Iron supplementation and gestational diabetes in midpregnancy

Article Outline

• Abstract
• Materials and Methods
  • Statistical analyses
• Results
• Comment
• References
• Copyright

Objective

Iron supplementation in pregnancy seems beneficial for neonatal/maternal outcomes, but it was associated with diabetes and hypertension in the general population.

Study Design

We investigated the association between iron supplementation during midpregnancy and metabolic/hypertensive abnormalities in 500 consecutive gestational diabetes mellitus (GDM) and 500 normoglycemic women.

Results

Iron-supplement users (n = 212/1000) showed significantly higher values of prepregnancy body mass index (BMI), actual BMI, waist circumference, blood pressure, fasting glucose, Homeostasis-Model-Assessment-Insulin-Resistance, and lower high-density lipoprotein-cholesterol than nonusers. The prevalence of GDM (70.8% vs 44.4%), hypertension (25.9% vs 9.8%), metabolic syndrome (25.9% vs 10.4%) was significantly higher in the former with a 2- to 3-fold-increased risk at multiple regression analyses. Most glucose values of the oral glucose tolerance test were significantly higher in iron supplemented women, both in GDM and normoglycemic individuals.

Conclusion

Iron supplementation is associated with glucose impairment and hypertension in midpregnancy; its potential harmful effects might be carefully debated regarding its effectiveness.

Key words: gestational diabetes mellitus, gestational hypertension, iron supplementation, metabolic syndrome

Increasing evidence suggests that iron, a transitional metal and a strong prooxidant, influences glucose metabolism, even in the absence of significant iron overload.¹ Large prospective cohort studies found that dietary iron intake, particularly heme iron derived from meat, was associated with a significant increased risk of type 2 diabetes.², ³ Furthermore, serum ferritin levels (a biomarker of body iron stores) were positively associated with diabetes risk,³, ⁴ hypertension,⁵ the metabolic syndrome,⁶ cardiovascular risk factors, and inflammation.⁷

In pregnancy, iron supplementation is recommended to reduce the risk of low birthweight or preterm delivery.⁸ However, excessive supplements might expose women to increased oxidative stress, lipid peroxidation, and pregnancy-induced hypertensive disorders.⁹, ¹⁰, ¹¹ Although there have been several studies investigating the possible role of dietary and serum iron on glucose metabolism, only a few studies are available about these associations during pregnancy. Studies performed in Chinese cohorts have found increased serum ferritin concentrations and higher maternal hemoglobin as independent risk factors for gestational diabetes mellitus (GDM),¹², ¹³ while iron deficient anemia was a protective condition.¹⁴ Studies in Caucasian cohorts are discordant, since no association between iron supplementation and GDM,⁸ and a predictive role for moderate elevation in serum ferritin levels during early gestation on the risk of gestational hyperglycemia,¹⁵ were found. Indeed, whether iron supplementation during pregnancy is a necessary or a toxic supplement is a highly controversial topic.¹⁶

We therefore investigated the association between iron supplementation during midpregnancy and the occurrence of GDM in a cohort of 1000 Caucasian pregnant women.

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Materials and Methods 

All pregnant women attending the Unit of Obstetrician and Gynecology of the University of Turin are routinely screened with a 50-g oral glucose test (oral glucose challenge test, OGCT) at 24-28 weeks of gestational age (as calculated by ultrasound examination performed during the first trimester of gestation). A positive screening result was a 1-hour serum glucose concentration ≥ 7.8 mmol/L. For the purpose of the study, all patients enrolled were submitted to a 3-hour OGTT (oral glucose tolerance test) with 100 g glucose after 1-2 weeks, independently by the result of the screening test. The test was performed in the morning after an overnight fast of at least 8 hours but not more than 14, and after at least 3 days of unrestricted diet (≥ 150 g carbohydrates/d) and exercise. Cut-off values were those proposed by Carpenter and Coustan.¹⁷ GDM was diagnosed in women displaying 2 or more serum glucose concentrations equaling or exceeding the following criteria: 5.3 mmol/L (fasting), 10.0 mmol/L (1 h), 8.6 mmol/L (2 h), 7.8 mmol/L (3 h).

Subject selection was based on a sequential screening in our department from 1997 to 2002. Exclusion criteria were: known prepregnancy conditions, such as diabetes mellitus, diseases affecting glucose metabolism, hypertension, chronic illness, and medical treatments (including hormonal preparations), and supplementation with micronutrients other than iron, presence of a positive screening test, but an OGTT not diagnostic for GDM. Inclusion criteria were: Caucasian origin, carrying singleton pregnancies, and having a negative screening test or an OGTT diagnostic for GDM. A total of 672 GDM were identified; after excluding women not satisfying the above reported criteria and 14 patients who did not give their informed consent to participate, 528 women resulted in being eligible. The first consecutive 500 GDM patients were enrolled. All consecutive 500 subjects with normoglycemia (OGCT negative and OGTT negative)—controls—satisfying the inclusion criteria and giving their informed consent to the study (12 declined to participate) were identified during the year 1997.

The procedures were in accordance with the Helsinki Declaration, as revised in 1983. All women participating gave their informed written consent. The study was exempt from institutional review board approval, since in 1997-2002 only protocols experimenting treatment (pharmacological or not) effects must be submitted to our board.

An interview was conducted on the morning of the 50 g glucose screening test by trained personnel. Information concerning medically diagnosed diabetes in first-degree relatives, smoking, alcohol intake, education level (primary, secondary school, or university), current employment, and health status were collected. Information on iron, vitamins, or other micronutrient supplementation was obtained by interview. A woman was included in the group “iron supplement users” if she was actually consuming iron and if the duration of the intake lasted at least 2 weeks. The dose, type, and duration of iron supplementation have been retrieved from the obstetric clinical records.

Height, weight, and blood pressure were measured at the time of the screening; prepregnancy weight was recorded from patients' recall. The body mass index (BMI) was calculated as prepregnancy weight in kilograms divided by the square of their height in meters. Waist circumference (at the point of minimal abdominal girth) was measured in all women, since it is minimally influenced by uterine growth between 24 and 28 weeks of gestational age.¹⁸

Serum insulin and plasma triglycerides, total and HDL-cholesterol were measured after an overnight fast at the time of the OGTT.

Serum glucose was measured by the glucose oxidase method (Glucose-Analyzer II; Beckman, Fullerton, CA; intra-assay coefficient of variation [CV] = 1.1%, interassay CV = 2.3%) and insulin by radioimmunoassay (Corning Kit; Modfield, MA; intra-assay CV = 3.4%, interassay CV = 5.1%). Plasma triglycerides were measured by enzymatic colorimetric assay (Poli, Clinical Chemistry CL7000; Shimadzu, Kyoto, Japan; intra-assay CV = 2.9%, interassay CV = 3.5%); HDL-cholesterol by enzymatic colorimetric assay after precipitation of LDL and VLDL fractions using heparin-MnCl₂ solution and centrifugation at 4°C (intra-assay variation CV = 2.5%, interassay CV = 4.1%).

There is no definition for the metabolic syndrome in pregnancy; it was defined in presence of at least 3 of the following 5 criteria: fasting serum glucose ≥ 6.1 mmol/L; arterial blood pressure ≥ 130/85 mmHg; plasma triglycerides ≥ 1.69 mmol/L; HDL-cholesterol < 1.29 mmol/L; waist circumference ≥ 2SD above the mean of the controls, in line with the National Cholesterol Education Program's Adult Treatment Panel III criteria.¹⁹ The Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) was used to assess insulin resistance, according to published algorithms.²⁰ Pregnancy-induced hypertension was defined according to the National High Blood Pressure Education Program.²¹

Statistical analyses 

Values in the text are means ± SD, unless otherwise noted. Since the distribution of HOMA-IR, insulin, and triglyceride values was positively skewed, their values were log-transformed, thus approximating a normal distribution. The log-transformed values of these variables were used in all analyses. For an easy interpretation, the median (and interquartile range) of nontransformed values are reported.

The Student t test and the χ² test were used to compare means for continuous variables or frequencies for discrete variables, respectively. A multiple logistic regression analysis was used to estimate the odds of having GDM, hypertension, or various metabolic abnormalities relative to those without iron supplementation for the iron-supplemented women, after adjustments for age, diabetes in first-degree relatives, prepregnancy BMI, education level, smoking habits, parity, duration of iron supplementation, and current employment.

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Results 

Women with GDM were significantly older and had higher prepregnancy weight and BMI, parity, weight increase at the time of the OGTT, proportion of diabetes in first-degree relatives, and smokers. They showed also a lower level of education, and more housewives and less employers (Table 1) than women who did not develop GDM. As expected, their actual values of BMI, waist circumference, blood pressure, fasting glucose and insulin, HOMA-IR, and triglycerides were significantly increased, while HDL-cholesterol values were lower (Table 1).

TABLE 1. Characteristics of women with GDM and controls

Characteristic	GDM(n = 500)	Controls(n = 500)	P
Age(y)	35.1±5.9	33.7±5.4	<.001
Diabetes in first-degree relatives(%)	39.6	30.8	.004
Housewives(%)	38.4	29.2
Workwomen(%)	15.0	14.8
Employees(%)	43.0	52.2
Managers(%)	3.6	3.8	.013
Primary school(%)	40.4	31.8
Secondary school(%)	48.4	51.8
University(%)	11.2	16.4	.005
Active smokers(%)	18.6	12.8	.01
Alcohol intake(g/day)	2.7±6.3	2.9±6.6	.58
Total number of pregnancy	0.9±1.0	0.7±0.8	<.001
Previous GDM	0.2±0.4	—	<.001
Prepregnancy weight(kg)	67.1±15.9	59.9±11.1	<.001
Height(m)	1.62±0.06	1.63±0.06	.01
Prepregnancy BMI(kg/m2)	25.5±5.8	22.5±3.8	<.001
Weight increase at the time of the OGCT(kg)	7.2±7.9	6.0±4.8	.007
Weight increase at the end of pregnancy(kg)	11.7±4.4	12.0±3.5	.18
Actual BMI(kg/m2)	28.2±5.7	24.7±3.8	<.001
Actual waist(cm)	95.9±14.2	88.1±15.5	<.001
Systolic blood pressure(mmHg)	118.1±15.2	109.8±13.3	<.001
Diastolic blood pressure(mmHg)	76.5±10.9	70.3±10.8	<.001
Fasting glucose at the OGTT(mmol/L)	5.1±0.6	4.4±0.3	<.001
Fasting insulin(pmol/L)	81.0(56.7)	52.2(33.0)	<.001
HOMA-IR(mmol/L × μU/mL)	2.98(2.31)	1.72(1.11)	<.001
Triglycerides(mmol/L)	1.7(1.2)	1.4(0.8)	.002
HDL-cholesterol(mmol/L)	1.7±0.4	1.9±0.4	<.001

BMI, body mass index; GDM, gestational diabetes mellitus; HOMA-IR, Homeostasis Model Assessment-Insulin Resistance; OGCT, oral glucose challenge test; OGTT, oral glucose tolerance test.

The Student t test and the χ² test were used to compare means for continuous variables or frequencies for discrete variables, respectively.

Bo. Iron and gestational diabetes. Am J Obstet Gynecol 2009.

The characteristics of participants were tested according to iron supplementation use (Table 2). Data regarding dose and type of iron supplementation were available for 93.4% of the iron supplement users (198/212). Most of them (189/198; 95.5%) used 525 mg of ferrous sulphate (Ferrograd, 1 tablet/d; Abbott Laboratories, Rome, Italy), which corresponds to 105 mg of elemental iron; the remaining 9 women used 80 mg of ferrous gluconate (FerroComplex, 1 tablet/d; Abbott Laboratories). The duration of iron supplementation ranges from 2 to 10 weeks (median 5 weeks). Iron supplement users did not significantly differ for age, familial diabetes, smoking habits, alcohol use, education level, current employment, previous GDM, pregnancy weight increase, but they showed significantly higher prepregnancy weight and BMI, actual BMI and waist circumference, and overall a significantly worse metabolic pattern (Table 2). The prevalence of women with GDM, hypertension, and the metabolic syndrome was about 2-fold higher in iron-supplemented women (Table 2).

TABLE 2. Characteristics of patients according to iron supplementation

	Iron supplement users
Characteristic	Yes = 212	No = 788	P
Age(y)	34.5±6.0	34.4±5.6	.74
Diabetes in first-degree relatives(%)	38.7	34.3	.23
Housewives(%)	31.6	34.4
Workwomen(%)	18.4	14.0
Employees(%)	48.1	47.5
Managers(%)	1.9	4.2	.17
Primary school(%)	37.3	35.8
Secondary school(%)	51.4	49.8
University(%)	11.3	14.5	.50
Active smokers(%)	11.3	14.5	.72
Alcohol intake(g/day)	2.7±6.4	2.8±6.5	.77
Total number of pregnancy	0.8±0.9	0.8±0.9	.65
Previous GDM	0.1±0.3	0.1±0.3	.99
Prepregnancy weight(kg)	67.2±15.8	62.5±13.5	<.001
Height(m)	1.63±0.07	1.63±0.06	.95
Prepregnancy BMI(kg/m2)	25.4±5.6	23.6±4.9	<.001
Weight increase at the time of the OGCT(kg)	6.6±7.3	6.6±6.4	.94
Weight increase at the end of pregnancy(kg)	11.5±4.4	11.9±3.9	.20
Actual BMI(kg/m2)	27.9±5.5	26.1±5.0	<.001
Actual waist(cm)	95.7±14.3	91.0±13.1	<.001
Systolic blood pressure(mmHg)	118.7±14.7	112.7±14.6	<.001
Diastolic blood pressure(mmHg)	77.3±11.2	72.3±11.0	<.001
Fasting glucose at the OGTT(mmol/L)	4.9±0.6	4.7±0.6	<.001
Fasting insulin(pmol/L)	86.7(62.7)	59.4(40.2)	<.001
HOMA-IR(mmol/L × μU/mL)	3.36(2.49)	2.03(1.49)	<.001
Triglycerides(mmol/L)	1.6(1.1)	1.5(0.9)	.05
HDL-cholesterol (mmol/L)	1.7±0.4	1.8±0.4	.002
GDM (%)	70.8	44.4	<.001
Hypertension (%)	25.9	9.8	<.001
Metabolic syndrome (%)	25.9	10.4	<.001

BMI, body mass index; GDM, gestational diabetes mellitus; HOMA-IR, Homeostasis Model Assessment-Insulin Resistance; OGCT, oral glucose challenge test; OGTT, oral glucose tolerance test.

The Student t test and the χ² test were used to compare means for continuous variables or frequencies for discrete variables, respectively.

Bo. Iron and gestational diabetes. Am J Obstet Gynecol 2009.

In a multiple regression model, the use of iron supplements was significantly associated with a 2- to 3-fold increased risk of having gestational hyperglycemia, insulin resistance, hypertension, and the metabolic syndrome, after adjustments for multiple confounders (Table 3). Data did not change significantly after adjusting for gestational age, number of prenatal visits at the time of the screening test (1 to 3 visits), number of previous GDM, weight increase during pregnancy, year of recruitment, and after excluding the only woman who was taking iron supplementation prior to pregnancy.

TABLE 3. Associations of iron supplements on metabolic end points at midpregnancy in a multiple logistic regression analysis

CI, confidence interval; GDM, gestational diabetes mellitus; HDL, high-density lipoprotein; HOMA-IR, Homeostasis Model Assessment-Insulin Resistance; OR, odds ratio.

Bo. Iron and gestational diabetes. Am J Obstet Gynecol 2009.

Intriguingly, most glucose values during the OGTT were significantly higher in iron-supplemented women, both in GDM patients (Figure 1) and normoglycemic individuals (Figure 2).

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• FIGURE 1. 

  Glucose values of GDM women according to iron supplements

• Oral glucose tolerance test glucose values of women with gestational diabetes mellitus (GDM), according to the use of iron supplements.

• * P < .01 by the Student t test.

• Bo. Iron and gestational diabetes. Am J Obstet Gynecol 2009.

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• FIGURE 2. 

  Glucose values of normoglycemic women according to iron supplements

• Oral glucose tolerance test glucose values of the controls, according to the use of iron supplements.

• * P < .01 by the Student t test.

• Bo. Iron and gestational diabetes. Am J Obstet Gynecol 2009.

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Comment 

We found that iron supplementation users during midpregnancy had a 2- to 3-fold higher risk of GDM, and metabolic syndrome, independently of many risk factors and confounders. Iron supplementation was associated with increased glucose values at the OGTT test both in GDM and normoglycemic women.

Limitations of our study should first be recognized. Measures of iron status, hemoglobin levels, and dietary habits were not available. Therefore, we were neither able to distinguish between iron deficiency (without or with anemia) and normal iron status, nor able to take into account indication for iron supplementation, and dietary iron intake. However, the usual practice of iron supplementation in pregnancy in our department in the years 1997-2002 is treating iron deficiency anemia (as defined by hemoglobin and ferritin values) with 60-100 mg of elemental ferrous iron a day, while preventive iron supplementation is usually not performed. Previous studies have found that the iron status and hemoglobin levels were significantly higher in women receiving iron supplementation, and that supplemental iron was positively and significantly associated with plasma ferritin concentrations, being one of the main determinants of its levels in women.¹⁰, ²² Further, iron absorption is highly regulated in humans, with an inverse relation between total iron absorption and body iron stores,¹ but with present supplementation schemes, the intestinal mucosal cells are constantly exposed to unabsorbed iron excess with evidence of oxidative stress.⁹ A continuous absorption by passive diffusion mass effect of a fraction of supplemental iron, resulting in excessive liver iron levels, has been hypothesized.⁹ Even if data have been adjusted for various potential confounders, the possibility of uncontrolled or unknown confounders cannot be ruled out. The finding of an association does not mean prospective prediction or causation; however, there is biological plausibility in the associations found, which were strong. Finally, only 20% of our patients were taking iron supplements in the second trimester of pregnancy. Few European data are available about proportion of women treated with iron supplements in the second trimester of pregnancy that are in line with our data: a Norwegian study demonstrated that 83% of practitioners recommended iron supplementation from the 20th gestational week,²³ a Danish paper showed that the proportion of women reporting intake of iron supplements increased sharply from about 20% at 19 weeks to 70% after 25 weeks,²⁴ about 27% of pregnant women complied with iron supplementation during the second half of pregnancy.²⁵

Iron was often prescribed for the last trimester of pregnancy as a routine supplementation. It was reported to improve newborn birthweight,⁸ even if adverse effects for iron overload on body proportion at birth were also reported.²⁶ Pregnancy is a condition characterized by higher susceptibility to oxidative stress due to increased basal oxygen consumption by the mitochondria-rich placenta.⁹ Iron is abundant in the placenta and is particularly important in the production of free radicals and exacerbation of inflammatory processes⁹; it catalyzes several reactions that result in the generation of reactive oxygen species with subsequent oxidative stress and tissue damage.¹ Oxidative stress reaches its peak by the second trimester of pregnancy, which is a very vulnerable period for fetal and gestational health.

Pregnancy is also a condition of increased maternal insulin resistance, with diminished glucose disposal leaving more glucose for fetal growth. Dietary and serum levels of iron, indeed, were associated with insulin resistance and type 2 diabetes.¹, ², ³, ⁴ Increased iron levels enhance oxidation of lipids, especially nonesterified fatty acids, and impede insulin extraction in the liver, leading to peripheral hyperinsulinemia²⁷; otherwise, direct iron deposition in pancreatic beta cells or in the liver with impairment in insulin secretion or hepatic neoglucogenesis suppression might be implicated.²⁸, ²⁹ Initially, iron excess might contribute to insulin resistance and subsequently to decreased insulin secretion.²⁸

In our women, iron supplementation was significantly associated with increased insulin resistance, hyperglycemia, and the metabolic syndrome. Intriguingly, gestational glucose values were increased, even if within range of normality, in normoglycemic iron users when compared to normoglycemic nonsupplemented women (Figure 2). This is in line with some recent findings,⁹, ¹⁰, ¹¹, ¹², ¹³, ¹⁴, ¹⁵ but differs from a study on Spanish women, where iron-supplemented patients had a similar prevalence of GDM, and a lower prevalence of preeclampsia.⁸ However, these latter women showed quite different characteristics from those of both previous studies¹², ¹⁴, ¹⁵ and ours: they were lean, more educated, about 40% active smoking, and cases delivered low-birthweight infants.

Prevalence of gestational hypertension was significantly and independently associated with iron supplementation in our women in line with previous data reporting a 2-fold increase in gestational hypertensive disorders in women receiving iron supplements.¹¹ Our iron-supplemented women were more insulin-resistant and had a higher prevalence of the metabolic syndrome. These associations remained significant after adjusting for presence of gestational hyperglycemia, and were in line with the hypothesis of a direct role for increased body iron in the pathogenesis of insulin resistance.²⁹, ³⁰

Furthermore, a high iron status could lead to increased platelet aggregation and higher thrombosis risk.³¹ It could therefore be hypothesized that iron depletion during pregnancy might represent a physiological condition to prevent the adverse effects of oxidation, insulin resistance, and thrombosis.

Routine iron supplementation in pregnancy is a matter of controversy and debate. The increasing reporting of harmful effects for unnecessary iron supplementation¹⁶ should be carefully considered. Further studies on larger cohorts are warranted to confirm these results, but glucose values should at least be monitored in iron-supplemented pregnant women.

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