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Maternal anemia, iron intake in pregnancy, and offspring blood pressure in the Avon Longitudinal Study of Parents and Children ^1,2,3,4

¹ From the MRC Centre for Causal Analyses in Translational Epidemiology, Department of Social Medicine, University of Bristol, Bristol, United Kingdom (M-JAB and GDS); the Department of Oral and Dental Science, University of Bristol, Bristol, United Kingdom (SDL and ARN); and the Rowett Research Institute, University of Aberdeen, Aberdeen, United Kingdom (HJM)

² The contents of this article represent the views of the authors and not necessarily those of the funding bodies.

³ Supported by collaborations developed during the European Communities Research and Technology Development program (Early Nutrition Programming for Adult Health, Project EARly Nutrition programming: long-term follow-up of Efficacy and Safety Trials and integrated epidemiological, genetic, animal, consumer, and economic research; EARNEST). The UK Medical Research Council, the Wellcome Trust, and the University of Bristol provided core support for ALSPAC. M-JAB was jointly funded by the Overseas Research Students Awards Scheme and the University of Bristol.

⁴ Address reprint requests and correspondence to M-JA Brion, MRC Centre for Causal Analyses in Translational Epidemiology, Department of Social Medicine, University of Bristol, Oakfield House, Oakfield Grove, BS8 2BN, United Kingdom. E-mail: marie-jo.brion{at}bristol.ac.uk.

	ABSTRACT

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Background: In animals, maternal iron deficiency during pregnancy results in elevated offspring blood pressure (BP). Studies in pregnant women are limited in number, have had inconsistent results, and have not accounted for maternal iron supplementation.

Objective: The objective was to assess the association between maternal iron status during pregnancy and offspring BP.

Design: Maternal hemoglobin (n = 1255), iron supplementation (n = 7484), food-based iron intake (n = 7130), and offspring BP were assessed in a prospective cohort at 7 y of age.

Results: Maternal anemia during pregnancy was associated with lower systolic BP in the offspring at 7 y of age (third trimester, age- and sex-adjusted: β = –1.09; 95% CI: –2.21, –0.05 mm Hg; P = 0.04). Adjustment for confounders attenuated this association (β = –0.49; 95% CI: –1.71, 0.72 mm Hg; P = 0.4). In women who did not take iron supplements during pregnancy, the observed association with maternal anemia was even stronger: minimally adjusted models (β = –2.11; 95% CI: –3.61, –0.61 mm Hg; P = 0.006) and fully adjusted models (β = –1.48; 95% CI: –3.21, 0.25 mm Hg; P = 0.09). Iron supplementation was not associated with offspring BP after confounding by multivitamin intake was accounted for, and no association with iron intake from food was observed.

Conclusion: In contrast with animal studies, maternal iron intake during pregnancy is not associated with offspring BP, and some evidence indicates that maternal anemia in contemporary pregnant women is associated with lower offspring BP. It is possible that, in well-nourished populations, low hemoglobin is more likely to reflect greater plasma volume expansion (and thus better maternal and offspring health) than iron deficiency.

	INTRODUCTION

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Iron deficiency is the most common and widespread nutritional deficiency in the world and is the only nutritional deficiency that is prevalent in virtually all industrialized nations (1). It is also the most common cause of anemia, which is characterized by low concentrations of hemoglobin, the molecule that transports oxygen throughout the body. Nearly one-half of the pregnant women in the world are estimated to be anemic, and most pregnant women in industrialized countries are thought to have at least some degree of iron deficiency (1).

Poor maternal nutrition during pregnancy could have adverse consequences on the developing fetus. Low birth weight (a proxy for poor fetal nutrition) has been shown to be associated with an increased risk of cardiovascular disease and diabetes mellitus (2), and associations between low birth weight and higher blood pressure (BP) have been found to be robust (3), although there is some disagreement (4). In animals, maternal iron deficiency during pregnancy results in lower birth weight (5, 6) and an elevated BP in offspring (5-8). However, in humans, the effect of maternal iron deficiency on offspring health is less clear. Inconsistent associations have been reported with preterm delivery and birth weight (9). In addition, only a small number of studies have explored associations of maternal anemia with offspring BP (10-14). The results of these studies have been inconsistent, and none have controlled for maternal iron supplementation.

If maternal iron status influences BP in children, this is likely to be an important public health issue because of the strong tracking of juvenile BP into adulthood (15) and the high prevalence of anemia and iron deficiency in pregnant women. Thus, we sought to investigate whether maternal iron status during pregnancy influences offspring BP in a contemporary cohort of children. In the present study we explored maternal anemia, maternal iron supplementation in pregnancy, and maternal iron intake from food.

	SUBJECTS AND METHODS

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The Avon Longitudinal Study of Parents and Children (ALSPAC) is a prospective cohort study investigating the health and development of children. A full description of the methodology is available elsewhere (16) and on the study website (www.alspac.bris.ac.uk). Briefly, pregnant women residing in 3 health districts in Bristol, United Kingdom, with an expected date of delivery between 1 April 1991 and 31 December 1992 were invited to take part in the study. Of these women, 14 541 enrolled and 13 678 had a singleton, live born child. The entire cohort of children was invited to a clinic at 7 y of age, at which time BP measurements were taken. A total of 8297 children attended the clinic. BP measures are available for 7638 singleton children. Data on maternal iron supplement use and offspring BP are available for 7484. Maternal hemoglobin concentrations during pregnancy, abstracted from antenatal records, are currently available for 2500 mothers. Data on maternal hemoglobin and offspring BP are available for 1255. Ethical approval of the study was obtained from the ALSPAC Law and Ethics Committee and 3 Local Research Ethics Committees.

Maternal hemoglobin and iron supplementation
Hemoglobin concentrations during pregnancy were abstracted from routine antenatal medical records by a team of midwives for a random subsample of mothers, because this was more feasible than for the whole cohort. Selection was based on random number generation, whereby mothers were randomly allocated a number from the Uniform (0, 1) distribution, and the lowest 2500 numbers were selected. The majority of this subsample had repeat measures of hemoglobin taken throughout pregnancy, which were used to derive 2 anemia variables: 1) anemia in early pregnancy, defined as any hemoglobin value <11 g/dL (based on WHO criteria) in the first or second trimester, and 2) third trimester anemia, defined as any hemoglobin value <11 g/dL during this time period. Data for anemia in the first and second trimesters were combined (women anemic in both trimesters were only counted once) because the prevalence of anemia was low at this stage of pregnancy, and individual analyses in each trimester separately would be underpowered. Analyses were also repeated using the alternative cutoff value 10g/dL and using hemoglobin as a continuous variable.

Maternal iron supplement use was obtained from questionnaires sent at 18 wk (relating to anytime during pregnancy before the questionnaire date) and 32 wk (relating to last 3 mo of pregnancy) gestation. Mothers were asked whether they had taken iron supplements, vitamins, or any other supplements or diet foods. In a separate question, women were also asked to list all pills, medicines, and ointments they used, with a reminder to include iron tablets, vitamins, herbal medicines, etc. Data on all types of iron supplementation (iron tablets, multivitamins with iron, multiminerals with iron, iron preparations, and iron and folic acid preparations) from responses to both questions at 18 and 32 wk were combined to generate a variable for any iron supplement used during pregnancy. In addition, responses from the 32-wk questionnaire were used to generate a variable for iron supplement use in the third trimester, which was used to restrict associations of maternal anemia in the third trimester by limiting possible effects due to subsequent supplementation. A variable for iron-only supplementation was also generated, which excluded positive responses for iron supplement use that were derived from multivitamin, multimineral, or iron and folate supplements.

Iron intake from food was assessed from a food-frequency questionnaire sent to mothers at 32 wk gestation relating to their current diet. Mothers were asked how often they were currently consuming each type of food and, together with nutrient information on standard sized portions, intakes for a range of nutrients, including iron, were derived. A detailed description of the methods is available elsewhere (17).

Blood pressure
Systolic BP (SBP) and diastolic BP (DBP) were measured with a Dinamap 9301 Vital Signs Monitor (Critikon, Tampa, FL). This device has been shown to be highly reliable with repeat measures, yielding correlation coefficients of 0.88 for SBP and 0.83 for DBP (18). Compared with sphygmomanometers, BP values from the Dinamap instrument may be 6–8 mm Hg greater for SBP and within a 1-mm Hg difference for DBP (18). A child-size cuff was used for children with an upper arm circumference of <18 cm, and a small adult cuff was used for children with an upper arm circumference of 18 cm. Initial inflation was set to 130 mm Hg. Two readings of SBP and DBP were recorded, and the mean for each measure was calculated. The current age of the child at measurement was calculated from the date of clinic attendance and the child's date of birth.

Potential confounders
Maternal age at childbirth was calculated from the mother's date of birth, which was provided at enrollment with ALSPAC. Mothers also provided height and prepregnancy weight, from which body mass index (BMI; in kg/m²) was calculated. Child BMI was assessed at the ALSPAC clinic (where the BP measurements were carried out) and was based on weight to the nearest 50 g measured with a Tanita Body Fat Analyser (model TBF 305; Tanita, Hoofddorp, Netherlands) and height measured to the nearest 0.1 cm with a Harpenden stadiometer (Harpenden, Sussex, United Kingdom). Infant gestational age was estimated by using the date of delivery and of the mother's last menstrual period, and, in some cases, with early ultrasounds. Infant sex and birth weight were obtained from obstetric records and/or birth notifications. The number of previous pregnancies (live or stillborn) was obtained from a questionnaire at 18 wk of gestation. The mother's and her partner's highest education levels were obtained from a questionnaire at 32 wk: none, Certificate of Secondary Education, vocational, O level (national school exams at 16 y), A level (national school exams at 18 y), or a degree. The mother's and her partner's occupations were also obtained with this questionnaire, which was used to allocate them to the Office of Population Censuses and Surveys social categories (19): I, II, III nonmanual, III manual, IV, and V, where I is the highest (professional) category and V (unskilled manual worker) is the lowest. In the whole cohort, a small number of women (<2%) were coded as missing because they were either a stay-at-home mother or had no partner. This measure was chosen in preference to the highest because it distributes children more evenly across socioeconomic groups. A single variable was derived from the lowest social class of both partners. Breastfeeding information (exclusive, partial, or never breastfed at 2 mo of age) was obtained from the mothers at 6 mo. Information on maternal smoking during each trimester was obtained from the 18- and 32-wk questionnaires. In a questionnaire sent at 12 wk gestation, mothers were asked whether they had ever had hypertension.

Statistical analysis
Means and SDs were calculated for continuous variables that were normally distributed. For variables that had skewed distributions, the geometric mean and interquartile range are presented, and proportions were calculated for categorical variables. Differences in maternal and child characteristics of the children included and excluded because of missing data were compared by using t tests for continuous variables and chi-square tests for categorical variables. Associations between confounding and mediating factors and BP were analyzed by using linear regression. Differences in confounding and mediating factors associated with maternal anemia and iron supplement use were analyzed by using t tests for continuous variables and a chi-square test for categorical variables. Associations between maternal iron status and offspring BP were assessed by using multiple linear regression with 3 stages of adjustment: 1) child sex and age at BP measurement, 2) model 1 plus confounders, and 3) model 2 plus mediators. For confounders, we considered socioeconomic position and maternal and infant proxies for socioeconomic position (family social class, maternal education, age at childbirth, parity, height, and breastfeeding) as well as maternal factors (prepregnancy BMI, smoking during pregnancy, and history of hypertension). We included birth weight, gestational age, and child BMI as possible mediators. Because animal studies have reported sex differences for effects of maternal iron restriction on offspring BP (6, 8), sex-specific associations were investigated for maternal anemia in the third trimester. Interaction terms for sex and maternal anemia were included in regression models using the 3 stages of adjustment. Minimally adjusted analyses were also repeated in participants with complete data for confounders and mediators to assess the potential effects of missing data. The correlation between iron intake from food and hemoglobin concentration was assessed. Analyses were performed with STATA software (version 9; StataCorp, College Station, TX).

	RESULTS

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Descriptive results
Sample characteristics of those with data on maternal anemia (n = 1255) are shown in Table 1. The data for these subjects did not differ markedly from those with data on maternal iron supplement use (n = 7484; data not shown). Compared with mothers excluded because of missing data on offspring BP, mothers included in the anemia analyses were more likely to have a degree, breastfeed their child, have had no previous pregnancies, have children with higher birth weights and gestational ages, be of nonmanual social class, and be less likely to smoke during pregnancy. Higher child SBP was associated with higher child's age, child's BMI, maternal height and BMI, lower family social class and maternal education, lack of breastfeeding in infancy, maternal smoking during pregnancy, and maternal history of hypertension (Table 2). Similar associations were observed in the 7484 children with data on maternal iron supplementation, and being female, having a low birth weight, and having a lower parity also were associated with a higher BP. Anemic mothers (third trimester) were more likely to have a lower prepregnancy BMI, one or more previous pregnancies, an education level above the Certificate of Secondary Education level, and offspring of the female sex with a lower BMI and higher birth weight than offspring of nonanemic mothers (data not shown). Anemic mothers also had lower hemoglobin concentrations in early pregnancy and were more likely to have taken iron supplements during pregnancy than nonanemic mothers. No other differences in characteristics were observed. Compared with unsupplemented mothers, mothers who used iron supplements during pregnancy had a lower prepregnancy BMI, were less likely to have had hypertension, were more likely to be anemic (third trimester), and were more likely to have 2 previous pregnancies and offspring of the female sex and a higher birth weight. No other differences in characteristics were observed. There was no correlation between iron intake from food and hemoglobin concentration (r = 0.0003, P = 0.99).

Table 3

In the larger sample (n = 7484), maternal iron supplement use during pregnancy was associated with modest reductions in offspring blood SBP (Table 4), which persisted after adjustment for confounders and mediators. Although we planned to adjust this association for maternal anemia status, in the subgroup with both supplement use and anemia data (maximum n = 1141), there was no association between iron supplementation and offspring BP, before anemia status was included in the analysis. When the analyses were repeated restricting iron supplement use only to women using iron-only supplements (ie, excluding iron supplementation from multivitamin and multimineral use; Table 4), an inverse association initially observed was attenuated to the null after adjustment for confounders. Weekly dietary iron intake, after adjustment for confounders, was not associated with offspring SBP or DBP in the larger sample (Table 4).

	DISCUSSION

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In this contemporary British cohort, maternal anemia during pregnancy was associated with lower offspring BP in women who did not take iron supplements. Although maternal iron supplementation in pregnancy was initially observed to be associated with lower offspring BP, this association appears to be confounded. Maternal iron intake from food was not associated with offspring BP.

Previous studies in humans that assessed maternal hemoglobin/anemia and offspring BP have reported positive (10, 11), inverse (12), and null (13, 14) associations. In animals, maternal iron deficiency is associated with higher BP in older offspring, but with lower BP in younger offspring (5-8). Thus, it is possible that associations with BP in ALSPAC may change as the children become older. One study also reported different associations in relation to offspring sex; however, this was only found in early ages and not later on (6). There was some evidence of sex differences in the present study, which may simply be a chance finding because the evidence was weak.

Our study is the first study with data on both maternal anemia and iron supplementation. An important complication that previous studies in humans have not been able to control for is that effects of maternal anemia are difficult to assess in isolation, because subsequent iron supplementation is likely to occur after identification of low hemoglobin. In such cases, either anemia will be transient (making potential effects difficult to detect) or it will be unclear whether observed associations reflect effects of initial low hemoglobin or of higher hemoglobin from subsequent iron supplementation. The association between maternal iron intake and offspring BP has only been reported in one other study that assessed iron intake from food (14). This study reported no association with second trimester iron intake and an inverse association with first trimester intake. Although animal studies have reported an association between maternal iron deficiency and offspring BP, these studies reflect extreme iron restriction. It is possible that the absence of an observed association in the present study was due to a lower extent of iron restriction in this well-nourished, contemporary British population, which did not enable assessment of extreme iron deficiency.

Hemoglobin-based assessments of prenatal iron status are also complicated by the physiologic anemia of pregnancy. This drop in hemoglobin concentrations occurs routinely during pregnancy as a result of increased blood volume (plasma volume expansion) and does not indicate iron deficiency (20). Thus, it is possible that the association between maternal anemia and lower offspring BP may be driven by hemoglobin concentrations that are low, not because of iron deficiency anemia but because of plasma volume expansion. Poor plasma volume expansion is associated with low infant birth weight (21, 22) and preeclampsia (9), and contraction of plasma volume occurs in acute dehydration (9). Furthermore, iron-deficient women show less plasma volume expansion than those with iron reserves (23). Thus, it is possible that low hemoglobin in pregnancy is an indicator of greater plasma volume expansion, which reflects better overall maternal health and pregnancies and, subsequently, optimal fetal nutrition and development.

A limitation of our study was the availability of only one serum measure of iron status (ie, hemoglobin). However, hemoglobin is used routinely to characterize anemia; current estimates from the World Health Organization (WHO) on the global prevalence of anemia in populations, including pregnant women, is based on hemoglobin concentration, and WHO data also indicate that, under many conditions, clinical- and public health–population-based decisions are commonly made on the basis of hemoglobin and hematocrit values (1). According to the WHO, although several well-established laboratory indexes for assessing iron status are available (eg, serum ferritin, serum iron, transferrin, transferrin saturation, and transferrin receptors), only hemoglobin and hematocrit tests can be routinely performed in field settings.

Loss to follow-up in this cohort and missing data on anemia, BP, iron supplementation, confounders, and mediators are also limiting factors in our study. However, after the analyses were restricted to individuals with complete data on confounders and mediators, effect sizes of minimally adjusted associations were not found to differ with respect to the direction of the association. In fact, because effect estimates for maternal anemia in the restricted analyses were lower than in the unrestricted analyses, the true association between low maternal hemoglobin and low offspring BP may be even stronger than what has been reported in this cohort.

The data on iron supplementation was based on the mothers' self-reported use. Medical records of iron prescription may be a more reliable source of data; however, it would omit nonprescription supplements (eg, over-the-counter vitamins and minerals). Furthermore, the use of 2 stages for recording iron supplement use, that is, tick box data (yes or no for iron supplement use) and textual data (listing all types of medications and pills), increases the likelihood that different sources of iron supplementation will be captured by the questionnaire. Finally, iron intake from food was assessed by using an unquantified food-frequency questionnaire. Diet diaries that assess weighed intakes of foods may provide a more accurate measure of iron intake; however, food-frequency questionnaires were used because of the large number of study participants. The specific questionnaire used in this study has not been formally calibrated against diet diaries or biomarker levels; however, the questionnaire on which it is based has been validated in another population, although not for iron specifically (24).

In summary, in this British cohort of children born in the 1990s, higher maternal iron intake in pregnancy was not independently associated with offspring BP. However, maternal anemia during pregnancy was associated with lower offspring BP in unsupplemented women. This may have been due to the effects of plasma volume expansion (a normal characteristic of pregnancy) on hemoglobin concentrations. Rather than indicating iron deficiency, low hemoglobin concentrations during pregnancy in well-nourished populations may reflect higher degrees of plasma volume expansion, which in turn may be associated with better offspring health, such as lower BP. However, this requires confirmation in studies with several measures of iron status that can distinguish maternal iron-deficiency anemia from anemia due to plasma volume expansion. If confirmed, it may suggest that, in population studies involving contemporary, well-nourished pregnant women, the validity of hemoglobin alone as an indicator of iron status may be questionable.

	ACKNOWLEDGMENTS

 
We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, including the interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses.

The authors' responsibilities were as follows—M-JB: carried out the analysis, prepared the first draft of the manuscript, and coordinated the subsequent revisions; SDL: extracted the data; ARN and GDS: conceived the idea for the analysis; and SDL, ARN, GDS, and HJM: provided M-JB with advice for the analyses and commented on the drafts of the manuscript. M-JB and ARN will serve as guarantors for the contents of this article. No conflicts of interest were declared.

	REFERENCES

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Brion, M.-J. A Articles by Ness, A. R PubMed PubMed Citation Articles by Brion, M.-J. A Articles by Ness, A. R Agricola Articles by Brion, M.-J. A Articles by Ness, A. R