2

ANEMIA IN PREGNANCY INCREASE RISK OF

PRETERM LABOR

Counselor:
dr. H. Undang Gani, Sp.OG

By
Kresna Denta Elygio
4151181462

DEPARTMENT OF OBSTETRY AND GYNECOLOGY

JENDERAL ACHMAD YANI UNIVERSITY
FACULTY OF MEDICINE
CIMAHI
2020
TABLE OF CONTENT
 3

TABLE OF CONTENT...........................................................................................1
CHAPTER 1 INTRODUCTION.............................................................................2
CHAPTER II LITERATURE REVIEW..................................................................5
2.1 Prevalence Of Anemia In Pregnancy........................................................5
2.2 Erythropoiesis In Pregnancy.....................................................................5
2.3 Types Of Anemia......................................................................................7
2.4 Physiological Anemia................................................................................7
2.5 Iron Deficiency Anemia............................................................................7
2.6 Effects Of Anaemia On Pregnancy...........................................................9
2.7 Clinical Features Of Iron Deficiency Anaemia.........................................9
2.8 Management Of Iron Deficiency Anemia...............................................12
CHAPTER III DISCUSSION................................................................................13
CHAPTER IV SUMMARY...................................................................................17

CHAPTER 1
INTRODUCTION
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Anemia is one of the most common and widespread global health

problems and affects 56 million women worldwide, and two thirds of them are in
Asia.1 In developing countries, anemia is a serious concern because its effects on
the mother and fetus contribute to maternal death 2. A large observational study in
the United States, based on data from the Centers for Disease Control’s pregnancy
nutrition surveillance system also supported an increased risk of preterm labor by
30 to 40% for mild anemia and up to 70% increased risk for moderate to severe
anemia.
A review of the literature performed by Allen further supports these
observations, concluding that there is significant evidence that iron deficiency
anemia increases the risk of preterm birth and low birth weight. 2 There can also be
longer lasting effects into infancy and childhood, including an increased risk for
childhood anemia. Maternal effects of anemia can be more subtle, similar to
nonpregnant persons, with symptoms including fatigue, weakness, and decreased
productivity. This could be detrimental to the mother and child, particularly in the
postpartum setting. Anemia is a significant issue worldwide, encompassing third-
world countries as well as the more wealthy western nations. 1 The prevalence of
anemia in pregnancy in the United States is 21.5 per 1,000 women. 15 Prevalence
data specific to iron deficiency anemia are limited.
According to Indonesia Basic Health study (2013), pregnant women are
one group that is at high risk of anemia. Pregnant women can suffer from anemia
due to iron requirements increase for the developing fetus during pregnancy.
Maternal anemia is a characteristic of physiological changes during pregnancy.4
The most common cause of anemia is iron deficiency. This is particularly true
in pregnancy, because of a significant increase in iron demand. Women with
insufficient iron stores are at risk for developing anemia during pregnancy, even if
not anemic initially. A pregnant woman with insufficient iron stores will still be
able to provide enough iron to her fetus for normal fetal development, except in
extreme cases. Rates of preterm delivery and low birth weight are increased if
anemia is identified in the first and second trimester, and if iron deficiency is
 5

identified as the cause of anemia. If iron intake is insufficient or if there are some
abnormalities in absorption during this period, iron deficiency anemia can be
exacerbated. There is evidence that demands for iron increases during the second
and third trimester of pregnancy, therefore it is recommended for pregnant women
to increase their iron intake during the second and third trimester. The results of
pregnancy with anemia include intra uterine growth retardation (IUGR), prema-
ture birth, low birth weight (LBW), and an increased risk of neonatal death. The
effects of anemia on maternal pregnancy include shortness of breath, fatigue,
palpitations, sleep disturbances, increased risk of bleed-ing during labor,
preeclampsia, and sepsis.1,3
Anemia is influenced by many factors, including gestational age, maternal
education, family income, pregnancy interval, parity, consumption of blood-
booster tablets, and history of illness. Anemia in trimester (TM) I and II are not
associated with the incidence of LBW and preterm birth, while anemia in TM III
has an influence on the incidence of LBW and preterm birth. 4 Lt Manu Tiwari et
al studied iron-deficiency anemia in pregnant women in the second and third
trimester in India and pointed out that in developing countries, the iron deficiency
is prevalent due to inappropriate eating habits and iron supplementation should be
prescribed as a routine whereas unlike in developed countries where iron
supplementation is prescribed according to serum ferritin and iron levels. During
the past decades, most studies concluded that anemia during pregnancy is
associated with increased incidence of adverse pregnancy outcomes. Therefore,
improving the hemoglobin levels during pregnancy will benefit both mother and
fetus. However, with the improvement of modern research methods, researchers
attempted to re-examine the iron supplementation during pregnancy and the
concept of increasing the hemoglobin level during pregnancy. Some randomized
controlled trials (RCT) and Meta-analysis showed that, routine iron
supplementation is of little use, even for pregnant women who have anemia
during pregnancy, and if hemoglobin exceeds a certain level, it can have a
negative effect.
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The contribution of anemia to death in Indonesia is estimated at 10% to

12%.Based on statistical data from DIY Health Office (2012) regarding the
number of pregnant women with anemia is 18.56% of 45,323 pregnant women
and increased to 22.89% from 46,104 pregnant women in 2013.5
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CHAPTER II
LITERATURE REVIEW

2.1 Prevalence Of Anemia In Pregnancy

According to world Health Organization estimates, up to 56% of all women
living In developing countries are anemic. 6 In India, National Family Health
Survey -2 in 1998 to 99 shows that 54% of women in rural and 46% women in
urban areas are anemics.7 The relative prevalence of mild, moderate, and severe
anemia are 13%, 57% and 12% respectively in India (ICMR data).
According to WHO, hemoglobin level below 11gm/dl in pregnant women
constitutes anemia and hemoglobin below 7gm/dl is severe anemia. The Center
for Disease Control and Prevention (1990) defines anemia as less than 11gm/dl in
the first and third trimester and less than 10.5gm/dl in second trimester 9,10. Serum
Ferritin of 15 micro gm/L is associated with iron deficiency anemia.8,9

2.2 Erythropoiesis In Pregnancy

The various factors required for erythropoiesis are proteins (erythropoietin),
minerals (iron), trace elements (including zinc, cobalt and copper), vitamins
(particularly folic acid, vitamin B12 [cyanocobalamin], vitamin C, pyridoxine;
and riboflavin), and hormones (androgens and thyroxine).
In addition to the common deficiencies of iron and folate, there is a growing
body of evidence to implicate vitamin A (important for cell growth and
differentiation maintenance of epithelial integrity and normal immune function)
and Zn (important in protein synthesis and nucleic acid metabolism) in nutritional
anemias.11,12
Anemia is a condition of low circulating haemoglobin (Hb) in which
concentration has fallen below a threshold lying at two standard deviations below
the median of a healthy population of the same
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Table 1: Prevalence of anemia globally and in South-East Asian countries

Table 2: The Indian Council of Medical Research Categories of anemia 5

Category Anemia Severity Haemoglobin Level (g/dl)
1 Mild 10.0-10.9
2 Moderate 7.0-10.0
3 Severe < 7.0
4 Very Severe (Decopensated) <4.0

age, sex and stage of pregnancy. The WHO definition for diagnosis of anemia in
pregnancy is a Hb concentration of less than 11 g/dl (7.45 mmoL/L) and a
hematocrit of less than 33%.
 9

2.3 Types Of Anemia

The types of anemia are delineated In Fig 1

Fig 1: Classification of Anemia

2.4 Physiological Anemia

During pregnancy there is a disproportionate increase in plasma volume, RBC
volume and haemoglobin mass. As plasma volume increase more than the RBC
mass hemodilution occurs called as physiological anemia of pregnancy.
Criteria are:
a. RBC 3.2 million/cumm
b. Hemoglobin 10 gm%
c. RBC morphology on peripheral smear is normal i.e. normocytic,
normochromic.
d. PCV 30%

2.5 Iron Deficiency Anemia

About 1000 mg of iron is required during pregnancy. 13 500-600 mg for RBC
expansion. 300 mg for fetus and placenta and the rest for the growing uterus. As a
result of amenorrhea there is a saving of about 150 mg of iron and therefore, about
850 mg of extra iron is required during pregnancy. Diet alone can not provide the
extra iron and stores which have around 500 mg of iron get depleted. But if iron
stores are already deficient, iron deficiency anemia manifests. Iron deficiency
 10

anemia (IDA) is the commonest type of anemia in pregnancy. 14 Iron nutritional

status depends on long-term iron balance and is favoured by ingestion of adequate
amounts of iron in the diet (native or fortified) or through iron supplementation as
shown in Table-3. The balance is adversely affected by the loss of Iron through
intestinal mucosal turnover and excretion, skin desquamation, menstruation and
lactation.15 Iron absorption is 15-30% (haem iron) and up to 50% in the iron
deficiency state reduce to 5-8% with an excessive haem diet. Its absorption is
usually not affected by inhibitors. The non haem iron pool is made of all other
sources of iron such as cereals, seeds, vegetables, milk and eggs. Its absorption
can be increased by enhancers (haem, proteins, ascorbic acid and fermentation)
and decreased by inhibitors (phytic acid, fibres, calcium, tannins, tea, coffee,
chocolate and herbal infusion).16 On the basis of type of food, iron bio-availability
can be characterized as follows.
Table 3: Factors affecting the iron status of a pregnant woman
 11

2.6 Effects Of Anaemia On Pregnancy

 Maternal effects
Mild, anemia may not have any effect on pregnancy and labour except that the
mother will have low iron stores and may become moderately to-severely anemic
in subsequent pregnancies. Moderate anemia may cause increased weakness, lack
of energy, fatigue and poor work performance. Severe anemia, however, is
associated with poor outcome. The woman may have palpitations, tachycardia,
breathlessness, increased cardiac output leading on to cardiac stress which can
cause de-compensation and cardiac failure which may be fatal. 12,17 Increased
incidence of pre-term labour (28.2%), pre-eclampsia (31.2%) and sepsis have
been associated with anemia.12
 Fetal effects
Irrespective of maternal iron stores, the fetus still obtains iron from maternal
transferrin, which is trapped in the placenta and which, in turn, removes, and
actively transports iron to the fetus. Gradually, however, such fetuses tend to have
decreased iron stores due to depletion of maternal stores. Adverse perinatal
outcome in the form of pre-term and small-for-gestational-age babies and
increased perinatal mortality rates have been observed in the neonates of anemic
mothers. Iron supplementation to the mother during pregnancy improves perinatal
outcome. Mean weight, Apgar score and haemoglobin level 3 month after birth
were significantly greater in babies of the supplemented group than the placebo
group.

2.7 Clinical Features Of Iron Deficiency Anaemia

 Symptoms
There may be no symptoms, especially in mild and moderate anemia. Patient may
complain of feelings of weakness, exhaustion and lassitude, indigestion and loss
of appetite. Palpitation, dyspnoea, giddiness, oedema and, rarely, generalized
anasarca and even congestive cardiac failure can occur in severe cases.
 12

Signs
There may be no signs especially in mild anemia. . There may be pallor, glossitis
and stomatitis. Patients may have edema due to hypoproteinaemia. Soft systolic
murmur can be heard in mitral area due to hyper dynamic circulation.
 Diagnosis
Haemoglobin estimation is the most practical method of diagnosis as it is cost
effective and can be easily performed by trained technician. The Taliquist’s
method of Hb estimation has simplicity and easy applicability, but is not very
-accurate. Sahil’s methods is reliable and accurate when done by expert, and is the
most communally used method, although the cyanomethaemoglobin, method
appears to be the most accurate.
Peripheral blood film is another bed.-side indicator for diagnosis of anemia which
will also differentiate between iron deficiency anemia, megaloblastic anemia and
haemolytic anemia. In iron deficiency anemia, there is microcytosis,
hypochromia. Anisocytosis, poilkilocytosis and target cells in the blood film. Iron
deficiency anemia must be differentiated from thalassemia as shown in table 4.18,19
Table 4: Red cell indices in iron deficiency and thalassemia

Serum ferritin level below 12 m/l is taken to indicate to iron deficiency. It is

stable, unaffected by recent iron intake, reflects iron stores accurately, and is the
 13

first abnormal laboratory test in iron deficiency. Serum iron varies from 60-120
mg/dl while TIBC is 300-350 mg/dl, (increased to 300-400 mg/dl in pregnancy).
Serum iron of less than 60 mg/dl, TIBC of more than 350 mg/dl and transferring
saturation of less than 15% indicates deficiency of iron during pregnancy table 5.
Table5: Categorization of women using haemoglobin and ferritin estimations

Free erythrocyte protoporphyrin (FEP) is the third estimation of Iron status rising
with defective iron supply to the developing red cells and takes 2-3 weeks to
become abnormal after depletion of iron stores. It also helps in differentiation
between iron deficiency anemia and thalassaemia.18
Serum transferrin receptor appears to be specific and sensitive marker of iron
deficiency in pregnancy. Its levels are increased in iron deficiency anemia Bone
marrow examination by staining with potassium ferrocyanate to see characteristic
blue granules of stainable iron in, erythroblasts is the most accurate method for
iron stores, but is not practical in most cases as the test is invasive, Bone marrow,
examination is only dated in cases where there is no response to iron therapy after
4 weeks or for diagnosis of Kala-azar or in suspected aplastic anemia. 20 As worm
infestations are common causes of anemia, stool examination for ova and cysts
should be done consecutively for 3 days in all cases. In areas where
schistosomiasis is prevalent, urine examination for occult blood and schistosomes
should be performed. As malaria is an important cause of anemia peripheral blood
should be examined for malarial parasites in the case. Significant bacteriuria
should also be ruled out. If the clinical scenario demands, other tests can be done,
such as sputum examination and chest X-ray for pulmonary tuberculosis
 14

(abdominal shielding should be done), renal function tests in suspected renal

disease and serum proteins in hypoproteinemia.18

2.8 Management Of Iron Deficiency Anemia

In developing countries, it is common to see patients of moderate and severe
anemia late in pregnancy. They have had nil or inadequate antenatal care and did
not take iron supplements in pregnancy. If the woman presents in mild-trimester
or early third trimester, oral iron is started.
Although for prophylaxis the Government of India, Ministry of Health
recommends 100 mg of elemental iron with 0.5 mg folic acid, for treatment more
than 180 mg of elemental iron per day is required. Three tablets of ferrous
sulphate (available free of cost in most Indian hospitals) per day are required. This
may cause increased incidence of side-effects and some recommend 120 mg
elemental iron per day, which is more suitable for supplementation rather than
treatment. Ferrous ascorbate is the most favorable iron for Indian Diet which have
high content of inhibitor for iron absorption.21 One needs to change a brand only
when the patient cannot tolerate it. Addition of folic acid, but not vitamin B12
helps in improving the results in supervised supplementation. Up to 10% of
women may have side- effects with oral iron in the form of gastrointestinal
symptoms such as nausea, vomiting, constipation, abdominal cramping and
diarrhoea which are dose-related. The treatment of choice is to reduce the dose. If
this does not work, another preparation (carbonyl) iron or haemoglobin
preparations may be better tolerated.
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CHAPTER III
DISCUSSION

Mechanisms that might underlie iron’s effects on preterm delivery and fetal
growth. There have been no studies of the effect of iron deficiency or anemia on
the biological mechanisms that can affect pre- term delivery or fetal growth. In
fact, only one study was found in which any hormonal differences were examined
in relation to maternal iron status and hemoglobin concentrations in pregnancy. In
population studies, placental size is inversely related to hemoglobin concentration
across a wide range of hemoglobin values (Godfrey et al. 1991). By 18 wk of
preg- nancy, placental volume may already be inversely correlated with maternal
hemoglobin and serum ferritin concentrations, even in industrialized countries. On
the basis of this observation, associations between maternal hemoglobin and iron
status and factors known to affect placental size, i.e., human chorionic
gonadotropin and human placental lactogen, were assessed during the first
trimester of pregnancy in 175 women who were consulting about pregnancy
termination. The aver- age duration of gestation was 68 d. Maternal hemoglobin
was significantly negatively correlated with the levels of human chorionic
gonadotropin and human placental lactogen across the normal hemoglobin range.
Although serum ferritin con- centrations were low in 21% of the women, there
was no correlation with the hormone concentrations. The authors suggest that the
oxygen content of maternal blood may have had an important influence on the
development of the pla- centa and subsequently on human chorionic gonadotropin
and human placental lactogen concentrations. There is no reason to believe that
increased human chorionic gonadotropin or human placental lactogen
concentration would have an ad- verse effect on pregnancy outcome.
 16

Because virtually nothing is known about the effects of iron deficiency or anemia
on the biological mechanisms that regulate the duration of gestation and fetal
growth, the discussion in this section focuses mainly on other factors and illnesses
that are known to influence these mechanisms and that could plausibly explain
any effects of anemia or iron deficiency. The postulated biological mechanisms
are as follows.
Iron deficiency or anemia may increase the stress hormones, norepinephrine
and cortisol. Iron deficiency increases norepinephrine (NE) concentrations
(Dallman 1986), as does hypoxia (Gu¨lmezoglu et al. 1996). Norepinephrine is a
strong stimulus for the release of CRH (Calogero et al. 1988) and cortisol. The
CRH and locus ceruleus/NE (LC/NE) sym- pathetic systems respond similarly to
many of the same neu- rochemicals (Chrousos and Gold 1992). Iron deficiency
and anemia were not mentioned among these, but this has not been studied.
Norepinephrine infusion into pregnant sheep caused a reduction in fetal protein
synthesis and accretion, indicating adverse effects on fetal growth (Milley 1997).
There is virtually no information concerning the effect of iron deficiency or
anemia on cortisol secretion. In one rat study of the effect of an iron-free diet, the
iron deficiency caused stress, as evidenced by a higher serum cortisol concen-
tration (Campos et al. 1998).
Chronic hypoxia activates the stress response. Low hemoglobin concentrations
can cause a state of chronic hypoxia, which is presumably exacerbated in
pregnancy when oxygen demands are particularly high because of the metabolism
of the mother and the fetus. Although changes in transplacental oxygen transfer
are relatively small when maternal hemoglbin concentrations fall, oxygen transfer
to the fetus is probably reduced in anemic women (Viteri 1994). Infant birth
weight was directly related to calculated maternal arterial oxygen content in a
study of women living at high altitude in the United States (Moore et al. 1982b).
Moreover, either mater- nal or fetal hypoxia could activate the stress response, de-
scribed below.
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As discussed above, iron deficiency causes an increased production of

norepinephrine, and norepinephrine is a strong stimulus of CRH secretion
(Calogero et al. 1988).
Hypoxia induces maternal and fetal stress, and the release of CRH. “Hypoxia
stimulates CRH production in cultured (placental) cells . . . which may be
associated with the increased concentration of CRH found in the blood of women
with toxemia of pregnancy and in the umbilical circulation of subjects with IUGR
and reduced umbilical artery blood flow.” This statement was made in a review by
Smith (1998), a pioneer in CRH research; unfortunately, no references to the
research supporting this statement were included.
Maternal stress is associated with preterm delivery. In a test of the general
hypothesis that maternal stress is associated with elevated maternal plasma
concentrations of CRH and a sub- sequently higher risk of preterm birth, Hobel et
al. (1999b) measured CRH at 18 –20, 28 –30 and 35–36 wk in 524 ethni- cally
and socioeconomically diverse pregnant women from California. Of this group,
18 women had spontaneous onset of preterm labor. Their samples were compared
with those of 18 control women who delivered at term, matched by age, pre- vious
birth outcome, smoking status and race. The preterm delivery cases had
significantly higher plasma CRH and adre- nocorticotropic hormone at all three
gestational periods and higher cortisol concentrations at 18 –20 and 28 –30 wk.
Ma- ternal stress level at 18 –20 wk, assessed by interview, predicted a significant
amount of variance in CRH at 28 –30 wk gesta- tion, with CRH at 18 –20 wk
controlled for. The authors concluded that maternal stress and CRH
concentrations may be good markers for risk of preterm birth.
Iron-deficiency anemia may increase oxidative stress. The fetoplacental unit is
very susceptible to oxidative damage induced by reactive oxygen species.
Oxidative stress is one mechanism thought to cause preeclampsia, pregnancy-
induced hypertension and pregnancy-induced diabetes (Cester et al. 1994, Poranen
et al. 1996). Interest is increasing in the pos- sibility that antioxidant nutrients
might improve pregnancy outcome by reducing oxidative stress (Scholl and Stein
2000, West et al. 2000).
 18

Iron deficiency may cause increased oxidative stress because it causes

erythrocytes to be more susceptible to oxidative damage. Erythrocytes are
normally protected from oxidative stress caused by free radicals released from the
potentially dangerous combination of iron and oxygen. Mechanisms that achieve
this protection include superoxide dismutase, reduced glutathione and catalase.
However, microcytic erythrocytes have a shorter survival time partly because of
Iron deficiency may increase the risk of maternal infections. There is some
evidence that iron deficiency adversely affects immune function. For example, it
can alter the prolif- eration of T and B cells, reduce the killing activity of phago-
cytes and neutrophils, and lower bactericidal and natural killer cell activity.
Infection is one of the main pathological risk factors for preterm labor. The
presence of bacteria or inflammatory cyto- kines in amniotic fluid or
chorioamnionitic membranes is strongly associated with preterm labor and
premature rupture of the membranes. The bacteria are believed to come from the
vagina. Early bacterial vaginosis (before 16 wk) is associated with a relative risk
of preterm delivery of 5–7.5. If this con- dition occurs after 26 wk, the risk is 1.4
–1.9 (Kurki et al. 1992). There is potential for CRH to regulate inflammatory
responses and vice versa. The cytokine interleukin-1 stimu- lates production of
CRH, and CRH in turn regulates cytokine production by immune effector cells.
Because maternal stress is associated with preterm birth, abnormalities in the
regulation of CRH and the production of inflammatory cytokines may be a
mechanism that could form the pathophysiological basis for this association.
 19

CHAPTER IV
SUMMARY

A negative association between anemia and duration of gestation and low

birth weight has been reported in the majority of studies, although a causal link
remains to be proven. This paper explores potential biological mechanisms that
might explain how anemia, iron deficiency or both could cause low birth weight
and preterm delivery. The risk factors for preterm delivery and intrauterine growth
retardation are quite similar, although relatively little is understood about the
influence of maternal nutritional status on risk of preterm delivery. Several
potential biological mechanisms were identified through which anemia or iron
deficiency could affect pregnancy outcome. Anemia (by causing hypoxia) and
iron deficiency (by increasing serum norepinephrine concentrations) can induce
maternal and fetal stress, which stimulates the synthesis of corticotropin-releasing
hormone (CRH). Elevated CRH concentrations are a major risk factor for preterm
labor, pregnancy-induced hypertension and eclampsia, and premature rupture of
the membranes. CRH also increases fetal cortisol production, and cortisol may
inhibit longitudinal growth of the fetus. An alternative mechanism could be that
iron deficiency increases oxidative damage to erythrocytes and the fetoplacental
unit. Iron deficiency may also increase the risk of maternal infections, which can
stimulate the production of CRH and are a major risk factor for preterm delivery.
It would be useful to explore these potential biological mechanisms in
randomized, controlled iron supplementation trials in anemic and iron-deficient
pregnant women.
 20

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