Submitted by: Wilson Y.

Bautista MCN 3

Iron supplementation and gestational diabetes in

midpregnancy

I. Introduction
Increasing evidence suggests that iron, a transitional metal and a
strong prooxidant, influences glucose metabolism, even in the absence of
significant iron overload. 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. Furthermore, serum ferritin
levels (a biomarker of body iron stores) were positively associated with
diabetes risk, hypertension, the metabolic syndrome, cardiovascular risk
factors, and inflammation.
In pregnancy, iron supplementation is recommended to reduce the risk
of low birthweight or preterm delivery. However, excessive supplements
might expose women to increased oxidative stress, lipid peroxidation, and
pregnancy-induced hypertensive disorders. 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.

II. Citation

1. Rajpathak SN, Crandall J, Wylie-Rosett J, Kabat GC, Rohan TE, Hu FB. The
role of iron intype 2 diabetes in humans. Biochim Biophys Acta
2009;1790:671-81.
2. Rajpathak SN, Ma J, Manson JA, Willett WC, Hu FB. Iron intake and the risk
of type 2 diabetes in women. Diabetes Care 2006; 29:1370-6.
3. Luan DC, Li H, Li SJ, Zhao Z, Li X, Liu ZM. Body iron stores and dietary iron
intake in relation to diabetes in adults in North China. Diabetes Care
2008;31:285-6.
4. Forouhi NG, Harding AH, Allison M, et al. Elevated serum ferritin levels
predict new-onset type 2 diabetes: results from the EPIC-Norfolk prospective
study. Diabetologia 2007;50: 949-56.
5. Piperno A, Trombini P, Gelosa M, et al. Increased serum ferritin is common
in men with essential hypertension. J Hypertens 2002;20: 1513-8.
6. Qi L, van Dam RM, Rexrode K, Hu FB. Heme iron from diet as a risk factor
for coronary heart disease in women with type 2 diabetes. Diabetes Care
2007;30:101-6.
7. Williams MJ, Poulton R, Williams S. Relationship of serum ferritin with
cardiovascular risk factors and inflammation in young men and women.
Atherosclerosis 2002;165:179-84.
8. Palma S, Perez-Iglesias R, Prieto D, Pardo R, Llorca J, Delgrado-Rodriguez
M. Iron but not folic acid supplementation reduces the risk of low birthweight
in pregnant women without anaemia: a case-control study. J Epidem Comm
Health 2008;62:120-4.
9. Casanueva E, Viteri FE. Iron and oxidative stress in pregnancy. J Nutr
2003;133: 1700S-8S.
10. Lachili B, Hininger I, Faure H, et al. Increased lipid peroxidation in
pregnant women after iron and vitamin C supplementation. Biol Trace Elem
Res 2001;83:103-10.

III. Methodology / Design

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.Thedose, 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

IV. Results of the Study

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 fewer
employers 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.
The characteristics of participants were tested according to iron
supplementation use. 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. The prevalence of women
with GDM, hypertension, and the metabolic syndrome was about 2-fold
higher in iron-supplemented women.
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. 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. Intriguingly, most glucose values during the OGTT were
significantly higher in iron-supplemented women, both in GDM patients and
normoglycemic individuals.

V. Author’s Conclusions / Recommendations

The authors 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 the 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. Further, iron absorption is highly regulated in humans, with an
inverse relation between total iron absorption and body iron stores, but with
present supplementation schemes, the intestinal mucosal cells are
constantly exposed to unabsorbed iron excess with evidence of oxidative
stress. A continuous absorption by passive diffusion mass effect of a fraction
of supplemental iron, resulting in excessive liver iron levels, has been
hypothesized. 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 the 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, 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, about27%of
pregnant women complied with iron supplementation during the second half
of pregnancy.

VI. Applicability ( In Nursing Education, Nursing Service or Nursing

Action)

Iron was often prescribed for the last trimester of pregnancy as a routine
supplementation. It was reported to improve newborn birth weight, even if
adverse effects for iron overload on body proportion at birth were also
reported. Pregnancy is a condition characterized by higher susceptibility to
oxidative stress due to increased basal oxygen consumption by the
mitochondria-rich placenta. Iron is abundant in the placenta and is
particularly important in the production of free radicals and exacerbation of
inflammatory processes; it catalyzes several reactions that result in the
generation of reactive oxygen species with subsequent oxidative stress and
tissue damage. 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. Increased iron levels enhance oxidation of
lipids, especially nonesterified fatty acids, and impede insulin extraction in
the liver, leading to peripheral hyperinsulinemia; otherwise, direct iron
deposition in pancreatic beta cells or in the liver with impairment in insulin
secretion or hepatic neoglucogenesis suppression might be implicated.
Initially, iron excess might contribute to insulin resistance and subsequently
to decreased insulin secretion.
Through this study we can somehow decrease the rate of GDM if this is
proven under series of research and tests correct and accurate. Because of
this not only the women and mother are the focus but also the conception
they brought. The fetus can be save from those harmful brought abotus of a
GDM preganancy.

VII. Reviewer’s Conclusion / Commentary

Iron was often prescribed for the last trimester of pregnancy as a routine
supplementation. It was reported to improve newborn birth weight, even if
adverse effects for iron overload on body proportion at birth were also
reported. Pregnancy is a condition characterized by higher susceptibility to
oxidative stress due to increased basal oxygen consumption by the
mitochondria-rich placenta. Iron is abundant in the placenta and is
particularly important in the production of free radicals and exacerbation of
inflammatory processes; it catalyzes several reactions that result in the
generation of reactive oxygen species with subsequent oxidative stress and
tissue damage. 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. Increased iron levels enhance oxidation of lipids, especially
nonesterified fatty acids, and impede insulin extraction in the liver, leading
to peripheral hyperinsulinemia; otherwise, direct iron deposition in
pancreatic beta cells or in the liver with impairment in insulin secretion or
hepatic neoglucogenesis suppression might be implicated. Initially, iron
excess might contribute to insulin resistance and subsequently to decreased
insulin secretion.
In women they used in the study, 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 non- supplemented women. This is in line
 with some recent findings, but differs from a study on Spanish women, where
iron-supplemented patients had a similar prevalence of GDM, and a lower
prevalence of preeclampsia. However, these latter women showed quite
different characteristics from those of both previous studies and ours: they
were lean, more educated, about 40% active smoking, and cases delivered
low birth weight 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. 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. Furthermore, a high iron status could lead to increased platelet
aggregation and higher thrombosis risk. 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 supplementation 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.

VIII. References

Bo S, Menato G, Villois P, et al. Iron supplementation and gestational

diabetes in midpregnancy. Am J Obstet Gynecol 2009;201:158.e1-6.