) | 86 | 85 | 0.9 |
| Diabetes during pregnancy (%) | 37 | 15 | 0.11 |
| Birth BMI > 30 (%) | 57.0 | 62.0 | 0.8 |
| Maternal pregnancy weight gain (kg) | 14.4 ± 0.8 | 14.6 ± 1.5 | 0.9 |
| Education ≥ high school (%) | 96 | 92 | 0.5 |
| Race/ethnicity: AA/W/L/O (%) | 5/87/5/3 | 15/69/8/8 | 0.5 |
| Maternal history of atopic disease (%) | 29 | 38 | 0.5 |
| Family history of atopic disease (%) | 57 | 54 | 0.8 |
Abbreviations: AA, African American; AGA, appropriate-for-gestational age; BMI, body mass index; C/S, cesarean section; L, Latina; LGA, large-for-gestational age; O, other; SGA, small-for-gestational age; W, white.
Laboratory tests at birth
Cord RE-ZnPP/H, reflecting iron incorporation in reticulocytes, was 34% higher in those who would develop eosinophilia, P < 0.05 (Table 2). In addition, cord ΔZnPP/H was 2.5-fold higher in those with eosinophilia, P < 0.01. However, the general ZnPP/H values in the cord blood were not linearly related to later eosinophil counts, nor were Hb and ferritin levels, until criterion values were employed. When the distribution of plasma ferritin values was considered, significantly fewer infants with eosinophilia had been born with ferritin in the upper quartile range (>200 µg l−1), P < 0.05. Having a birth ferritin value in one of the three upper birth quartiles (>84 µg l−1), defined by Siddappa et al.,20 resulted in a 90% negative predictive value for eosinophilia. Conversing, being in the lowest quartile (≤84 µg l−1), resulted in a 25% positive predictive value for eosinophilia developing by 1 year of age. Taking into account a familial history of prior atopic airway disease, the negative predictive value of cord ferritin values in the three upper quartiles rose to 94% and the positive predictive value for newborns in the lowest quartile to 38.5% for eosinophilia by 1 year. In multivariate analysis, a significant interaction was found between low cord ferritin and history of maternal allergic airway disease, F2,88 = 4.02, P < 0.05.
Table 2.
Laboratory data at birth by the presence of eosinophilia
| Low eosinophils < 470 (1012 l−1), n = 84 | High eosinophils ≥ 470 (1012 l−1), n = 13 | P-value | |
|---|---|---|---|
| Hb (g l−1) | 160 ± 3 | 163 ± 7 | 0.7 |
| MCV (fl) | 113.0 ± 0.7 | 114.3 ± 1.3 | 0.5 |
| ZnPP/H (µm m−1) | 96.8 ± 3.5 | 103.5 ± 15.2 | 0.5 |
| RE-ZnPP/H (µm m−1) | 118.3 ± 5.0 | 158.6 ± 38.8 | < 0.05 |
| Δ-ZnPP/H (µm m−1) | 21.4 ± 2.5 | 55.1 ± 29.0 | < 0.01 |
| Plasma ferritin (µg l−1) | 146.9 ± 10.6 | 109.5 ± 28.3 | 0.11 |
| Plasma ferritin > 75th percentile (%) | 32 | 4 | < 0.05 |
Abbreviations: Hb, hemoglobin; MCV, mean cell volume; RE-ZnPP/H, reticulocyte-enriched zinc protoporphyrin/heme; ZnPP/H, zinc protoporphyrin/heme; Δ, delta (RE-ZnPP − ZnPP/H).
Italics indicate significant P-value.
Characteristics of atopic disease in infancy
No relationship was found between infant eosinophilia and 12-month weight, number of siblings, number respiratory or total infections, recurrent wheezing or ER visits for wheeze in the first year of life (Table 3). There were also no differences in beta-agonist use. However, in those with eosinophilia, the number of systemic steroid therapy for allergic airway disease was sevenfold higher, P < 0.008, and the percentage of infants receiving systemic steroid therapy for allergic airway disease was 4.5-fold higher, P < 0.003 (Table 3). Breastfeeding duration averaged 3.1 months longer in the eosinophilia group, P < 0.05 (Table 3). Two other laboratory values also supported the presence of generalized inflammation during infancy (Table 4). Infants who developed eosinophilia, the total white blood cell count was 18% higher, P < 0.04, and lymphocyte count was 24% higher, P < 0.02. Infant iron measures and timing of any of the supplemental iron source (either cereal, iron supplements or formula) did not differ by eosinophil group, although many infants from both groups exhibited low Hb or plasma ferritin, or high ZnPP/H.22 In addition, when grouping by high or low ferritin either at birth or in infancy, timing of the supplemental iron source did not differ by group.
Table 3.
Characteristics related to atopic disease risk in infancy by the presence of eosinophilia
| Low eosinophils < 470 (1012 l−1), n = 84 | High eosinophils ≥ 470 (1012 l−1), n = 13 | P-value | |
|---|---|---|---|
| 12-Month weight (kg) | 10.26 ± 0.23 | 10.79 ± 1.14 | 0.4 |
| Breastfeeding ≥ 6 months (%) | 55 | 82 | 0.09 |
| Month stopped breastfeeding | 6.70 ± 0.56 | 9.82 ± 0.99 | < 0.045 |
| % With siblings older or same age | 57 | 50 | 0.7 |
| Daycare first 6 months (%) | 46 | 27 | 0.4 |
| Number of respiratory infections in the first year | 3.2 ± 0.3 | 3.1 ± 0.8 | 0.9 |
| Number of infections in the first year | 3.9 ± 0.3 | 4.00 ± 0.8 | 0.9 |
| Recurrent wheeze in the first year (%) | 25 | 18 | 0.7 |
| Number of ER visits for wheezing in the first year | 0.1 ± 0.04 | 0 ± 0.0 | 0.4 |
| Times using beta agonist in the first year | 0.25 ± 0.06 | 0.27 ± 0.20 | 0.9 |
| % Using beta agonist | 17 | 45 | 0.9 |
| Times using steroids | 0.05 ± 0.03 | 0.36 ± 0.20 | < 0.003 |
| % Using steroids | 6 | 27 | < 0.008 |
Italics indicate significant P-value.
Table 4.
Laboratory data in infancy by the presence of eosinophilia
| Low eosinophils < 470 (1012 Ll−1), n = 84 | High eosinophils ≥ 470 (1012 l−1), n = 13 | P-value | |
|---|---|---|---|
| WBC (109 l−1) | 10.9 ± 0.3 | 12.9 ± 1.1 | < 0.035 |
| Lymphocytes (109 l−1) | 6.80 ± 0.24 | 8.44 ± 0.83 | < 0.02 |
| Eosinophil (%) | 2.0 ± 0.1 | 6.3 ± 0.7 | < 0.0001 |
| Abs eosinophils (1012 l−1) | 198 ± 13 | 726 ± 53 | < 0.0001 |
| Hb (g l−1) | 117 ± 2 | 119 ± 7 | 0.8 |
| MCV (fl) | 78.0 ± 0.4 | 78.1 ± 0.5 | 0.95 |
| ZnPP/H (µm m−1) | 99.0 ± 4.4 | 92.3 ± 9.5 | 0.6 |
| RE-ZnPP/H (µm m−1) | 109.5 ± 4.5 | 98.3 ± 11.8 | 0.4 |
| Δ-ZnPP/H (µm m−1) | 14.8 ± 1.6 | 10.7 ± 2.2 | 0.3 |
| Plasma ferritin (µg l−1) | 27.0 ± 3.2 | 23.0 ± 4.7 | 0.98 |
Abbreviations: Abs, absolute; Hb, hemoglobin; MCV, mean cell volume; RE-ZnPP/H, reticulocyte-enriched zinc protoporphyrin/heme; WBC, white blood cell count; ZnPP/H, zinc protoporphyrin/heme; Δ, delta (RE-ZnPP − ZnPP/H).
Italics indicate significant P-value.
Obese environment during gestation
Mothers who exceeded the maximum recommended pregnancy weight gain21 were more likely to have infants with elevated eosinophil counts, P < 0.04, as well as to birth neonates with higher cord Hb, higher cord RE-ZnPP/H and lower cord ferritin, P < 0.05. Weight gain was associated with higher maternal and neonatal BMI values, and with the larger infant BMI still evident at 6 and 12 months, P < 0.05. Furthermore, women exceeding recommended pregnancy weight gain had infants with higher white blood cell counts, P < 0.04 and lymphocyte counts, P < 0.02. The relative effect on eosinophilia was examined in a multivariate analysis and demonstrated that cord iron status rather than excessive gestational weight gain was a better predictor of later eosinophilia, F2,78 = 4.0, P < 0.05, and there was not a significant interactive effect of weight gain and neonatal iron level (Table 5).
Table 5.
Characteristics by excessive weight gain in pregnancy
| ≤ 18 kg Gain, n = 59 | 418 kg Gain, n = 32 | P-value | |
|---|---|---|---|
| Newborn birth weight (kg) | 3.457 ± 0.05 | 3.681 ± 0.08 | < 0.02 |
| Newborn birth BMI (kg m−2) | 13.93 ± 0.14 | 14.64 ± 0.28 | < 0.02 |
| Gestation (weeks) | 39.1 ± 0.1 | 39.3 ± 0.2 | 0.2 |
| Maternal age (years) | 29.7 ± 0.5 | 28.9 ± 0.7 | 0.3 |
| Maternal birth BMI (kg m−2) | 31.34 ± 0.49 | 35.16 ± 0.92 | < 0.0001 |
| Maternal pregnancy weight gain (kg) | 11.2 ± 0.5 | 22.5 ± 0.9 | < 0.0001 |
| Birth Hb (g l−1) | 158 ± 3 | 170 ± 5 | < 0.04 |
| Birth RE-ZnPP/H (µmol mol−1) | 118.9 ± 3.7 | 133.0 ± 7.0 | < 0.05 |
| Birth delta ZnPP/H (µmol mol−1) | 23.5 ± 3.1 | 36.8 ± 6.5 | < 0.005 |
| Birth plasma ferritin (ng ml−1) | 146.0 ± 7.4 | 118.1 ± 8.9 | < 0.02 |
| 6-Month weight (kg) | 7.97 ± 1.1 | 8.51 ± 0.16 | < 0.006 |
| 6-Month BMI (kg m−2) | 17.10 ± 0.21 | 18.01 ± 0.34 | < 0.02 |
| 12-Month weight (kg) | 9.81 ± 0.17 | 11.73 ± 0.68 | < 0.0006 |
| 12-Month BMI (kg m−2) | 16.96 ± 0.19 | 17.81 | < 0.009 |
| Total WBC in infancy (109 µl−1) | 10.61 ± 0.35 | 12.11 ± 0.75 | < 0.04 |
| Lymphocytes in infancy (109 µl−1) | 6.61 ± 0.25 | 7.87 ± 0.51 | < 0.02 |
| Eosinophils in infancy (1012 l−1) | 240 ± 23 | 343 ± 57 | < 0.05 |
| Lowest Hb in infancy (g l−1) | 119 ± 2 | 119 ± 2 | 0.9 |
| Highest ZnPP/H in infancy (µmol mol−1) | 94.2 ± 4.4 | 104.9 ± 7.7 | 0.2 |
| Lowest ferritin in infancy (µg l−1) | 27.6 ± 3.5 | 23.1 ± 3.6 | 0.4 |
Abbreviations: BMI, body mass index; Hb, hemoglobin; RE-ZnPP/H, reticulocyte-enriched zinc protoporphyrin/heme; WBC, white blood cell count; ZnPP/H, zinc protoporphyrin/heme.
Italics indicate significant P-value.
DISCUSSION
The burden of pediatric atopic disease and asthma is substantial,23 impacting well over 10% of all children in the US, and a disproportionately high percentage in children of minority status.24 Although familial factors contribute to atopic disease or wheezing risk, inheritance accounts for less than one-third of cases.25 Thus there is a need to understand other processes involved in the cascade of events leading to allergy and the airway hyperresponsiveness. Our parent study of a larger cohort of infants at risk for developing IDA found that excessive maternal pregnancy weight gain was associated with poorer fetal iron status and an inflammatory bias at birth.4 Iron is known to be essential for the normal immune development,2,13,14,15 which led us to consider the linkage between an obese in utero environment, iron status and allergic airway disease: perinatal and pediatric conditions normally viewed as distinct. Although not population-based research, it revealed an association between poor iron status at birth and the likelihood of developing eosinophilia, an accepted clinical marker of allergic disease. Eosinophilia is one of the several commonly employed risk indices for allergies and asthma7,8,9,10 with improved predictive utility when persistent.8,9,26 Infants with eosinophilia in our study were more likely to be prescribed systemic steroidal medications for allergic airway disease, indicative of more symptomatic airway disease. Although we found that maternal weight gain during pregnancy may impact the likelihood of eosinophilia, iron status predominated in defining this relationship. With respect to the healthy, unaffected infants, sufficient iron status at birth emerged as a negative predictor for eosinophilia. Thus, both with respect to the compromised newborn as well as for the ones with sufficient iron stores, iron status may help to explain one of the mediating pathways from the prenatal environment to allergic disease.
Iron delivery to the fetus is normally proportional to fetal weight. Thus the combination of normal ZnPP/H and higher reticulocyte ZnPP/H in infants prone to eosinophilia supports a time-sensitive, late gestational linkage. Lower fetal storage iron coincided with the massive perinatal lymphocyte expansion reinforces this temporal relationship. Clinically, iron status is not normally assessed at birth, but more typically later in infancy when our study found iron status no longer differed between infants with and without eosinophilia. In the current study, timing of any supplemental iron source did not differ by eosinophil group, supporting similar postnatal iron supply. It is possible that a limited iron supply at a critical perinatal window during the T cell maturation that accompanies the perinatal lymphocyte expansion may be more critical for programming long-term function than contemporaneous iron supply at 1 year of age. It is known that when fetal iron supply is limited, iron is prioritized to the erythrocyte at the expense of other vital developing tissues.27 This prioritization may compromise the vulnerable Th1 lymphocyte clones that have previously been shown to have lower intracellular iron stores. A developmental programming window for lymphocyte function is consistent with previous findings demonstrating different cytokine patterns at birth for infants predisposed to atopic disease.28,29 A recently published study found a relationship between maternal iron status, pulmonary function and reactive airways in her offspring,30 and the current study extends these findings by reporting a relationship between fetal iron status and eosinophilia. We did not observe a relationship between iron and eosinophilia in later infancy, when growth rate, dietary factors and infant absorptive ability can impact infant iron status. However, this question should be studied in a larger cohort to determine the critical developmental window that programs an allergic predisposition.
Maternal atopic disease was common, but in the multivariate analysis, did not emerge as an independent predictor of infant eosinophilia. Instead this factor appeared to have a summative influence along with neonatal iron status. Inflammatory processes in women with atopic conditions and asthma during pregnancy could negatively impact fetal iron supply through impaired placental iron transfer. In addition, it is known that maternal obesity during pregnancy increases fetal growth rate and thus iron demand. We have reported previously that obesity during gestation and higher maternal pregnancy weight gain, both inflammatory processes, are linked to poorer cord iron status.4 In another large cohort, Halonen et al.6 reported that excess pregnancy weight gain was associated with childhood asthma. Studies have also shown that in non-pregnant older adults, rapid weight gain increases inflammation.31,32 Obesity and diabetes during pregnancy may thus have proinflammatory effects while simultaneously reducing placental iron transfer and increasing iron demands due to augmented fetal growth.3,33,34 Of interest, the infants in our cohort born after pregnancies with higher maternal weight gain were not only larger at birth, but also continued to have larger BMIs at 6 and 12 months of age. Given the current prevalence of maternal and childhood obesity, the significance of these associations between excessive growth, iron utilization and proinflammatory reactions will continue to have clinical significance. It may also be possible to employ novel preventative strategies, such as delayed umbilical cord clamping, which can improve erythrocyte mass through provision of considerable blood volume, and thus iron endowment for meeting the iron needs during immediate postnatal life. Iron administration can reduce airway hyperreactivity and eosinophilia in animal studies.28,29
Our findings should be replicated and extended in a larger cohort, because they are limited by a small number of infants with eosinophilia by 1 year of age and an inability to follow this cohort further into childhood. Although preliminary, the results bring to light a novel relationship between low iron at birth and greater risk for later atopic disease. Clinicians should be aware that a history of high maternal weight gain may predispose infants to low iron at delivery and increase the risk for developing atopic disease.
Acknowledgments
We thank the participating families, Meriter Hospital Birthing Center Staff, Sharon E Blohowiak, BS, MS; Daphne Q-D Pham, PhD; Anthony P Auger, PhD; Robert F Lemanske Jr, MD; and the Kling Laboratory Research Team. RW and MEB-C received fellowship support from the University of Wisconsin Medical Student Shapiro Summer Research and Cardiovascular Research Center Research Fellowships. NCD received grant support from the UW Hilldale Undergraduate Research Fellowship. PJK received grant support from NIH UL1TR000427 (UW CTSA Program), Meriter Foundation, Wisconsin Partnership Collaborative Health Sciences Program Grant and the Thrasher Research Fund. TWG and CLC have no relationships to declare for this manuscript.
Footnotes
CONFLICT OF INTEREST
The authors declare no conflict of interest.
AUTHOR CONTRIBUTIONS
RW and MEB-C recruited patients, processed and analyzed samples, collected and entered data, analyzed data and contributed in writing the manuscript. NCD performed literature review, analyzed data, wrote and revised the manuscript. CLC and TWG assisted with study design, data analysis and revised the manuscript. PJK, the principal investigator for the larger study, assisted with study design, obtained funding, supervised enrollment, assays and data development and supervised in writing the manuscript.
References
- 1.Kim HY, DeKruyff RH, Umetsu DT. The many paths to asthma: phenotype shaped by innate and adaptive immunity. Nat Immunol. 2010;11(7):577–584. doi: 10.1038/ni.1892. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Spencer SJ, Galic MA, Pittman QJ. Neonatal programming of innate immune function. Am J Physiol Endocrinol Metab. 2011;300(1):E11–E18. doi: 10.1152/ajpendo.00516.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.McLimore HM, Phillips AK, Blohowiak SE, Pham DQ, Coe CL, Fischer BA, et al. Impact of multiple prenatal risk factors on newborn iron status at delivery. J Pediatr Hematol Oncol. 2013;35(6):473–477. doi: 10.1097/MPH.0b013e3182707f2e. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Phillips AK, Roy SC, Lundberg RS, Guilbert TW, Auger AP, Blohowiak SE, et al. Iron status at birth is impaired by maternal obesity and excessive gestational weight gain. J Perinatol. 2014;34(7):513–518. doi: 10.1038/jp.2014.42. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Lowe A, Braback L, Ekeus C, Hjern A, Forsberg B. Maternal obesity during pregnancy as a risk for early-life asthma. J Allergy Clin Immunol. 2011;128(5):1107–1109. e1101–1102. doi: 10.1016/j.jaci.2011.08.025. [DOI] [PubMed] [Google Scholar]
- 6.Halonen M, Lohman IC, Stern DA, Ellis WL, Rothers J, Wright AL. Perinatal tumor necrosis factor-alpha production, influenced by maternal pregnancy weight gain, predicts childhood asthma. Am J Respir Crit Care Med. 2013;188(1):35–41. doi: 10.1164/rccm.201207-1265OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med. 1995;332(3):133–138. doi: 10.1056/NEJM199501193320301. [DOI] [PubMed] [Google Scholar]
- 8.Castro-Rodriguez JA, Holberg CJ, Wright AL, Martinez FD. A clinical index to define risk of asthma in young children with recurrent wheezing. Am J Respir Crit Care Med. 2000;162(4 Pt 1):1403–1406. doi: 10.1164/ajrccm.162.4.9912111. [DOI] [PubMed] [Google Scholar]
- 9.Guilbert TW, Morgan WJ, Zeiger RS, Bacharier LB, Boehmer SJ, Krawiec M, et al. Atopic characteristics of children with recurrent wheezing at high risk for the development of childhood asthma. J Allergy Clin Immunol. 2004;114(6):1282–1287. doi: 10.1016/j.jaci.2004.09.020. [DOI] [PubMed] [Google Scholar]
- 10.Guilbert TW, Stern DA, Morgan WJ, Martinez FD, Wright AL. Effect of breastfeeding on lung function in childhood and modulation by maternal asthma and atopy. Am J Respir Crit Care Med. 2007;176(9):843–848. doi: 10.1164/rccm.200610-1507OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Youroukova VF, Oddera S, Silvestri M, Spallarossa D, Rossi GA. Blood eosinophilia and degree of sensitization to house dust mites in preschool and school children with asthma. J Asthma. 1998;35(6):489–496. doi: 10.3109/02770909809071002. [DOI] [PubMed] [Google Scholar]
- 12.Silvestri M, Oddera S, Spallarossa D, Frangova Yourukova V, Rossi GA. In childhood asthma the degree of allergen-induced T-lymphocyte proliferation is related to serum IgE levels and to blood eosinophilia. Ann Allergy Asthma Immunol. 2000;84(4):426–432. doi: 10.1016/s1081-1206(10)62276-4. [DOI] [PubMed] [Google Scholar]
- 13.Jason J, Archibald LK, Nwanyanwu OC, Bell M, Jensen RJ, Gunter E, et al. The effects of iron deficiency on lymphocyte cytokine production and activation: preservation of hepatic iron but not at all cost. Clin Exp Immunol. 2001;126:466–473. doi: 10.1046/j.1365-2249.2001.01707.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Bowlus CL. The role of iron in T cell development and autoimmunity. Autoimmun Rev. 2003;2(2):73–78. doi: 10.1016/s1568-9972(02)00143-x. [DOI] [PubMed] [Google Scholar]
- 15.Coe CL, Lubach GR, Shirtcliff EA. Maternal stress during pregnancy predisposes for iron deficiency in infant monkeys impacting innate immunity. Pediatr Res. 2007;61:520–524. doi: 10.1203/pdr.0b013e318045be53. [DOI] [PubMed] [Google Scholar]
- 16.Mbugi EV, Meijerink M, Veenemans J, Jeurink PV, McCall M, Olomi RM, et al. Effect of nutrient deficiencies on in vitro Th1 and Th2 cytokine response of peripheral blood mononuclear cells to Plasmodium falciparum infection. Malar J. 2010;9:162. doi: 10.1186/1475-2875-9-162. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Shaheen SO, Newson RB, Henderson AJ, Emmett PM, Sherriff A, Cooke M. Umbilical cord trace elements and minerals and risk of early childhood wheezing and eczema. Eur Respir J. 2004;24(2):292–297. doi: 10.1183/09031936.04.00117803. [DOI] [PubMed] [Google Scholar]
- 18.Blohowiak SE, Chen ME, Repyak KS, Baumann-Blackmore NL, Carlton DP, Georgieff MK, et al. Reticulocyte enrichment of zinc protoporphyrin/heme discriminates impaired iron supply during early development. Pediatr Res. 2008;64:63–67. doi: 10.1203/PDR.0b013e31817328e5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Just J, Belfar S, Wanin S, Pribil C, Grimfeld A, Duru G. Impact of innate and environmental factors on wheezing persistence during childhood. J Asthma. 2010;47(4):412–416. doi: 10.3109/02770900903584035. [DOI] [PubMed] [Google Scholar]
- 20.Siddappa AM, Rao R, Long JD, Widness JA, Georgieff M. The assessment of newborn iron stores at birth: a review of the literature and standards for ferritin concentrations. Neonatology. 2007;92:73–82. doi: 10.1159/000100805. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Weight Gain during Pregnancy: Reexamining the Guidelines. Institute of Medicine; National Research Council; Washington, D.C: 2009. Committee to Reexamine the IOM Pregnancy Weight Guidelines. [Google Scholar]
- 22.Baker RD, Greer FR. Diagnosis and prevention of iron deficiency and iron-deficiency anemia in infants and young children (0–3 years of age) Pediatrics. 2010;126(5):1040–1050. doi: 10.1542/peds.2010-2576. [DOI] [PubMed] [Google Scholar]
- 23.Pedersen SE, Hurd SS, Lemanske RF, Jr, Becker A, Zar HJ, Sly PD, et al. Global strategy for the diagnosis and management of asthma in children 5 years and younger. Pediatr Pulmonol. 2011;46(1):1–17. doi: 10.1002/ppul.21321. [DOI] [PubMed] [Google Scholar]
- 24.Bloom B, Cohen RA, Freeman G. Summary health statistics for U.S. Children: National Health Interview Survey, 2011. Vital Health Stat. 2012;10(254):1–88. [PubMed] [Google Scholar]
- 25.Burke W, Fesinmeyer M, Reed K, Hampson L, Carlsten C. Family history as a predictor of asthma risk. Am J Prev Med. 2003;24(2):160–169. doi: 10.1016/s0749-3797(02)00589-5. [DOI] [PubMed] [Google Scholar]
- 26.Karakoc F, Remes ST, Martinez FD, Wright AL. The association between persistent eosinophilia and asthma in childhood is independent of atopic status. Clin Exp Allergy. 2002;32(1):51–56. doi: 10.1046/j.0022-0477.2001.01273.x. [DOI] [PubMed] [Google Scholar]
- 27.Georgieff MK, Schmidt RL, Mills MM, Radmer WJ, Widness JA. Fetal iron and cytochrome c status after intrauterine hypoxemia and erythropoietin administration. Am J Physiol. 1992;262:R485–R491. doi: 10.1152/ajpregu.1992.262.3.R485. [DOI] [PubMed] [Google Scholar]
- 28.Gern JE, Brooks GD, Meyer P, Chang A, Shen K, Evans MD, et al. Bidirectional interactions between viral respiratory illnesses and cytokine responses in the first year of life. J Allergy Clin Immunol. 2006;117(1):72–78. doi: 10.1016/j.jaci.2005.10.002. [DOI] [PubMed] [Google Scholar]
- 29.Sumino K, Tucker J, Shahab M, Jaffee KF, Visness CM, Gern JE, et al. Antiviral IFN-gamma responses of monocytes at birth predict respiratory tract illness in the first year of life. J Allergy Clin Immunol. 2012;129(5):1267–1273. e1261. doi: 10.1016/j.jaci.2012.02.033. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Nwaru BI, Hayes H, Gambling L, Craig LCA, Allan K, Prabhu N, et al. An exploratory study of the associations between maternal iron status in pregnancy and childhood wheeze and atopy. Br J Nutr. 2014;112:2018–2027. doi: 10.1017/S0007114514003122. [DOI] [PubMed] [Google Scholar]
- 31.Gentile M, Panico S, Rubba F, Mattiello A, Chiodini P, Jossa F, et al. Obesity, overweight, and weight gain over adult life are main determinants of elevated hs-CRP in a cohort of Mediterranean women. Eur J Clin Nutr. 2010;64(8):873–878. doi: 10.1038/ejcn.2010.69. [DOI] [PubMed] [Google Scholar]
- 32.Saito I, Yonemasu K, Inami F. Association of body mass index, body fat, and weight gain with inflammation markers among rural residents in Japan. Circ J. 2003;67(4):323–329. doi: 10.1253/circj.67.323. [DOI] [PubMed] [Google Scholar]
- 33.Lesser KB, Schoel SB, Widness JA, Kling PJ. Elevated zinc protoporphyrin/heme ratios in umbilical cord blood after diabetic pregnancies. J Perinatol. 2006;26:671–676. doi: 10.1038/sj.jp.7211600. [DOI] [PubMed] [Google Scholar]
- 34.Lott DG, Zimmerman MB, Labbe RF, Kling PJ, Widness JA. Erythrocyte zinc protoporphyrin ratios are elevated with prematurity and with fetal hypoxia. Pediatrics. 2005;116:414–422. doi: 10.1542/peds.2004-1601. [DOI] [PubMed] [Google Scholar]