Anemia in Pregnancy

Anemia
in
Pregnancy
Anemia
in
Pregnancy
Editor
SS Trivedi
Director Professor, Head of Department
Obstetrics and Gynecology
Lady Hardinge Medical College
New Delhi, India
Co-Editor
Manju Puri
Professor, Department of Obstetrics and Gynecology
Lady Hardinge Medical College and SSK Hospital
New Delhi, India
JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD

New Delhi Ahmedabad Bengaluru Chennai Hyderabad
Kochi Kolkata Lucknow Mumbai Nagpur
Published by
Jitendar P Vij
Jaypee Brothers Medical Publishers (P) Ltd
B-3 EMCA House, 23/23B Ansari Road, Daryaganj,
New Delhi 110 002, India
Phones: +91-11-23272143, +91-11-23272703, +91-11-23282021,
+91-11-23245672, Rel: +91-11-32558559, Fax: +91-11-23276490,
+91-11-23245683 e-mail: jaypee@jaypeebrothers.com
Visit our website: www.jaypeebrothers.com
Branches
2/B, Akruti Society, Jodhpur Gam Road Satellite, Ahmedabad 380 015
Phones: +91-79-26926233, Rel: +91-79-32988717, Fax: +91-079-26927094
e-mail: ahmedabad@jaypeebrothers.com
202 Batavia Chambers, 8 Kumara Krupa Road, Kumara Park East
Bengaluru 560 001, Phones: +91-80-22285971, +91-80-22382956
Rel: +91-80-32714073, Fax: +91-80-22281761
e-mail: bengaluru@jaypeebrothers.com
282 IIIrd Floor, Khaleel Shirazi Estate, Fountain Plaza, Pantheon Road
Chennai 600 008, Phones: +91-44-28193265, +91-44-28194897, Rel: +91-44-
32972089, Fax: +91-44-28193231 e-mail: chennai@jaypeebrothers.com
4-2-1067/1-3, 1st Floor, Balaji Building, Ramkote Cross Road
Hyderabad 500 095, Phones: +91-40-66610020, +91-40-24758498, Rel:+91-40-
32940929, Fax:+91-40-24758499 e-mail: hyderabad@jaypeebrothers.com
No. 41/3098, B & B1, Kuruvi Building, St. Vincent Road, Kochi 682 018,
Kerala, Phones: 0484-4036109, +91-0484-2395739, +91-0484-2395740
e-mail: kochi@jaypeebrothers.com
1-A Indian Mirror Street, Wellington Square, Kolkata 700 013
Phones: +91-33-22651926, +91-33-22276404, +91-33-22276415, Rel: +91-33-
32901926, Fax: +91-33-22656075 e-mail: kolkata@jaypeebrothers.com
Lekhraj Market III, B-2, Sector-4, Faizabad Road, Indira Nagar
Lucknow 226 016 Phones: +91-522-3040553, +91-522-3040554
e-mail: lucknow@jaypeebrothers.com
106 Amit Industrial Estate, 61 Dr SS Rao Road, Near MGM Hospital, Parel,
Mumbai 400 012, Phones: +91-22-24124863, +91-22-24104532, Rel: +91-22-
32926896, Fax: +91-22-24160828 e-mail: mumbai@jaypeebrothers.com
KAMALPUSHPA 38, Reshimbag, Opp. Mohota Science College, Umred Road,
Nagpur 440 009 (MS), Phones: Rel: 3245220, Fax: 0712-2704275
e-mail: nagpur@jaypeebrothers.com
Anemia in Pregnancy
2008, Jaypee Brothers Medical Publishers
All rights reserved. No part of this publication should be reproduced, stored in a retrieval
system, or transmitted in any form or by any means: electronic, mechanical, photocopying,
recording, or otherwise, without the prior written permission of the editors and the publisher.
This book has been published in good faith that the material provided by editors is
original. Every effort is made to ensure accuracy of material, but the publisher, printer
and editors will not be held responsible for any inadvertent error(s). In case of any
dispute, all legal matters are to be settled under Delhi jurisdiction only.
First Edition: 2008
ISBN 978-81-8448-299-7
Typeset at JPBMP typesetting unit
Printed at Rajkamal Press
CONTRIBUTORS
Abha Singh Manju Puri

Professor Professor
Department of Obstetrics Department of Obstetrics
and Gynecology and Gynecology,
Lady Hardinge Medical
College and SSK Hospital,
New Delhi College and SSK Hospital,
New Delhi.
Anjali Taneja
Senior Resident Nayantara Sharma
Department of Obstetrics Professor
and Gynecology, Obstetrics and Gynecology
College and SSK Hospital,
Ratna Biswas
New Delhi.
Associate Professor
Chitra Raghunandan Department of Obstetrics
Professor and Gynecology
Department of Obstetrics
and Gynecology
Lady Hardinge Medical College and SSK Hospital,
College and SSK Hospital, New Delhi
New Delhi
Sharda Patra
Kiran Aggarwal
Assistant Professor
Associate Professor
and Gynecology and Gynecology
Lady Hardinge Medical Lady Hardinge Medical
College and SSK Hospital, College and SSK Hospital,
New Delhi New Delhi
vi ANEMIA IN PREGNANCY
Shashi Narayanan Usha Gupta

Professor Professor
Department of Pathology Department of Obstetrics
Lady Hardinge Medical and Gynecology
College and SSK Hospital, Lady Hardinge Medical
New Delhi College and SSK Hospital,
New Delhi
SS Trivedi
Director, Professor and Varsha Parakh
HOD Senior Resident
Department of Obstetrics Department of Obstetrics
and Gynecology and Gynecology
Lady Hardinge Medical Lady Hardinge Medical
College and SSK Hospital, College and SSK Hospital,
New Delhi New Delhi
FOREWORD
Anemia is recognized as a major public health problem

especially among economically weaker section of the
population in developing countries like India. It is widely
prevalent in pregnant women and magnitude of the problem
is enormous. About half of the pregnant women in the world
are anemic. Anemia adversely affects obstetric outcome. It
is responsible for over 20 percent of maternal deaths and
significant perinatal loss in India. The faculty of the Department
of Obstetrics and Gynecology of Lady Hardinge Medical
College and Hospital must be complimented for the significant
publication of this book on the very important subject of
Anemia in Pregnancy. It contains ten relevant chapters on
different aspects of anemia in pregnancy mainly based on
its leading causes. The chapter on Iron deficiency,
Megaloblastic, Haemolytic, Sickle Cell, Aplastic anemias, etc.
have been written with meticulous care providing latest
information in their etiopathogenesis, diagnosis, clinical
manifestation and management. The first chapter deals with
the magnitude of the problem, challenges in eradicating
anemia and preventive strategies to eliminate severe anemia
during pregnancy.
The chapters are educative, comprehensive and up-to-
date. The learned editors have done an admirable job and
deserve our high appreciation for their devoted efforts. The
scientific contents of the book are of great calibre and this
viii ANEMIA IN PREGNANCY
edition is most welcome in the field of Obstetrics and

Gynecology. The unique project of putting in the thought on
all types of anemias encountered in pregnancy collectively
in a book is praiseworthy. The volume is superb and skillfully
edited to become user-friendly. It is ardently hoped that this
excellent publication will be profitably used by students and
specialists practicing Obstetrics and Gynecology.
SN Mukherjee
Formerly
Professor and Head, Dept. of Obstetrics and Gynecology,
JIPMER Pondicherry, HP Medical College, Shimla
UCMS and SJ Hospital, MAMC and LN Hospital, New Delhi
Dy. Commissioner (Technical) Family Planning
Director CGHS, DGHS Government of India
PREFACE
Anemia is the commonest medical disorder in pregnancy, with

a prevalence rate of up to 80 percent in some populations.
It is a major contributor to maternal morbidity and mortality
in our country. The effects of anemia in pregnancy on the
newborns future health are also a cause for concern.
Nutritional anemia, the commonest anemia in pregnancy, is
easy to diagnose and simple to treat, but its eradication still
eludes us. In-depth knowledge of all types of anemia is
essential for practitioners providing health care to pregnant
woman. Hence, a need was felt for a complete and
comprehensive book on anemia that provides a deep insight
into all aspects of anemia in pregnancy. This book aims at
sensitizing the readers to the magnitude of the problem and
takes them through a detailed description of all different types
of anemia encountered in pregnancy, the differential diagnosis
and specific therapy for each one of them. This book will
be an interesting and useful reading material for not only the
undergraduate and postgraduate medical students but also
for the practicing obstetricians and practitioners involved in
ensuring maternal well-being.
We are thankful to all the contributors and are grateful
to our patients who prompted us to bring out this manual
and hope it will benefit them the most.
SS Trivedi
Manju Puri
CONTENTS
1. Anemia in Pregnancy: Magnitude of Problem ........ 1

SS Trivedi, Sharda Patra
2. Hematopoiesis ...................................................... 19
Shashi Narayan
3. The Work-up of a Pregnant Woman with Anemia 33

Chitra Raghunandan
4. Iron Deficiency Anemia of Pregnancy ................... 45

Usha Gupta
5. Megaloblastic Anemia in Pregnancy ..................... 67

Nayantara Sharma
6. Thalassemia in Pregnancy .................................... 81

Manju Puri, Anjali Taneja
7. Hemolytic Anemia in Pregnancy ......................... 107

Kiran Aggarwal
8. Sickle Cell Anemia in Pregnancy ....................... 137

Ratna Biswas
9. Aplastic Anemia in Pregnancy ............................ 159

Abha Singh, Varsha Parakh
10. Severe Anemia in Pregnancy .............................. 185

Reena Yadav
Appendix ......................................................................... 201
Index ............................................................................... 203

CHAPTER 1
Anemia in
Pregnancy:
Magnitude of
Problem
SS Trivedi
Sharda Patra
2 ANEMIA IN PREGNANCY
Introduction
Prevalence of anemia
Effect of anemia on obstetric outcome
What constitutes anemia?
Why is anemia common in pregnancy?
Eradication of anemiachallenges
Preventive strategies
Controversies and concerns
Key points
INTRODUCTION
Anemia is one of the most commonly encountered medical
disorders during pregnancy. In developing countries it is a cause
of serious concern as, besides many other adverse effects on
the mother and the fetus it contributes significantly to high
maternal mortality. According to United Nations declaration
1997, anemia is a major public health problem that needs
total elimination. It is estimated that globally two billion people
suffer from anemia or iron deficiency.1
PREVALENCE OF ANEMIA
Exact data on prevalence of anemia in women is not available
but a crude estimate is that 500 million women between 15
and 49 years of age worldwide are anemic.2 According to World
Health Organization estimates, up to 56% of all women living
in developing countries are anemic.3 In India, National Family
ANEMIA IN PREGNANCY: MAGNITUDE OF PROBLEM 3
Health Survey-2 in 1998 to 99 shows that 54% of women

in rural and 46% of women in urban areas are anemic. In
US 12 to 16% non pregnant women between ages 16 to 48
are iron deficient and 2 to 4% women are anemic.4
Prevalence of anemia during pregnancy is much higher and
has far reaching consequences, especially the severe degrees
of anemia. It is estimated that 60 million pregnant women
world wide are anemic. Only 4 million of these are in developed
countries. In developing countries the prevalence of anemia
in pregnant women varies anywhere between 50 to 90% among
different populations. In contrast to this, 18 to 20% of pregnant
women in developed countries are anemic. Throughout Africa,
about 50% of pregnant women are anemic. West Africa is
most affected and Southern Africa the least. In Latin America
prevalence of anemia in pregnant women is about 40%.
The prevalence is high in the Caribbean, reaching 60% in
pregnant women on some islands.5 South Asia has the highest
prevalence of anemia.
More important still is the fact that a high percentage of
pregnant women in some of the developing countries have
severe anemia. In a steering committee report from India, 13%
women were reported to have hemoglobin less than 5 gm%
and 34% had hemoglobin less than 8 gm%.6
In a study conducted in a tertiary care government hospital
in north India, the hemoglobin estimation in 10,267 pregnant
women attending the antenatal clinic from Jan 2005 till Sep
2006 revealed that 76% women had hemoglobin less than
11 gm% and 1% had less than 7 gm%.Only 23% of the total
had hemoglobin of 11 gm% or more (Fig. 1.1) (unpublished).
Fig. 1.1: Hemoglobin levels in 10,267 antenatal women

(Lady Hardinge Medical College and Smt SK Hospital,
New Delhi, Jan 2005 to Sep 2006)
EFFECT OF ANEMIA ON OBSTETRIC OUTCOME

Anemia is responsible for adverse obstetric outcome in large
number of women in developing countries. More than 1000
severely anemic young women are reported to die every week
because of their inability to cope with the stress of childbirth.1
In India 16% of maternal deaths are due to anemia.7 Anemia
is also a contributory factor in many maternal deaths due to
other causes. FOGSI-WHO study on maternal mortality
revealed that 64.4% of women who died had hemoglobin of
8 gm% and 21.6% had hemoglobin level of less than 5 gm%.8
Cardiac failure, cerebral anoxia, infections especially puerperal
sepsis and inability to stand even slight blood loss during
pregnancy or delivery are seen in these women, especially in
those who are severely anemic. Abortions, preterm labor, IUGR
and low birth weight babies are more common in anemic
women. There is evidence that time of onset of anemia or
iron deficiency affects the obstetric outcome. Anemia in early
pregnancy, that is, before second trimester is more likely to
be associated with preterm and low birth weight babies. A

2-fold increase in the risk of preterm birth has been observed
in women who have anemia in mid pregnancy.9 Newborns
of iron deficient women have lower iron stores. Lower APGAR
scores, neurological and mental impairment has also been
reported in some but not all studies. Hypertrophy of placenta,
a consequence of anemia, and an increased placental: fetal
ratio has been suggested to be a predictor of diabetes and
cardiovascular disease in later life.
WHAT CONSTITUTES ANEMIA?

According to WHO, hemoglobin level below 11 gm/dl in
pregnant women constitutes anemia and hemoglobin below
7gm/dl is severe anemia. The Centers for Disease Control and
Prevention (1990) defines anemia as less than 11 gm/dl in
the first and third trimester and less than 10.5 gm/dl in second
trimester. Serum Ferritin of 15 micro gm/L is associated with
iron deficiency anemia.
WHY IS ANEMIA COMMON IN PREGNANCY?

The anemia of pregnancy is multi-factorial. Nutritional anemia
is the commonest, especially in the developing countries.
Various factors responsible for anemia during pregnancy include
the following:
INCREASED DEMANDS OF IRON IN PREGNANCY

About 1000 mg of iron is required during pregnancy; 500 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 this extra iron and stores which have around
500 mg of iron get depleted. But if iron stores are already
deficient, iron deficiency anemia manifests.
DEFICIENT IRON STORES

Total iron in an adult woman is about 50 mg/kg weight as
compared to 70 mg/kg in an adult male. 20% of total iron
is in the stores (Reticulo-endothelial system-liver, spleen, bone
marrow), Majority of the women in child bearing age have
deficient iron stores because of blood loss from menstruation.
Menorrhagia depletes the iron stores further in many women
of child bearing age. In multigravida repeated child bearing
does not give them time to replenish iron store in between
the pregnancies thus perpetuating the anemia. In an iron
deficient woman, it may take a year for hemoglobin to come
to pre pregnancy value while iron supplementation restores it
in 5 to 7 days postpartum.10
DEFICIENT INTAKE OF IRON AND OTHER

HEMATOPOIETIC FACTORS
Deficient or defective intake of iron and other hematopoietic
factors during pregnancy due to poverty, ignorance or absorption
disorders lead to nutritional deficiency during pregnancy.
Deficiency of iron, folic acid or both is common. Multiple
micronutrient deficiencies are often encountered along with
calorieprotein malnutrition leading to severe anemia and
hypoproteinemia. Deficient iron stores in infancy, childhood,
adolescence and in childbearing years perpetuate anemia during
pregnancy and beyond. Vitamin B12 deficiency, although a
rare cause of anemia during pregnancy, is sometimes seen in

strict vegans.
CHRONIC AND ACUTE BLOOD LOSS

Chronic blood loss due to various causes also contributes to
the iron deficiency anemia. Malaria which is endemic in certain
parts of the world causes anemia by hemolysis. Some parasitic
infections, e.g. hookworm, trichuriasis, amoebiasis and vesical
and intestinal schistosomiasis cause blood loss directly and
lead to iron deficiency anemia.
Acute blood loss is sometimes the cause of anemia.
INFECTIONS
Infections may impair hematopoiesis and consequently cause
anemia. Chronic and recurrent infections or inflammations,
as the cause of anemia have been reported to rank second
only to iron deficiency in prevalence. Acute infections can also
lead to anemia.
OTHER CAUSES OF ANEMIA

Although nutritional anemia accounts for most of the anemia
that occurs globally in underprivileged environments, several
other possible causes could also be present.
Genetic factors, e.g. thalassemia, sickle cell trait, and
glucose-6-phosphate dehydrogenase deficiency (G6PD) should
be considered when dealing with populations in which these
conditions are prevalent. These conditions, with the exception
of thalassemia major which is rare, usually have concomitant
iron deficiency during pregnancy.
Aplastic anemia is a rare cause of anemia during pregnancy.
ERADICATION OF ANEMIACHALLENGES
Although easy to prevent and treat, nutritional anemia, the
commonest anemia, continues to affect millions of women
throughout the world. Improving nutritional status of woman
through diet, the most desirable and sustainable strategy, entails
improvement of economic as well as social status of woman.
Elimination of poverty and accessibility to good quality food
for all is still a distant reality.
Iron supplementation during pregnancy is a widely accepted
strategy but has not been effective in most of the developing
countries mainly because of logistical and compliance problems.
National Anemia Prophylaxis Program (NAPP) was started in
India in 1972. Review of the program revealed that majority
of women was not taking Iron Folic Acid (IFA). NFHS-2 showed
Iron Folic Acid (IFA) coverage as only 57.6% of all pregnant
women with 24% in Bihar, 32% in UP and 39% in Rajasthan.6
Lack of effective implementation mechanisms and poor comp-
liance due to ignorance or side-effects are the main impediments
in effectiveness of IFA supplementation during pregnancy.7
Fortification of food with iron and folic acid has been
successful in developed and in some of the developing countries,
but it requires multi-sectoral efforts. It is expensive and its
universal availability to atleast the target population has not
been possible till now in most of the developing countries.
PREVENTIVE STRATEGIES
The strategies to prevent nutritional anemia, the commonest
anemia during pregnancy, aim at improving diet, increasing
bioavailability of dietary iron, prevention and treatment of
infections like hookworm and malaria and iron folic acid

supplementation. Food fortification and genetic modification
of food are some of the other strategies being evaluated.
IMPROVING DIET
Improving dietary intake of macro as well as micronutrients
is obviously the most acceptable strategy to prevent nutritional
anemia. Protein calorie malnutrition is often associated with
anemia in developing countries.
A good quality diet not only provides sufficient proteins
for hemoglobin synthesis but also all the micronutrients required
for erythropoiesis. Increased calorie intake results in increased
intake of micronutrients including iron.
In a poor quality diet, micronutrients other than iron are
affected, including vitamin A, zinc, calcium, riboflavin, and
vitamin B12. Some of these micronutrient deficiencies also
contribute to the severity of anemia Dietary diversification
provides all the nutrients like folic acid , iron, ascorbic acid
vitamin A, etc. Haem iron in animal food is better absorbed
than non haem iron of vegetarian diet. Bio-availability of iron
from a vegetarian diet is poor but can be increased by taking
iron rich diet with enhancers of iron absorption like vitamin
C containing foods and avoiding inhibitors like tea and coffee
with meals. Phytates in diet also interfere with iron absorption
Cooking, fermentation, or germination, by thermal or enzymatic
action, reduce the phytic acid and the hexa- and penta-inositol
phosphate content thereby improving iron absorption.
Processing procedures that lower the number of phosphate
groups improve bioavailability of non-haem iron.11
IRON AND FOLIC ACID SUPPLEMENTATION

Since in most of the pregnant women it is not possible to meet
the increased demands of iron during pregnancy through diet
despite the increased absorption of iron (from 1 to 2 mg/day
to 6 mg/day) in later part of pregnancy, iron and folic acid
supplementation is a widely accepted strategy.
WHO/UNICEF recommend that all pregnant women in
developing countries should receive routine daily supplemen-
tation of 60 mg of elemental iron and 400 microgram folic
acid for at least six months. In a woman seen late in pregnancy
120 mg of elemental iron daily is recommended during
pregnancy and puerperium.
Weekly iron supplementation was suggested on the basis
that it will synchronize with the turnover of the intestinal mucosal
cells and will have fewer side effects. In public health programs
it may be a more efficacious preventive approach. Weekly iron
and folic acid supplementation under supervised and
unsupervised program conditions have been studied and have
been found to have an impact on reducing anemia or improving
iron status. Weekly iron supplementation during pregnancy is
however, not recommended especially for populations where
prevalence of anemia is very high.
Attention over iron deficiency anemia in pregnancy has
recently shifted from providing supplements during pregnancy
to ensure that women, especially adolescents, have adequate
iron stores prior to conception. WHO/ UNICEF/INACG guide-
lines state that in populations where iron deficiency is highly
prevalent, other groups especially adolescent girls should also
be given iron supplementation. Recently 60 mg of iron and
400 microgram folic acid supplementation daily or weekly for
the adolescents has been included in anemia prevention

program.
WHO recommends treatment of those already anemic by
periodic repeated administration of daily iron supplements in
populations with high prevalence of iron deficiency anemia.
The benefits include improved womens health, enhanced
cognitive performance, increased productivity and more
importantly healthy motherhood.
MULTIPLE MICRONUTRIENT SUPPLEMENT

Supplementation with iron (and folate) alone may be sufficient
for well nourished pregnant woman but may not be effective
in correcting nutritional anemia in pregnant women with
multiple micronutrient deficiency. Consequently, where multiple
nutrient deficiencies are common, a more appropriate multiple
micronutrients supplement formulation is indicated.
FOOD FORTIFICATION
Food fortification has been found to be one of the most effective
and simple ways to deliver micronutrients to all sections of
the population in many developed and developing countries.
As a result of the global efforts of WHO, UNICEF, WB and
CDC, flour fortification has extended internationally.
The fortification of a widely consumed food with iron can
be a cost effective, long-term measure for preventing iron
deficiency anemia in the population.
Foods that can be centrally produced and are widely
consumed by target population are usually fortified with addition
of iron.
Rice in the Philippines is fortified with a standard ferrous

sulphate mixture. Metallic iron (Sweden, UK, and USA) and
ferrous fumarate (Venezuela) also have been used to fortify
flour (wheat or maize). Curry powder in South Africa and sugar
in Guatemala has been successfully fortified with iron-EDTA.
The Joint FAO/ WHO Expert Committee on Food Additives
(JECFA) examined the existing data on iron-EDTA and found
no objection to its use at a level of 2.5 mg/kg of body weight
per day.12
In India fortification of salt with iron was developed by
the National Institute of Nutrition and its efficacy was confirmed
in the trials. Since providing iodized salt is the government
policy, double fortified salt that is common salt fortified with
iodine and iron was tried with good results.13
Usefulness of fortified foods is however, limited in many
developing countries as very few households consume
commercially processed foods as these are more expensive and
there are difficulties in distribution of these to the neediest.
Effective and wide distribution of iron fortified food supplements
through general food distribution programs to only the target
population is required as there are concerns about providing
excess iron to iron replete population.
GENETICALLY MODIFIED FOODS

Genetically modified foods with high iron content have the
potential for improving the nutritional status of undernourished
populations. Rice, a poor source of iron, has been genetically
modified to decrease the phytate content, to increase the iron
content and to increase the amount of amino acid cysteine
which enhances the absorption of iron from the intestine.
Benefits and risks, if any of biomanipulations are being eva-

luated.
OTHER MEASURES
Preventive measures against hookworm and malaria should
also be considered in populations with high prevalence of these
conditions. Antihelmenthics like mebendazole can be given
during pregnancy except in first trimester.
Optimal intra-partum care is an important strategy for
prevention of anemia in the mother and the neonate. Routine
administration of oxytocics during delivery is advocated to
reduce blood loss at delivery. Although the newborn of an
anemic mother does not have iron deficiency anemia but the
iron stores of fetus are related to maternal iron status.14 Late
clamping of cord in baby at delivery prevents anemia in infancy
and should be practiced in all normal babies. 80 ml of blood
with 50 mg of iron is thus transferred to the baby. Breast feeding
during the first six months after delivery reduces maternal iron
loss.15 Iron supplementation to the mother should be continued
in postpartum period.
STRATEGIES TO ELIMINATE SEVERE ANEMIA

Since women with severe anemia are most vulnerable to adverse
pregnancy outcomes, its detection and management deserves
highest priority.
It has been suggested that in resource poor settings attention
may first be directed to eliminate severe anemia as in these
women routine, universal, unmonitored supplementation with
oral iron may not be of much benefit.16
Although all efforts must be made to detect and intensively

manage severe anemia during pregnancy, the consensus is that
programs to prevent anemia including routine and universal
iron folic acid supplementation during and before pregnancy
should continue.
CONTROVERSIES AND CONCERNS

SHOULD SUPPLEMENTS BE GIVEN TO ALL
PREGNANT WOMEN?
Some of the earlier studies questioned the routine administration

of iron to all pregnant women. Healthy women in industrial
countries with good diets and adequate iron stores did not
show any benefit from supplemental iron in terms of birth
weight, length of gestation, maternal and neonatal morbidity
and mortality. Most of the women in child bearing age however
do not have adequate stores. More recent studies have shown
beneficial effects of iron supplementation during pregnancy
especially on the fetus. Women who receive daily antenatal
iron supplementation are less likely to have iron-deficiency
anemia at term.17 WHO recommends 30 to 60 mg/d for iron
replete and 120 to 240 mg /d in women with absent iron stores.
ACOG recommendations for prevention of iron deficiency
anemia in pregnancy include administration of 30 mg of iron
per day along with encouraging iron rich diet and diets that
enhance iron absorption .However, recent studies have shown
an increase in the risk of developing type 2 diabetes mellitus
with moderately increased iron stores18 and increased ferritin

levels have been shown to be risk factor for development of
diabetes mellitus both in pregnant and non-pregnant women.
Increased oxidative stress with increased iron stores has also
been documented. Risk benefit of increased maternal status
and stores from prophylactic iron supplementation is being
evaluated.
Iron supplementation is useful if iron deficiency is present
but it may increase the risks if mother is not iron deficient.
It has been suggested that women at risk for iron deficiency
anemia can be identified by estimating serum ferritin concen-
tration in the first trimester. With serum ferritin of less than
50 ng / l in first trimester iron supplementation is advocated.19
HIGH HEMOGLOBIN
High levels of hemoglobin, hematocrit, and ferritin have been
reported to be associated with an increased risk of fetal growth
restriction, preeclampsia and preterm delivery. Likely explanation
for increased hemoglobin in IUGR and pre-eclampsia is failure
of plasma expansion due to underlying pathology rather than
iron supplementation. High serum ferritin levels observed in
preterm labor may be due to inflammation or infection.
It has been suggested that higher than normal hemoglobin
concentrations should be regarded as an indicator of possible
pregnancy complications as iron supplementation does not
increase hemoglobin higher than the optimal concentration
needed for oxygen delivery.20
KEY POINTS
Prevalence of iron deficiency anemia during pregnancy
varies from 20% in developed countries to more than 80%
in some of the developing countries.
Nutritional anemia is the commonest anemia in deve-
loping countries and contributes significantly to maternal
and fetal morbidity and mortality.
Overall improvement in the diet is the most desirable
strategy to eradicate nutritional anemia as poor quality
diet, deficient in calorie, protein and other micronutrients,
leads to severe anemia. Health education and promotion
of healthy food habits is essential to anemia eradication
program.
Iron folic acid supplementation is recommended for all
pregnant women in areas with high prevalence of anemia
(more than 40%).
Preventive measures against infections like hookworm
and malaria should be taken.
Fortification of food with iron and folic acid has been
successful in many developed and developing countries
but is expensive and requires multisectoral involvement.
Genetically modified foods with higher iron content are
being investigated.
Eradication of anemia although challenging, is essential
for enhancement of health of woman, for human develop-
ment and economic advancement in developing countries.
Anemia control program should not be taken as an
isolated activity but as an integral part of total health care
and socioeconomic development.
REFERENCES
1. UNICEF and The Micronutrient Initiative. Vitamin and mineral
deficiency: a global progress report March 2004.
2. UN Standing Committee on Nutrition 5th annual report on
the world nutrition situation: nutrition for improved
development outcomes. March 2004.
3. World Health Organization. The prevalence of anemia in
Women: A Tabulation of Available Information; Second
Edition. Geneva: WHO, 1992. (WHO/MCH/MSM/92.2).
4. Kennedy E. Dietary reference intakes: development and uses
for assessment of micronutrient status of women-a global
perspective Am J Clin Nutr 2005; 81 (suppl):1194S-7S
5. WHO Global Database on Iron Deficiency and Anemia (IDA).
The Micronutrient Deficiency Information System (MDIS).
Internet: http://WHO.Int/nut/db_mdis.htm, 2005.
6. Report of steering committee on Nutrition for tenth five year
plan (2002- 2007). Government of India, Planning
commission. Sept. 2002. Micronutrient deficiencies pp 75
107.
7. Abou ZahrC, Royston E. Maternal mortality. A global
factbook. Geneva: World Health Organization, 1991.
8. Bhatt RV. Maternal Mortality in India FOGSI-WHO study.
J Obs Gynec Ind. 1997; 47; 207.
9. Theresa O Scholl. Iron status during pregnancy: setting the
stage for mother and infant. American Journal of Clinical
Nutrition, 2005; 81 (5),1218S-22S.
10. Letsky EA 1998 The hematological system. In Broughton
Pipkin F, Chamberlain GVP (Eds): Clinical Physiology in
Obstetrics, (3rd ed), 71-110 Oxford: Blackwell Science.
11. Brune M et al. Iron absorption from bread in humans:
Inhibiting effects of cereal fiber, phytate and inositol
phosphates with different numbers of phosphate groups.
Journal of Nutrition, 1992;122:442-9.
12. Evaluation of certain food additives and contaminants. Forty-
first report of the joint FAO/WHO Expert Committee on Food
Additives. Geneva, World Health Organization, 1993. (WHO
Technical Report Series, No. 837).
13. Madhavan Nair, K Brahamam Impact evaluation of iron and
iodine fortified salt. Indian J Med Res.1998;108:203.
14. Blot I, Diallo D, Tchernia G: Iron deficiency in pregnancy.
Effects on the newborn.Curr Opin Hematol.1999;6:65.
15. Guidotti RJ. Anemia in pregnancy in developing countries.

Br J Obstet Gynaecol 2000;107:437-8.
16. Van den Broek EN, Letsky EA. Etiology of anemia in
pregnancy in south Malawi. Am J Clin Nutr 2000;72(suppl):
247S56S].
17. Pena-Rosas J, Viteri F. Effects of routine oral iron supplemen-
tation with or without folic acid for women for women during
pregnancy.Cochrane Database Syst Rev. 2006 Jul
19;3:CD004736.
18. Jiang R, Manson JE, Meigs JB et al. Body Iron stores in relation
to risk of type 2 diabetes in apparently healthy women JAMA
2004;291:711-7.
19. Benteley DP. Iron metabolism and anemia in pregnancy.
Clinics in hematology 1985;14:613-28.
20. Yip Ray. Significance of an abnormally low or high hemo-
globin concentration during pregnancy: special consideration
of iron nutrition American Journal of Clinical Nutrition,
2000;72(1):272s-9s.
CHAPTER 2
Hematopoiesis
Shashi Narayan
Introduction
Regulation of hematopoiesis
Erythropoiesis
Myelopoiesis
Megakaryopoiesis
Key points
INTRODUCTION
The blood contains several types of cells which are distinct
in appearance and have a specific biologic function. Though
there are structural and functional differences in these cells,
strong evidence exists that all blood cells are the progeny of
a single type of cell: the hematopoietic stem cell.
The processes which are involved in production of various
cells of the blood from the hematopoietic stem cell is termed
as hematopoiesis. It includes self renewal of stem cells,
commitment of most progeny of stem cells to differentiate
ultimately into a particular cell type, and the proliferation of
the progenitor cells and their differentiation along a pathway
leading to mature blood cells.
REGULATION OF HEMATOPOIESIS
Differentiation and maturation of hematopoietic cells is
regulated by endogenously produced glycoproteins termed as
cytokines. They have a weight of around 20 to 50 kd. More
than 20 cytokines have been cloned and sequenced and more
HEMATOPOIESIS 21
are being discovered everyday. The receptors for these cytokines

present on the surface of the cells are biochemically similar
and quite different from other known classes of surface
receptors. These receptors are small, span the plasma
membrane once and do not exhibit intrinsic kinase activity.
The three most well characterized cytokines are
erythropoietin (EPO), granulocyte colony stimulating factor
(G-CSF) and granulocyte macrophage colony stimulating factor
(GM-CSF). Erythropoietin is produced primarily by the cells
of the renal proximal tubule and hepatic kupffer cells.
Levels of EPO are regulated by arterial oxygen content. When
the oxygen delivered to these cells diminishes, they produce
erythropoietin which then circulates in the blood to the bone
marrow, where it binds to receptors on the surface of erythroid
precursors cells, causing them to divide and mature.
Cytokines that stimulate neutrophil production (G-CSF, GM-
CSF) are regulated by a complicated network that senses the
presence of bacteria and other foreign cells. G-CSF receptors
are present on segmented neutrophils and their precursors, the
receptor density decreases with maturation. GM-CSF receptors
are present on monocytes and eosinophils in addition to
neutrophils.
Recombinant G-CSF and GM-CSF have been used primarily
to treat patients with serious forms of neutropenia.
ERYTHROPOIESIS
The process by which red cells are produced in the bone marrow
is termed erythropoiesis. Under normal conditions, the whole
process of erythropoiesis results in a red cell production rate
such that the red cell mass in the body stays constant.
Erythropoietin is the major hormone regulating red cell

production.
The process involves a great variety and number of cells
at different stage of maturation, starting with the first stem
cell progeny committed to erythroid differentiation and ending
with the mature circulating red cell.
ERYTHROID PROGENITORS
Erythroblasts in the bone marrow are generated from
proliferating immature erythroid cells termed erythroid
progenitors. These progenitor cells cannot be identified
morphologically but are detectable functionally by their ability
to form invitro colonies of erythroblasts. By using tissue culture
techniques two erythroid progenitors, the colony-forming unit
(CFU-E) and the burst-forming unit erythroid (BFU-E) have
HEMATOPOIESIS 23
been recognized. Under the influence of EPO, these progenitors

can grow in culture media to give rise to colonies of well
hemoglobinized erythroblasts.
Colony-forming Unit Erythroid

Morphologically they appear as immature cells with fine nuclear
chromatin, well defined large nucleolus, high nuclearcytoplasmic
ratio, perinuclear clear zone and a basophilic cytoplasm with
pseudopods.
Burst-forming Unit Erythroid

It is much more immature than the CFU-E. Morphologically
it has an oval moderately basophilic cytoplasm with occasional
pseudopods, very fine nuclear chromatin and large nucleoli.
ERYTHROID PRECURSORS
The least mature recognizable erythrocyte precursor cell is known
as Proerythroblast. Cells characteristic of subsequent stages
of maturation are called normoblasts or erythroblasts.
Cytoplasmic maturation in each stage can be assessed by
the change in staining characteristics, as the deep blue color
from the high RNA content of immature cells gives way to
the red color characteristic of hemoglobin. Nuclear maturation
is evaluated by the disappearance of nucleoli and the
condensation of chromatin as nuclear activity ceases.
Stages of Normoblastic Differentiation

1. Proerythroblast
It is a round/oval cell of moderate to large size (14 to 19 m
in diameter) with a large nucleus and a rim of basophilic
cytoplasm. Prominent nucleoli may be present. At this stage,

only very small amounts of hemoglobin are present that cannot
be detected by Giemsa stain.
2. Basophilic Erythroblast
It is morphologically similar to Proerythroblast except that the
nucleoli are not visible and the cell size is small (12 to 17m
in diameter). Condensation of chromatin begins at this stage
and on light microscopy it may appear as coarse and granular.
The ribosomal content is maximum at this stage and therefore
the cytoplasm is deeply basophilic.
3. Polychomatophilic Erythroblasts
Appearance of hemoglobin occurs at this stage and is indicated
by pink areas near the nucleus. There is an intense condensation
of nuclear chromatin. Nucleoli are not visible. The nuclear size
is small (7 to 9 m) and the cell size also decreases (12 to 15 m).
4. Orthochromatic Erythroblast
At this stage the cytoplasm possesses almost its full complement
of hemoglobin. The nucleus undergoes pyknotic degeneration
and the chromatin becomes greatly condensed. The nucleus
may also assume various bizarre forms such as buds, rosettes,
clover leaves and finally it is extruded out of the cell. The cell
size at this stage is the smallest of the nucleated erythrocyte
precursors (8 to 12 m).
5. Reticulocyte
After the nucleus has been extruded, the cell is known as a
reticulocyte. They are larger than the mature erythrocytes and
contain cytoplasmic organelles such as ribosomes, mitochondria
and the golgi complex and have special staining characteristics.
Certain supravital staining techniques cause the ribosomal RNA
to precipitate or aggregate into a network of strands or clumps
HEMATOPOIESIS 25
that have been termed reticulum. The amount of reticulum

decreases as the cells mature and in mature reticulocyte only
a few granules or scattered threads may be found.
6. Mature Erythrocyte
Morphologically the normal human erythrocyte is shaped like
a flattened, bilaterally indented sphere, commonly referred to
as a biconcave disk. It has a diameter of 7 to 8 m and is
anucleate. More than 95% of the cytoplasmic protein is
hemoglobin.
MYELOPOIESIS (Fig. 2.1)

The cells of the myeloid series arise from cells restricted to
a single lineage potential. These progenitor cells include CFU-
G, CFU-M, CFU-Pre B and CFU-DL for colony forming units
granulocyte, macrophage, B lymphocyte and dendritic/
Langerhans cells respectively.
There is remodeling of the cell during the maturation process.
It involves extensive selective proteolysis and is not yet well
understood. In myelocytes, granules that contain specific
proteolytic enzymes are formed in the cytoplasm. The nuclei
undergo a condensation process that ultimately results in a
multilobular nucleus that is retained in the mature cell. Maturing
monocyte precursors undergo similar changes.
STAGES OF MYELOPOIESIS
In the first three morphologic stages, the myeloblast
promyelocyte and myelocyte cells are capable of replication
but in the later stages, the cells cannot divide but continue
to differentiate. The morphologic criteria of classifying each
cell is based on the criteria like cell size, ratio of size of nucleus
Fig. 2.1: Myelopoiesis

HEMATOPOIESIS 27
to cytoplasm, fineness of nuclear chromatin, nuclear shape,

the presence or absence of nucleoli, the presence and type
of cytoplasmic granules and the cytoplasmic color of stained
cell (Fig. 2.1).
Myeloblast
It is the earliest recognizable precursor of the granulocytic series,
normally comprising about 2% of the marrow cells. The cell
varies in size (10 to 18 m diameter), having a large round
to oval nucleus with a high nuclear cytoplasmic ratio, fine
nuclear chromatin and contains 2 to 5 well defined pale
nucleoli. The cytoplasm is basophilic and is devoid of granules.
Promyelocyte
It is slightly larger than the myeloblast (12 to 18 m diameter).
It possesses a round to oval nucleus, having fine nuclear
chromatin which is slightly condensed around the nuclear
membrane. The nucleoli are present but are less prominent
and fewer than those in the myeloblast. The Azurophilic, primary
granules appear and accumulate in increasing numbers during
this stage.
Myelocyte
At this stage specific secondary granules appear in the
cytoplasm and accordingly the cell can be identified at this
stage as belonging to the neutrophilic, eosinophilic or basophilic
myelocyte. The nucleus is eccentric, round to oval having a
coarse nuclear chromatin and no visible nucleoli. The cells
up to this stage continue to divide.
Metamyelocyte
The cell is 10 to 18 m in diameter and is characterized by
a clearly indented or horse shoe shaped nucleus without
nucleoli. The nuclear chromatin is moderately dense, with
considerable clumping evident along the nuclear membrane.
The cytoplasm is filled with primary, secondary and tertiary
granules, but the secondary granules predominate. The
metamyelocytes are distinguished from the monocytes by the
clumped nuclear chromatin while the latter have fine
chromatin.
Band Forms
It is characterized by further condensation of nuclear chromatin
and transformation of nuclear shapes into sausage or band
configurations that have approximately uniform diameters
throughout their length. The indentation of the nucleus should
be less than one-half or two-thirds of the nuclear breadth to
be classified as a band cell.
Segmented Granulocytes
Further constrictions in the nucleus divide it into two or more
lobes connected by filamentous strands of heterochromatin
termed the polymorphonuclear stage. They are further classified
into neutrophils, eosinophils and basophils.
Neutrophil Granule Development

Neutrophilic granules are synthesized and released from the
golgi apparatus of the cells. The mature primary granules bind
neutral red dye and are seen as neutral red bodies in supravital
preparations, thus termed as azurophilic granules. The secondary
HEMATOPOIESIS 29
granules of the neutrophil lack peroxidase and sulphated

mucosaccharide. Alkaline phosphatase, lysozymes, lactoferrin
and BR binding protein are the main constituents of these
granules.
A third type of granule, the tertiary granule also known
as the gelatinase granule, is synthesized mainly during the band
and segmented neutrophil stages.
MONOCYTEMACROPHAGE SERIES
Monoblast
It is the least mature and recognizable cell of monocyte-macro-
phage series. It is found only in the bone marrow. The cell is non
motile and measures approximately 14 m in diameter. It has
a deeply basophilic cytoplasm, large nucleus with little indentation
fine chromatin and one or two large nucleoli. Distinguishing the
monoblast from the myeloblast based on morphology is difficult
and impossible even using the electron microscope.
Promonocyte
It is the earliest cell clearly recognizable morphologically in the
monocyte series. The cell is 11 to 13 mm in diameter and
has a high nuclear to cytoplasmic ratio. The cytoplasm is
basophilic and has fine granules. The nucleus is indented with
fine chromatin and may contain a nucleolus.
Monocyte
Monocytes are 10 to 11 mm in diameter, being generally smaller
than promonocytes but larger than other mature leukocytes.
The nucleus is large and oval or indented and centrally placed
nuclear chromatin is delicate and nucleoli are not visible.

Cytoplasm is abundant, gray or light blue and contains
numerous fine azurophilic granules. These granules contain
peroxidase but are much smaller than those found in neutrophils.
LYMPHOPOIESIS
The primary lymphopoietic organs in humans are the bone
marrow and thymus. The lymphoid stem cells undergo
spontaneous division which is independent of any antigenic
stimulation. Lymph nodes, spleen and gut associated lymphoid
tissue constitute the secondary or reactive lymphoid tissue.
Antigenic stimulation leads to lymphocyte production from the
germinal centers of lymphoid follicles of these tissues.
Functionally, the cells are divided into T and B lymphocytes
depending on their activity in cell mediated immune response
or in humoral antibody response.
Development of B cells takes place in the bone marrow
in humans. After antigenic stimulation, B cells proliferate and
mature into plasma cells which secrete specific immunoglobulin
antibodies. Development of T cells takes place both in the
thymus and the bone marrow.
Lymphoblast
It is the earliest identifiable precursor and is a rapidly dividing
cell. The cell is large, 10 to 18 m in diameter having a large
round to oval nucleus containing clumped or stippled nuclear
chromatin. Nuclear membrane is dense and has 1 to 2 nucleoli.
Cytoplasm is scanty, basophilic and non-granular.
HEMATOPOIESIS 31
Prolymphocyte
The cell is 9 to 18 m in diameter having a round to indented
nucleus with slightly stippled or coarse chromatin and may
have 0-1 nucleoli.
Lymphocyte
Mature lymphocytes are further classified as small (9 to
12 m) and large (12 to 16 m) in diameter. They have round
to slightly indented nucleus with coarsely clumped chromatin
and scanty basophilic cytoplasm.
Plasma Cell
They are derived from B-lymphocytes under antigenic
stimulation. Nucleus is eccentric and has a cartwheel pattern
of clumped nuclear chromatin. Cytoplasm is deeply basophilic
with a pale perinuclear zone .
MEGAKARYOPOIESIS
Progenitors for megakaryopoiesis and erythroid cells display
many common features. Bipotent erythroid and megakaryocytic
progenitors resemble small lymphocytes but can be distinguished
by a specific pattern of cell-surface protein display.Several
cytokines stimulate the proliferation and survival of megakaryo-
cytic progenitor cells, first identified as megakaryocyte colony-
stimulating factors.
MEGAKARYOBLAST/ STAGE I MEGAKARYOCYTE

It is a 6 to 24 m in diameter and contains a large, minimally
indented nucleus with loosely organized chromatin and multiple
nucleoli and scant basophilic cytoplasm containing few granules.
STAGE II MEGAKARYOCYTE
The cell is 14 to 30 m in diameter containing a lobulated
nucleus and a more abundant but less intense basophilic
cytoplasm containing abundant granules.
STAGE III/IV MEGAKARYOCYTE

The cell is large (40 to 60 m in diameter) with a low nuclear
cytoplasmic ratio. Nucleus is eccentrically placed and is highly
lobulated but single. There is waning of cytoplasmic basophilia
in this stage. Stage IV megakaryocytes are wholly engaged
in platelet function.
PLATELETS
Platelets are formed by fragmentation of megakaryocyte
cytoplasm. Each megakaryocyte gives rise to 1000 to 5000
platelets before the residual nuclear material is engulfed and
eliminated by marrow macrophages.
The cells are small, approximately 2 m in diameter
anucleate with occasional reddish granules.
KEY POINTS
All blood cells are the progeny of hematopoietic stem cell.
Differentiation and maturation of hematopoietic cells is
regulated by endogenously produced cytokines like
erythropoietin, granulocyte colony stimulating factor and
granulocyte macrocyte colony stimulating factor.
The process by which red cells, white blood cells and
platelets are produced in bone marrow is termed as
erythropoiesis, myelopoiesis and megakaryopoiesis
respectively.
All these processes start with the stem cell progeny and
after passing through different stages of maturation end
with mature circulatory RBC, WBC or platelets.
CHAPTER 3
The Work-up of
a Pregnant
Woman with
Anemia
Chitra Raghunandan
Introduction
Clinical diagnosis of anemia
Hematological diagnosis
Other investigations
Key points
INTRODUCTION
The life span of circulating Red Blood Cells (RBC) varies from
100 to 120 days. About 1% of total RBCs in the body are
destroyed and removed from circulation every day. The red
cell mass however remains constant, subject to the effect of
erythropoietic feed back loop and availability of basic substrate
for hemoglobin synthesis. Anemia is defined as a decrease in
red cell mass, in the blood to deliver adequate oxygen to
peripheral tissues. It is the consequence of an acquired or genetic
abnormality of impaired synthesis or increased destruction of
RBCs. Anemia is established by any of the three measure-
ments.1
Hemoglobin (Hb) level gm /dl
Hematocrit (%)
RBC number 1012 / L.
Hemoglobin concentration of 14 gm/dl and 12 gm/dl are
considered as lower limits of normal at sea levels, in adult
men and women, in most population surveys. In pregnancy
the total RBC mass is increased in amount, but to a lesser
degree than the increase in plasma volume and hence
hemoglobin content falls in pregnancy. WHO recommends that
THE WORK-UP OF A PREGNANT WOMAN WITH ANEMIA 35
Hb level should be maintained at or above 11 gm/dl in pregnancy

and should not be allowed to fall below 10.5 gm/dl in the
second and third trimesters.2
There is a growing demand of substrates for hemoglobin
synthesis, i.e iron and folic acid in pregnancy, due to increase
in red cell mass as well as for the growing fetus and placenta.
This cannot be met with normal mixed diet inspite of increase
in iron absorption in latter half of pregnancy. As many women
enter pregnancy with already depleted iron stores, anemia
develops rapidly in them. The commonest cause of anemia
in pregnancy is iron deficiency.3 The important aspect of
management of anemia in pregnancy is to assess the degree
and type of anemia to find the cause. This is essential for
correct approach to its treatment and prevention of recurrence.
CLINICAL DIAGNOSIS OF ANEMIA

Anemia in pregnant women can be diagnosed without difficulty.
This may be evident in asymptomatic pregnant women during
routine antenatal check up. With increasing severity of anemia,
the pregnant women may seek medical attention because of
easy fatiguability, decreased work or exercise tolerance,
shortness of breath, palpitations on exertion or otherwise. The
work-up of the pregnant woman involves detailed history and
clinical examination, followed by evaluation of hematological
laboratory data.
HISTORY
A thorough history and physical examination of a pregnant
woman is important, to diagnose anemia and to arrive at the
probable cause.
Age and parity of the patient are important as young

adolescents and elderly multipara are more likely to be anemic.
Mothers with multifetal gestations are more likely to suffer from
anemia.
The duration of symptoms and their onset, whether insidious
or acute should be ascertained. It is important to establish
or rule out the presence of infections like malaria, tuberculosis,
lymphomas or collagen diseases. Presence of bruises, ecchy-
moses and petechiae may suggest associated platelet disorder.
Abnormal color of urine suggesting blood or hemoglobin may
signify urological or hematological problem. A darker urine
due to excessive concentration of urobilinogen may be associated
with hemolytic anemia. Presence of tarry or bulky stools, chronic
diarrhea and worm infestations must be enquired. History of
chronic loss of blood from bleeding gums or bleeding piles may
be obtained. The past history of blood transfusion in self or
family is important. Any prolonged illness and drug intake by
the patient must be noted. The patients family history with
respect to hereditary hemolytic anemia and bleeding disorders
is recorded.
The dietary history must be obtained including the pattern,
amount, idiosyncrasy, cooking habits, vegetarianism, etc. with
respect to folic acid intake.
The personal history including occupation and travel to
endemic areas of malaria must be asked for and recorded.
The menstrual history should include cycle length, duration
and amount of bleeding. Heavy menstrual blood loss must
be noted. The last menstrual period and period of gestation
is to be recorded.
The obstetric record of abortions, repeated child births and

hemorrhagic losses are important. The use of IUCD and
associated excessive bleeding during menses may cause chronic
anemia in the patient.
CLINICAL EXAMINATION
The physical examination must be done in detail. The vital
signs must be correctly recorded including pulse rate, JVP,
respiratory rate, temperature and blood pressure. Features of
anemia like facial pallor, pale conjunctiva, tongue, palmer
creases and nail beds should be looked for. Tongue may have
painful ulcers and necrotic lesions may occur in the mouth
in pernicious anemia.
Sternal tenderness near lower or middle third of sternum
may be elicited which may be a feature of acute leukemia.
Palpation of liver and spleen and generalized lymphadenopathy
may suggest chronic infectious diseases and tendencies for
hemolytic anemia. Swelling of the feet and lower abdominal
wall suggests associated hypoproteinemia or congestive heart
failure.
In the examination of cardiovascular system, hemic
murmurs are common cardiac signs associated with anemia
and are best herard in pulmonary area. Presence of basal
crepitations in lungs suggest congestive heart failure associated
with severe anemia.
Obstetric examination should include correct assessment
of gestational age, fetal growth and wellbeing.
HEMATOLOGICAL DIAGNOSIS
The data from medical history and clinical examination must
be correctly integrated with key investigative laboratory tests.
HEMOGLOBIN ESTIMATION
The measurement of hemoglobin is the simplest, non invasive
test based up on which, further investigations are carried out.
Hb should be estimated atleast 3 times during pregnancy, at
first visit, at 28/30 weeks and around 36 weeks.4 Any detectable
change in hemoglobin levels is preceded by depletion of iron
stores and reduction in serum iron levels. If the Hb levels are
less than 10.5 gm/dl in the second trimester, it requires further
investigation. Hemoglobin is estimated by manual, physical
and chemical methods which are easy to perform and are
most practical.
Taliquiests method
Sahlis method
Cyano methhemoglobin method.
The electronic methodThe current electronic complete
blood counts and erythrocyte indices are most accurate
and reproducible. Hemoglobin concentration, RBC number
and corpuscular volume are directly measured and these
values are used to calculate the hematocrit, MCH and
MCHC. The red cell distribution width (RDW), an index
of red cell size, is also generated by the electronic counters.
Red cell IndicesThese help in classification of anemia.
Normal valuesSee Appendix.5
PERIPHERAL BLOOD SMEAR EXAMINATION

This is the most important aspect of diagnostic evaluation of
anemia. It reveals abnormal blood cell population, and helps
in early diagnosis of anemia. It differentiates between various
types of anemia, e.g. iron deficiency anemia, megaloblastic
anemia and hemolytic anemia. Thick and thin films may detect
malarial parasite. Differential leukocyte count can also be done
along with platelet morphology. It provides guidelines for further
testing.
A well made peripheral smear gives information about size,
shape of RBCs and their variations and extent of their
hemoglobinization. These features help in characterizing different
types of anemias based upon red cell morphology,
Microcytic hypochromic anemia characterized by aniso-
cytosis, poikilocytosis, e.g Iron deficiency anemia or
thalassemia.
Macrocytic anemia characterized by hypersegmented
neutrophils, thrombocytopenia for, e.g. Folic acid and
vitamin B12 deficiency anemia.
Polychromatophilia, nucleated RBCs, abnormal sphero-
cytes, sickle cells, target cells, schistocytes, neutrophilia,
thrombocytosis are seen in hemolytic anemia.
Dimorphic anemia demonstrates dual population of
macrocytes and hypochromic microcytes in peripheral
smear and is seen in cases of combined folic acid and
iron deficiency (Fig. 3.1).
OTHER INVESTIGATIONS
Stool examination is done for documentation of worm
infestations which is the commonest cause of anemia. Stool
Fig. 3.1: Dimorphic anemia

1. Microcyte 2. Macrocyte 3. Ovalocyte
(For colour version see Plate 1)
should be examined for ova and cyst, atleast in three consecutive

samples.
Urine should be examined for occult hematuria, pus cells
and casts. Urine culture is doneto detect infections.
X-ray chest for pulmonary Kochs or in patients with conges-
tive cardiac failure, renal function tests for renal diseases, liver
function test for liver disease, serum proteins for hypopro-
tienemia and electrophoresis for hemoglobinopathies are certain
other investigations, which are carried out, whenever indicated.
If there is no response to iron and folic acid, therapy there
is need to do special investigations.6 The various special
investigations are as follows:
a. Serum ferritinIt is a high molecular weight glycoprotein

in circulation and indicates iron store status. It is assessed
by ELISA method. A value less than 12 ng/ml indicates
iron deficiency accurately.7
b. Serum ironThe normal value is 60 to 150 g/dl. It is
lowered to 60 g/dl and less, in iron deficiency anemia.
c. Serum iron binding capacityThe normal value is 250
to 435 g/dl. It is increased in iron deficiency anemia. The
transferrin saturation is less than 15% in iron deficiency
anemia.
d. Serum transferrin receptorsIt is a specific and sensitive
marker of iron deficiency in pregnancy. Transferrin receptors
are disulphide-linked transmembrane proteins that facilitate
the entry of transferrin bound iron into cells. A soluble
truncated form of protein can be detected in the plasma
and their levels are increased in iron deficiency and
this helps in distinguishing from the anemia of chronic
disorders.8
e. Free erythropoietin protoporphyrinsIt represents the
unused substrate in heam synthesis and levels rise with
defective iron supply. It takes 2 to 3 weeks to become
abnormal after depletion of iron stores. The rise is also
associated with chronic diseases, infections and malignancy
and is thus misleading.9 It is indicated in patients of
microcytic hypochromic anemia in absence of iron
deficiency where thalassemia is suspected.
f. Nestroft testIt is naked eye single tube, red cell osmotic
fragility test, a screening test for thalassemia trait. If the
test is found positive, the cases can be subjected to HbA2
estimations which is 3.6 to 8% in these cases.
Algorithm of approach to anemia in pregnancy
42
ANEMIA IN PREGNANCY
g. Bone marrow examinationIt is an invasive procedure

and is indicated where there is no response to iron therapy
and other cell lines are affected as in megaloblastic anemia
and aplastic anemia.10
Non megaloblastic anemia with reticulocytosis may suggest
hemolytic anemia or hemorrhagic anemia, but if reticulocytes
are normal or reduced, hypothyroidism and liver disease should
be considered. When the peripheral blood smear shows
abnormal red cell forms including polychromatophilia, basophilic
stipling, erythroblastosis and abnormal red cell forms, hemolytic
anemia should be looked for. Hemoglobinemia, hemoglobi-
nuria, hemosiderinuria, methalbuminemia suggest intravascular
hemolysis and should be investigated.
KEY POINTS
Anemia in pregnancy warrants investigations in both
symptomatic and asymptomatic pregnant woman.
Investigations are needed to assess the degree, type and
cause of anemia, for correct approach to its treatment and
to prevent its recurrence.
The clinical diagnosis depends upon a thorough history
and clinical examination and this should be followed by
hematological investigations.
Hemoglobin level of less than 11 gms per dl is defined
as anemia in pregnancy.
Peripheral blood smear examinations along with red cell
indices help in classifying anemia.
Stool and urine examination are necessary to rule out
common causes of anemia.
Special investigations are necessary if
therapeutic response to iron and folic acid is not satis-
factory
peripheral blood smear examination shows that other
cell lines are affected or there is megaloblastosis
there is abnormal reticulocytosis

These investigations include serum ferritin, serum iron,
serum folic acid, hemoglobin electrophoresis and bone
marrow examination.
REFERENCES
1. Glader Bertil, Anemia-General Consideration. In Wintrobes
Clinical Hematology (2nd edn.). Lippincott and Williams
2004;948.
2. World Health Organization. The prevalence of anemia in
pregnancy, WHO technical reports [1992-1993].
3. Elizabeth LA. Bloood volume,hematinics anemia, Medical
Disorders of Pregnancy (4th edn.). Micheal Deswiet,
Blackwell publishing company 2002;28.
4. Daftary S. Anemia in pregnancy. Manual of Obstetrics (2nd
edn.). Elsevier 2005;115.
5. Perkins SL. Normal blood and bone marrow values in
humans. In Greer JP, Foerster J, Lukens JN, Rodgers GM etal
(Eds) Wintrobes Clinical Hemotology (11th edn.). Lippincott
Willams and Wilkins 2004.
6. Singh T, Anemia, Textbook of hematology. Arya publication
2002.
7. Finln CA, Plasma Ferritin determinant as a diagnostic tool.
West J Med 1986;145(5):657-63.
8. Carriga MT, Skikne BS, Finly B, Culten B, Coule JD. Serum
transferin receptor, for the detection of iron deficiency anemia
in pregnancy. Am J 1991;54:1977-87.
9. Zanella A. Sensitivity and predictive value of serum ferritin
and free ery throcyte protoporphyrin in iron deficiency. J Lab
Clin Med 1989;113(1):73-8.
10. Lewis BJ, Laras RK. Leukemia and lymphoma in pregnancy.
In Lavos RK (Ed) Blood Disorders in Pregnancy. Lea and
Febriger: Philadelphia 1986;85-101.
CHAPTER 4
Iron Deficiency
Anemia of
Pregnancy
Usha Gupta
Introduction
Definition of anemia
Etiopathogenesis of iron deficiency anemia
Clinical features
Laboratory diagnosis
Normal values of red cell indices and serum levels of
erythropoeitic factors
Management of iron deficiency anemia
Dietary advice
Drug treatment
Conclusion
Key points
INTRODUCTION
Iron deficiency anemia is the most common type of anemia
in pregnancy. The increased demand of iron during pregnancy
contributes to increased incidence and severity of this anemia.
Inadequate production of red cells and reduced synthesis of
hemoglobin cause anemia. Normal erythropoiesis is dependant
on several hematopoietic nutrients. These include:
Minerals like iron
Vitamins like folic acid, vitamin B12, vitamin C, pyridoxine
and riboflavin
Proteins
Trace elements like copper, zinc, magnesium, cobalt and
molybdenum.
IRON DEFICIENCY ANEMIA OF PREGNANCY 47
The commonest deficiency in pregnancy is that of iron,

followed by deficiency of folate and vitamin B12. Deficiency
of other nutrients usually coexists with any of the above
mentioned deficiencies.
DEFINITION OF ANEMIA
The commonly used definition for diagnosis of anemia in
pregnancy is that of WHO 1where a hemoglobin concentration
of less than 11 gm/dl and hematocrit of less than 33% is defined
as anemia. According to Indian Council of Medical Research2
anemia is defined as a Hb level of less than 11 gm/dl, mild
anemia with Hb of 10 to 10.9 gm/dl, moderate anemia with
Hb of 7 to 10 gm/dl and severe anemia with Hb of less than
7 gm/dl. The Centers for Disease Control and Prevention3 has
defined anemia in pregnancy as a Hb of less than 11gm/dl
in first and third trimesters of pregnancy and Hb of less than
10.5 gm/dl in second trimester of pregnancy.
ETIOPATHOGENESIS OF IRON
DEFICIENCY ANEMIA
DIETARY DEFICIENCY
The various factors causing dietary deficiency of iron are:
Overall deficiency in diet due to poverty
Lack of knowledge of iron rich diet
Intake of vegetarian diet. Heme iron in non-vegetarian diet
is better absorbed and bioavailable.
Presence of non absorbable compounds like phytates,
phosphates, polyphenols, calcium and tannins in diet that
inhibit iron absorption.
POOR ABSORPTION
This can be due to malabsorption syndromes like sprue.
INFECTIONS
Worm infestation especially hookworm infestation, amoebiasis,
malaria, kala-azar, tuberculosis and other chronic diseases can
cause anemia.
INCREASED DEMAND OF IRON

The demand is increased in conditions like
Normal pregnancy
Frequent and closely spaced pregnancies
Multiple pregnancies
Prolonged lactation.
The total demand of iron in pregnancy is approximately
1240 mg 4 of this 500 to 600 mg is required for red cell
expansion, 300 mg for fetus and placenta and the rest for
the growing uterus and blood loss during delivery. On the other
hand 150 mg of iron is saved during pregnancy as a result
of amenorrhea.Thus after deducting the iron conserved by
pregnancy related amenorrhea the average iron demand during
pregnancy is 6 mg /day.
BLOOD LOSS
Blood loss due to any reason either before pregnancy due to
menstrual disturbances, or during pregnancy due to hemorrhagic
complications of pregnancy and labor, hemorrhoids or bleeding
from any other site can cause anemia.
CLINICAL FEATURES
Women are usually asymptomatic in mild anemia. However,
in moderate and severe anemia, patient complains of easy
fatigability which is progressive. Patient also complains of loss
of appetite, indigestion, palpitations, dyspnea and black out
or fainting episodes.
Physical signs will depend on the degree of anemia. While
pallor may be the only feature in mild anemia, in severe anemia
one or more of the following signs may be present. Tachycardia,
increased respiratory rate, crepitations at the lung bases, systolic
murmur due to hyperdynamic circulation, hepatosplenomegaly,
edema of feet or anasarca depending on presence of hypo-
proteinemia or congestive cardiac failure. Deficiency of several
nutrients may manifest as glossitis or stomatitis, bleeding spots
in skin and polyneuropathy. In severe anemia patient may have
cerebral anoxia and she may be disoriented, irritable and restless
and often misdiagnosed as a non cooperative patient.
LABORATORY DIAGNOSIS
Hemoglobin estimation confirms the diagnosis of anemia and
its severity. The diagnosis of iron deficiency anemia is made
by several investigations.
The most easily done test is the peripheral blood film which
shows microcytic hypo-chromic red cells with anisocytosis and
poikilocytosis (Figs 4.1 and 4.2).
Red cell indices in iron deficiency anemia show a decrease
in packed cell volume (PCV) to less than 36%, mean
corpuscular volume (MCV) to below 80 fl, mean corpuscular
Fig. 4.1: Normocytic normochromic red cells

1. Normocyte normochromic red cell 2. Lymphocyte
Fig. 4.2: Microcytic hypochromic anemia

1. Tear drop cell 2. Elliptocyte 3. Microcytic hypo-
chromic cell 4. Lymphocyte 5. Platelet
hemoglobin (MCH) to less than 27 pg and mean corpuscular

hemoglobin concentration (MCHC) to less than 33 gm/dl.
Serum studies are also helpful in identifying iron deficiency
anemia. Serum iron value of less than 60 g/dl, serum ferritin
less than 12 g/dl, Total Iron Binding Capacity (TIBC) of more
than 400 g/dl and iron saturation of less than 15% indicate
iron deficiency anemia. Serumferritin is the best non-invasive
indicator of bone marrow stores of iron and has largely replaced
bone marrow examination.
Iron deficiency anemia rarely exists alone. It is often
associated with deficiency of other minerals, vitamins and
proteins.
NORMAL VALUES OF RED CELL INDICES

AND SERUM LEVELS OF ERYTHROPOIETIC
FACTORS
RBC count 4.5 to 5.1 million/cumm
Hb 12.3 to 15.3 gm/dl
PCV 36 to 45%
MCV 80 to 96 fl
MCH 27.5 to 33.2 pg
MCHC 33.4 to 35.5 gm/dl
S. Iron 60 to 150 gm/dl
TIBC 250 to 435 gm/dl
S.iron/TIBC 30%
Reticulocyte count 0.5 to 2.5%
MANAGEMENT OF IRON DEFICIENCY ANEMIA

Correction of anemia should start well before the pregnancy
occurs. Young girls should be targeted from school itself. The
school health scheme should screen all the girls for anemia
and determine its cause. Remedial steps for its correction should
include not only therapeutic correction of anemia but also
include appropriate steps to prevent future recurrence.
All pregnant women should be covered by antenatal care
and screened for anemia at least once every trimester and
once just before or at the onset of labor. In moderate and
severe anemia emphasis should be laid on its cause and
presence of complications like congestive heart failure and
appropriate treatment should be instituted. Antepartum fetal
monitoring for early detection of fetal growth retardation is
important especially in the third trimester.
DIETARY ADVICE
Iron deficiency anemia is often accompanied by the deficiency
of other hematopoietic factors hence, iron supplementation
should be coupled with nutritional education which is likely
to be an effective strategy for better compliance and improve-
ment in iron status.
Dietary modification involves increasing total calorie intake
with increased intake from locally available iron rich food stuffs
and dietary practices which increase absorption of iron.
Iron is absorbed in the proximal small intestines close to
gastric outlet. Humans have two distinct pathways for iron
absorption, one for uptake of heme iron and another for ferrous
iron. Dietary iron must be converted to one of these forms
before absorption. Dietary non-heme iron is present in form
of ferric hydroxide or is loosely bound to organic molecules
like phytates, citrates, oxalates, lactates, sugars or aminoacids.
Gastric acidity is essential for converting this non-heme iron
into absorbable ferrous form. Heme iron on the other hand,

is derived from hemoglobin, myoglobin and other heme
proteins in foods of animal origin. Acidity of stomach and
proteases in the gastric juices frees heme from its apoprotein.
This heme iron is oxidized to its ferric state forming hemin
which enters the mucosal cells intact hence, its bioavailability
is high. This however, is available in non-vegetarian diet which
in India is consumed by only a small percentage of women.
Absorption of non-heme iron is profoundly affected by
certain dietary constituents, making its bioavailability highly
variable. The factors which inhibit absorption of non-heme
iron are vegetable proteins like soya proteins, bovine milk
proteins, phytates present in grains, bran and some other fibers
and vegetable foods. Polyphenols present in legumes, coffee,
tea and wines, phosphates in eggs and milk and calcium and
metals like zinc also interfere with absorption of iron.
Absorption of iron is increased by ascorbic acid which
converts ferric iron to ferrous iron. Animal proteins also enhance
non-heme iron absorption. Absorption of heme iron, on the
other hand is not affected by composition of the diet.
Absorption of iron is increased whenever, iron stores are
depleted and when there is increase in the overall rate of
erythropoiesis.
DRUG TREATMENT
ORAL IRON THERAPY
Oral iron supplementation is effective both for prevention of
anemia during pregnancy and for treatment of iron deficiency
anemia. Ferrous salts are much more effectively used than
ferric salts but there is little difference in the efficacy of the
various iron salts used. Of late however, ferrous ascorbate by

virtue of its ascorbate content which prevents oxidation of ferrous
content to ferric iron and due to its antioxidant property which
protects the GI mucosa is promising to become an ideal oral
iron supplement. It has been shown to have high bioavailability
of 30.6 to 43.7% in different studies5, 6 and is used as a
reference oral iron to evaluate bioavailability of other oral iron
sources. A large prospective study has shown that in severe
anemia one tablet of ferrous ascorbate of 100 mg of elemental
iron was able to improve hemoglobin by 3.6 gm/dl in 45 days.6
Thus it been suggested that ferrous ascorbate is the most
favorable iron salt for Indian diets which have high content
of inhibitors for iron absorption.7
Iron content of different salts is as follows
Salt Dose of salt Elemental iron
in mg in mg
Ferrous fumarate 200 65
Ferrous gluconate 300 35
Ferrous glycine sulphate 225 45
Ferrous succinate 100 35
Ferrous sulphate 300 60
Ferrous sulphate dried 200 65
Newer Iron Preparations

Iron Amino Acid Chelates
These are conjugates of ferrous or ferric ions with amino acids.
Ferrous glycine sulphate is the only iron amino acid chelate
available in India. Its main advantage is its relatively high
bioavailability in the presence of dietary inhibitors. The chelates
prevent iron from binding to inhibitors in food or precipitating

it as an insoluble complex in the gut.
Sustained release preparations like Iron polymaltose
complex (IPC) and Iron hydroxide polysucrose complex are
available. These have nonionic iron in a stable complex.
Absorption is not affected by food or milk and these can be
given with food. It has better absorption and lesser side effects
than ferrous salts.
Carbonyl Iron
It is pure form of elemental iron which has low toxicity and
is tolerated in larger doses when compared to ferrous salts.
Carbonyl iron refers to manufacturing process whereby
pentacarbonyl iron is reduced by heating to very fine
microspheres of less than 5 microns in diameter which are
better absorbed and associated with lesser gastrointestinal side
effects. It is available as modified release preparation.
While selecting iron preparations for therapy, it is important
to bear in mind that modified release formulations release iron
gradually as they pass along the gut hence, a part of the iron
is released beyond the most actively absorbing regions of the
intestines, that is the first part of duodenum, thereby reducing
overall absorption of iron.
Of all the iron preparations ferrous sulphate, ferrous
fumarate and ferrous ascorbate are the preferred formulations.
Prophylactic Iron Therapy During Pregnancy

This is recommended during second and third trimester of
pregnancy in women who are not anemic in a dose of one
tablet of ferrous sulphate containing 60 mg of elemental iron
per day. Ministry of Health and Family Welfare, Government

of India (1987) however, recommends one tablet of 100 mg
of elemental iron with 500 gm of folic acid per day for a
minimum of 100 days to be taken in the second half of
pregnancy for prevention of anemia during pregnancy.
In patients on oral iron therapy it is important to counsel
her not to take it along with antacids or foods containing
phosphates or phytates like milk and cereals which reduce iron
absorption.
Prophylactic iron should be avoided when hemoglobin of
patient is high that is above 13.5 gm% as iron in this situation
causes increase in oxidative stress which can cause increased
incidence of complications like PIH, accidental hemorrhage,
IUGR, etc. with deleterious effect on the mother and her fetus.
Therapeutic Iron Therapy

For therapeutic effect a minimum of 180 to 200 mg of
elemental iron per day is recommended. Thus 3 tablets of
ferrous sulphate per day or its equivalent are required for
correcting iron deficiency anemia. Along with this folic acid,
vitamin C and proteins should also be supplemented.
Under the National Anemia Control Program, Government
of India (1987) recommends that for therapeutic use a dose
of 100 mg of elemental iron with 500 gm of folic acid be
taken twice a day till hemoglobin becomes normal, and
continued in the same dose for another 12 weeks to replenish
the iron stores and then switch over to prophylactic dose of
iron.
Side Effects of Oral Iron Therapy

Gastrointestinal irritation causing nausea, vomiting, diarrhea
and abdominal pain is a common side effect. Occasionally
constipation may be associated with iron intake.
The side effects may be reduced by either starting the
treatment with lower dose or taking the tablets after meals
or by changing to another preparation containing carbonyl iron
or sustained release tablets.
Several studies8-10 have demonstrated that compliance of
patient can be increased without loss of efficacy when iron
is administered twice in a week or even once a week.
Parenteral Iron Therapy

This is indicated in the following conditions:
Poor tolerance to oral iron therapy
Poor absorption of iron like in chronic diarrhea, ulcerative
colitis, coeliac disease or inflammatory bowel disease
Non-compliance
Oral iron is ineffective
Women near term with severe anemia
Presence of concurrent diseases like chronic renal failure
when patient is on hemodialysis or being treated with
erythropoietin.
Preparations for parenteral therapy should have certain
properties to be safe and efficacious It must be possible to
give a substantial dose in the form which can be taken up
avidly by macrophages or bound form, does not get deposited
in liver or kidney parenchyma and is minimally excreted by
the kidneys.
Preparations
Severalpreparations are available for intravenous or intramus-
cular therapy
Iron dextran complex (Imferon). Each ampoule has
2 ml containing 50 mg of elemental iron per ml
Iron sorbitol citric acid complex (Jectofer/ Jectocos) Each
ampoule has 1.5 mg containing thing of elemental 50
mg/ml)
Iron sucrose complex (Venofer) Each ml has 20 mg of
elemental iron.
Iron gluconate is available as sodium ferric gluconate
(Ferrlecit) each ml has 12.5 mg of elemental iron and is
available as 5 ml ampoules.
Iron Dextran
It is a stable parenteral iron product with a molecular weight
of 100 to 500 kDa. These iron complexes show high structural
homogenicity and are slowly and competitively bound to iron
bonding proteins. These complexes are actively phagocytosed
by macrophages of the reticuloendothelial cells before they are
released and become available for hemoglobin synthesis. The
stability of iron dextran complex allows administration of high
single doses in total dose therapy.
Iron Gluconate
This is labile type of iron compound with fast degradation
kinetics and iron is released directly to the plasma proteins
like apotransferrin, apoferritin and others. About 80% of the
iron supplied as iron gluconate is delivered to transferrin in
24 hours. Potential toxicity of iron gluconate is caused by
oversaturation of transferrin binding capacity. Non-transferrin

bound free ionic iron may induce acute endothelial cell injury
and a transient capillary leak syndrome. Clinical symptoms
in such circumstances include nausea, vomiting, hypotension,
tachycardia, dyspnea due to lung edema and edema of hands
and feet which should be distinguished from anaphylaxis.
Delayed allergic reactions are uncommon.
Iron Sucrose Complex

It is a much smaller molecule than iron dextran being only
36 to 60 kDa and hence, carries no risk of anaphylaxis. It
is a partially stable compound and has medium degradation
kinetics and the iron released is partially taken up by plasma
proteins like apotransferrin and partially by reticuloendothelial
system. When it is given in a single high dose, non-transferrin
bound free iron may precipitate transient reactions like
hypotension, tachycardia and dyspnea like in iron gluconate
therapy. Delayed reactions are uncommon.
Calculation of Iron Requirement

This needs to be carefully calculated to avoid potential risk
of overload and side effects of iron therapy.
Elemental iron requirement in milligrams can be calculated
by any of the formulae given below:
1. Weight of patient in kilograms Normal hemoglobin
patients actual hemoglobin in gm/dl 2.21 +1000 mg
Here normal hemoglobin is taken as 14 gm% and 2.21
is standard coefficient. To the value calculated by above
formula 1000 mg is added for the stores.
2. Weight of patient in pounds multiplied by hemoglobin deficit

in percentage multiplied by 0.3. To the calculated dose
add 50% for replenishing the stores.
3. It takes 200 mg of elemental iron to raise the hemoglobin
level by 1 gm %.
Total dose should be calculated according to the
hemoglobin deficit and additional amount of atleast
500 mg should be added for the stores.
Technique of Giving Parenteral Iron

It can be given by intramuscular route or by intravenous route.
a. Intramuscular route: It is simpler and associated with lesser

side effects than intravenous route.
For giving intramuscular injection it is important to test for
hypersensitivity. For this 0.5 ml of the iron preparation is given
by intramuscular injection. One must wait for a minimum of
6 hours before giving full dose of iron as allergic reaction can
take place late. Full dose can be given daily on alternate buttocks
by deep intramuscular injection by Z technique to prevent the
drug from tracking to superficial layers and staining the area.
Intramuscular route should be avoided when there is associated
folic acid deficiency with thrombocytopenia as hematoma and
abscess formation may occur at site of injection.
Side Effects
The various side effects of intramuscular route of iron
administration are: Nausea and vomiting, headache, fever, joint
pains, myalgia, skin rashes, lymphadenopathy, abscess
formation at site of injection, skin discoloration and rarely severe

allergic reaction.
b. Intravenous route: Iron dextran: can be given as total dose
infusion or it can be given as smaller fractionated doses.
Iron sucrose: can be given as single dose of 300 mg, it
should not exceed a maximum of 600 mg/week. Speed of
infusion should not exceed 4 mg of iron/min or single total
dose of iron should not be more than 7 mg/kg, to avoid adverse
reactions.
Iron gluconate should not exceed 100 mg per day.
Procedure
It is very important to stop oral iron therapy before giving iron
by intravenous route
Test dose is given by dissolving one ml of iron preparation
in 100 ml of normal saline or 5% dextrose solution, and given
very slowly, at not more than 10 drops/min under strict
supervision. Small amount of solution is prepared initially so
that should the patient have severe allergic reaction, full dose
of drug is not wasted.
Before giving test dose it is essential to have all resuscitation
equipment and drugs ready. The equipment should include
intravenous fluids ready with I/V line set up, Boyles apparatus
or Ambu bag, endotracheal tubes , laryngoscope, and oxygen.
Drugs should include adrenaline, nor-epinephrine, dopamine,
hydrocortisone and antihistaminics like chlorpheniramine. If
no side effects are observed full dose can be given at faster
rate of 20 to 40 drops/min.
Side Effects of Intravenous Iron:

Major reactions may occur immediately or may be delayed.
Immediate reactions are in the form of anaphylactic reaction
requiring resuscitation, cardiac arrest, respiratory arrest, chest
pain, dyspnea, hypotension, headache, hemolysis and renal
failure.
Minor reactions in the form of flushing, metallic taste in
mouth, nausea, vomiting, urticaria, chills and rigors and fever.
Delayed reactions are joint pains, myalgias, skin rashes,
lymphadenopathy and thrombophlebitis at the site of injection.
Iron dextran complex and sorbitol citric acid complex are
associated with anaphylactic reactions and other more frequent
and more severe side effects. On the other hand iron sucrose
complex and iron gluconate cause fewer and minor side effects
and are considered to be safe preparations.
Response to Therapy
Subjective improvement appears earlier than rise in hemoglobin.
Thus patient may notice a decrease in fatigue and other
symptoms. The rate of increase of Hb is 0.1 g% per day
irrespective of the route of administration of iron. The rise in
the hemoglobin level is seen only after 2 to 3 weeks of therapy.
Earlier response however, can be judged by rise of reticulocyte
count which becomes apparent by 5 to 10 days. The maximum
value usually ranges from 5 to 10%. The reticulocytosis is
accompanied by a steady rise in red cell count which should
be apparent and significant by day 15. When treatment is
effective hemoglobin values become normal within 4 to 10
weeks of initiating therapy.
Suboptimal response may be due to inadequate supple-

mentation of the nutrient deficiency, underlying infection like
tuberculosis, renal infection, rheumatoid arthritis, thyrotoxi-
cosis and incipient cardiac failure.
CONCLUSION
Iron deficiency anemia during pregnancy continues to be a
major health problem in India. To eradicate it certain steps
can be taken at individual and community level like education
of the women as regards anemia, its causes and health
implications. Imparting nutritional education, with special
emphasis on strategies based on locally available food stuffs
to improve the dietary intake of proteins and iron, administra-
tion of appropriate iron supplements and ensuring maximum
compliance, deworming, treatment of chronic diseases like
malaria and universal antenatal care to pregnant women will
help in combating this serious problem. Long term policies
by government, non-government agencies and the community
can be directed to formulate effective plans like eradicating
anemia in children and adolescent girls.
KEY POINTS
Iron deficiency anemia is the most type of anemia in the
pregnant women.
Normal erythropoiesis is dependant on several
hematopoietic nutrients like iron, vitamins and proteins.
Oral iron supplementation is effective both for prevention
and treatment of anemia during pregnancy.
Newer iron preparations include Iron amino acid chelates,
sustained release preparations like Iron polymaltose
complex (IPC) and carbonyl iron. Their main advantages
are relatively high bioavailability even in the presence of
dietary inhibitors and lesser side effects.
Prophylactic iron therapy should be avoided when

hemoglobin of patient is high as it causes increase in
oxidative stress which has been implicated in adverse
pregnancy outcome.
Several studies have demonstrated that compliance of
patient can be increased without loss of efficacy when iron
is administered twice in a week or even once a week.
Newer parenteral iron preparations like Iron sucrose
complex (Venofer) and Iron gluconate are very safe and
efficacious.
Earliest response to iron therapy is observed as a rise
in reticulocyte count which becomes apparent by 5 to 10
days.
Dietary modification should involve increasing total calorie
intake with increase intake from locally available iron rich
food stuffs and dietary practices which increase absorption
of iron.
REFERENCES
1. WHO, Iron deficiency anemia: assessment, prevention and
control. WHO/NHD/01.3, Geneva.2001.
2. Indian Council of Medical Research. Evaluation of the
National Nutrition anemia Prophylaxis programme. Task force
study. New Delhi. ICMR, 1989.
3. Centres for Disease Control. Criteria for anemia in children
and childbearing aged women. MMWR 1989;38:400-4.
4. Milman N, Bergholt T, Byg K.E, Erikson L, Graudal N. Iron
status and iron balance during pregnancy. A critical
reappraisal of iron supplementation. Acta Obstet Gynecol
Scand 1999;78:74957.
5. Hallberg L, Hulthen L. Prediction of dietary iron absorption:
an algorithm for calculating absorption and bioavailability
of dietary iron. Am J Clin Nutri 2000;71:1147-60.
6. Olivares M, Pizarro F, Pineda O, Name J.J, Hertrampf E,
Walter T. Milk inhibits and ascorbic acid favors ferrous bis-
glycine chelate bioavailability in humans. J Nutr 1997;127
(7):1407-11.
7. Review of Indian clinical experience with ferrous ascorbate.
In Allahabadia Shroff, Agarwals 2006, Feb/Mar Issue. Pg
15. (Eds). Fogs I Times 2006, Feb/Mar Issue P15.
8. Ridwan E, Schultink W, Dillon D, Gross R. Effects of weekly
iron supplementation on pregnant Indonesian women are
similar to those of daily supplementation. Am J Clin Nutr.
1996;63(6):853-5.
9. Ekstrom EC, Hyder SM, Chowdhury SA, Lonnerdal B,
Habicht JP, Persson LA. Efficacy and trial effectiveness of
weekly and daily iron supplementation among pregnant
women in rural Bangladesh: disentangling the issues. Am
J Clin Nutr. 2002;76(6):1392-400.
10. Gomber S, Agarwal KN, Mahajan C, Agarwal N. Impact of
daily versus weekly hematinic supplementation on anemia
in pregnant women. Indian Pediatr. 2002;39(4):339-46.
CHAPTER 5
Megaloblastic
Anemia in
Pregnancy
Nayantara Sharma
Introduction
Incidence
Pathogenesis
Etiology
Diagnosis
Laboratory work up of megaloblastic anemia
Morphological changes in megaloblastic anemia
Treatment
Prevention
Key points
INTRODUCTION
Despite improvement in socioeconomic status and general well
being of the population, megaloblastic anemia continues to
be one of the major health problems in the developing world.
Improper dietary habits, multiparity, high incidence of enteric
worm infestations, hemolytic disorders coupled with poor intake
of nutrients resulting from overcooking of food are considered
to be important causative factors. Most megaloblastic anemias
are due to the deficiency of folic acid and / or cobalamin vitamin
B12 and manifests in late pregnancy.
INCIDENCE
In the developed world megaloblastic anemia occurs in only
3 to 4% of the women with anemia during pregnancy. In most
MEGALOBLASTIC ANEMIA IN PREGNANCY 69
of the cases of megaloblastic anemia there is folic acid

deficiency. Vitamin B12 deficiency is uncommon with only one
out of every 8500 pregnant women with megaloblastic anemia
having Vitamin B 12 deficiency. This low incidence of
megaloblastic anemia during pregnancy is because of the
abundance of both folic acid and vitamin B12 in the vegetarian
and non-vegetarian diets. In the developing world the incidence
is considerably higher approximately 25% of women with
anemia during pregnancy.
PATHOGENESIS
Role of vitamin B12 and folic acid in the synthesis of DNA.
Vitamin B12 and folic acid are coenzymes required for the
synthesis of thymidine, one of the four bases found in DNA.
A deficiency of these vitamins or impairment in their metabolism
results in defective nuclear maturation due to deranged or
inadequate DNA synthesis with an attendant delay or block
in cell division. The synthesis of RNA and protein is relatively
unaffected. In the synthesis of DNA, uridylate molecules are
converted to thymidylate through the action of thymidylate
synthetase which uses tetrahydrofolate as a cofactor. Tetrahy-
drofolate is synthesized from methyltetrahydrofolate by action
of methyltetrahydrofolate reductase and vitamin B12 which
serves as a cofactor. Vitamin B12 is also required for the
conversion of homocysteine to methionine. Defective DNA
synthesis results in impaired nuclear development where as the
cytoplasmic maturation proceeds normally which gives rise to
nuclear cytoplasmic asynchrony. This results in the formation
of megaloblasts. Since the megaloblast precursors do not
mature enough to be released into the blood, they undergo
intramedullary destruction, thus marrow cellularity is often

increased but production of red blood cells (RBC) is decreased
which is termed as ineffective erythropoiesis. As the name implies
erythroid precursors and red cells are abnormally large due
to defective cell maturation and division.
The molecular basis for megaloblastosis is thus a failure
in the synthesis and assembly of DNA. The most common
causes of megaloblastosis are cobalamin and folate deficiencies.
Cobalamin metabolism and folate metabolism are intricately
related, and abnormalities in these pathways are believed to
lead to the attenuated production of DNA.
RELATIONSHIP OF FOLIC ACID AND VITAMIN B12 IN THE
SYNTHESIS OF DNA
Homocystine Methionine
Vit.B12 cofactor
ETIOLOGY
The three main factors which cause megaloblastic anemia are
inadequate intake, poor absorption or increased utilization. All
these mechanism may occur during pregnancy.
Inadequate intake may occur due to prolonged cooking
which destroys the vitamin, lack of raw food in the diet and
food with higher content of animal protein Poor absorption

of folate despite adequate intake occurs because ingested folic
acid polyglutamates cannot be degraded to absorbable
monoglutamates. This is due to the presence of an inhibitor
of the enzyme in the diet or an acidic intestinal pH. Women
with sickle cell disease are at increased risk for folic acid
deficiency. Drugs such as phenytoin, nitrofurantoin, trimetho-
prim, and alcohol decrease the absorption of folic acid. Isolated
vitamin B12 dificiency results from poor intestinal absorption
due to active tropical sprue, regional enteritis or chronic
giardiasis.
Pernicious anemia results from decreased release of gastric
intrinsic factor causing malabsorption of vitamin B12. This is
age related and is often accompanied by infertility, and hence,
it is rarely seen in pregnancy. Folic acid deficiency is associated
with neural tube defects, abruptio placentae, pre-eclampsia,
prematurity and IUGR.
FOLIC ACID DEFICIENCY

Folic acid is the common name for pteroylmonoglutamic acid.
It is synthesized by many different plants and bacteria. Fruits,
leafy vegetables, meat and eggs constitute the primary dietary
source of folic acid. Some forms of dietary folic acid are labile
and may be destroyed by cooking.
Dietary folic acid exists in a polyglutamate form but is
deconjugated to monoglutamates in the intestines and primarily
absorbed in the jejunum. After absorption the folate is reduced
and methylated to form 5-methyltetrahydrofolate, which is then
transported in the blood by folate binding protein.
The minimum daily requirement for folic acid is approxi-

mately 50 g. but this may be increased several fold during
periods of enhanced metabolic demands such as pregnancy.
Body stores of folate average 2000 to 5000 g, providing a
few months reserve before signs of deficiency develop.
Inadequate dietary intake as in alcoholics, an increased
demand as in pregnancy and lactation, periods of rapid growth,
chronic hemolytic processes, primary intestinal disease such
as inflammatory bowel disease, tropical sprue interfering with
absorption of folic acid are various causes of folic acid deficiency.
Various medications such as phenytoin, impair absorption
while methotrexate interferes with its metabolism. Daily folate
requirement during pregnancy is increased. The fetus and the
placenta extract folate from the maternal circulation so
effectively that the fetus is not anemic even when the mother
is severely anemic due to folate deficiency.
The distinction between folic acid and vitamin B 12
deficiencies can usually be established by measuring serum
levels of these compounds. Direct tests include the serum and
red cell folate assay. The serum folate is always low in folate
deficiency and is normal or raised in vitamin B12 unless
concomitant folate deficiency is also present.
Vitamin B12 deficiency

Vitamin B12 is a complex organo metallic compound known
as cobalamin. The absorption of vitamin B12 requires intrinsic
factor which is secreted by the parietal cells of the mucosa
of the fundus of the stomach. After binding with transcobalamin
II a major carrier protein, vitamin B12 is secreted into the
plasma. Transcobalamin II delivers vitamin B12 to the liver
and other cells of the body, particularly the rapidly proliferating

cells in the bone marrow and mucosal lining of the gastro-
intestinal tract.
Human beings are totally dependent on dietary animal
products for their vitamin B12 requirement. Plants and vegetables
contain little cobalamin except that contributed by microbial
contamination. Hence, strict vegetarian or macrobiotic diets
do not provide adequate amounts of this essential nutrient.
The daily requirement is 2 to 3 mg. A balanced diet contains
significantly larger amounts and normally results in accumu-
lation of vitamin B12 in sufficient quantities so as to last for
several years.
Inadequate intake in the diet, strict vegetarianism, impaired
absorption as in intrinsic factor deficiency, pernicious anemia,
gastrectomy, malabsorption, ileal resection, parasitic infestation,
fish tape worm infestation, bacterial overgrowth in blind loops
and diverticula of bowel, increased requirement in pregnancy,
hypothyroidism disseminated cancer, and chronic infections
cause vitamin B12 deficiency.
Vitamin B12 is known to be involved in only three reactions
in human tissues: as ado-B 12 in the isomerization of
methylmalonyl CoA to succinyl XoA and of leucine to
leucine and as methyl B12 in the methylation of homocysteine
to methionine, a reaction that also requires methyltetra-
hydrofolate.
DIAGNOSIS
CLINICAL FEATURES
Irrespective of the fact whether the deficiency is due to vitamin
B12 or folic acid, the clinical features of megaloblastic anemia
are similar. In general folate deficiency develops more rapidly

(months) than does vitamin B12 deficiency (years). Clinically
the most important difference is the development of neurological
symptoms in cases of vitamin B12 deficiency, secondary to
degeneration of the posterior and lateral columns of the spinal
cord. These neurological symptoms may become irreversible
if prompt therapy is not instituted. Such neurological findings
are not seen with folate deficiency.The patient may demonstrate
a fairly severe anemia which fails to respond to genuine intake
of iron.
DIFFERENTIAL DIAGNOSIS OF
MEGALOBLASTIC ANEMIA
The similarities in the morphologic effects on red and white
blood cells caused by folate and vitamin B12 deficiencies as
well as the fact that the anemia caused by the deficiency of
one of them can be corrected by administering the other, cannot
obscure the fundamental difference between the two processes.
Vitamin B12 deficiency causes progressive demyelinization but
folate deficiency does not and treatment of vitamin B12 anemia
with folate does not arrest the progression of neurologic damage.
Therefore differential diagnosis between these two major causes
of megaloblastic anemia is important and necessary. The
hematological manifestation, in both bone marrow and blood,
are identical for both folic acid and vitamin B12 deficiencies.
The distinction between folic acid and vitamin B 12
deficiencies can usually be established by measuring serum
levels of these compounds. Direct tests include the serum and
red cell folate assay. The serum folate is always low in folate
deficiency and is normal or raised in B12 deficiency unless folate
deficiency is also present...
LABORATORY WORK UP OF
The basic workup for vitamin B12 or folate deficiency includes
CBC, peripheral blood smear, serum and red cell folate, and
serum B12 estimation (Fig. 5.1).
Fig. 5.1: Macrocytic anemia 1. Macrocyte

Criteria for the diagnosis of Megaloblastic anemia

The hemoglobin level must be below 10 gm%, and at least
two of the following features, must be present in the films of
the buffy coat layer.
a. More than 4% of the neutrophil polymorphs must have
5 or more lobes;
b. Orthochromatic macrocytes must be present with diameters
exceeding 12 um;
c. Howell-Jolly bodies which are residual nuclear inclusion

bodies within the erythrocytes are demonstrable;
d. Nucleated red cells, that is to say normoblasts showing
premature hemoglobinization for their stage of nuclear
development are found;
e. Macropolycytes may be present .There are giant polymorphs
within the buffy coat layer.
MORPHOLOGICAL CHANGES IN
The peripheral blood examination usually reveals pancytopenia,
as all myeloid lineages are affected. There is marked variation
in size and shape of red cells (anisocytosis) with mean
corpuscular (cell) volumes above 100 fl (normal 82 to 98),
normochromic with normal MCH and MCHC. They are thicker
than normal, may appear hyperchromic due to the lack of
the central pallor but the MCHC is not elevated. The reticulocyte
count is low and nucleated red cells occasionally appear in
the circulation with severe anemia. Neutrophils are also larger
than normal (macropolymorphonuclear) and hypersegmented
that is they have five to six or more nuclear lobules. The marrow
is also hyper cellular due to increased numbers of all types
of myeloid precursors, which may completely replace the fatty
marrow. Megaloblastic change is detected in all stages of red
cell development.
In severe cases the anemia may be associated with
leucopenia and thrombocytopenia.
Iron deficiency anemia can be masked by both folate and
vitamin B12 deficiencies because the synthesis of red cells is
inhibited during the vitamin deficiency. Available iron is
underused and increased saturation of transferrin occurs. As
soon as therapy with folate or B12 is initiated, red cell synthesis

starts again, with resultant increase in iron utilization and iron
deficiency becoming apparent.
The fasting serum folate level is less than 6 g /L (normal
is 6 to 12 g /L) and RBC folate is less than 165 g /L (normal
is 190 to 165 g / L). In severe disease serum iron concentration
and serum lactate dyhydrogenase (LDH) increase. Red blood
cell folate is the best reflection of the amount of folate in the
tissue. Its value is fairly constant with a few fluctuations and
it is the test of choice for the diagnosis of the deficiency.
Examination of the bone marrow will reveal megaloblastic
erythropoiesis. This procedure is rarely done now. Further as
the maternal folate deficiency becomes severe, thrombo-
cytopenia, leucopenia or both may occur.
In vitamin B12 deficiency, the findings are all similar to
those in folate deficiency except, Serum vitamin B12 is less
than 190 g /L (normal is 190 to 950 g/L) measured by radio-
immunoassay. The Schilling test, which is used to assess the
causes of malabsorption of vitamin B12 , is usually done after
delivery in the postpartum period, once cobalamin deficiency
has been established. Schilling test is the inability to absorb
an oral dose of cobalamin is assessed by urinary excretion
of radiolabelled cyanocobalamin given orally.
TREATMENT
FOLIC ACID SUPPLEMENTATION
The treatment should include folic acid, a nutritious diet, and
usually iron. The dose of folic acid is 1 mg tid orally. By 4
to 7 days of therapy the reticulocyte count is appreciably
increased and leucopenia and thrombocytopenia are promptly
corrected.
Hemoglobin (Hb) will gradually increase to normal levels

after several weeks of therapy because after initiating folic acid
therapy the blood volume usually increases considerably so
that even though Hb is being rapidly added to the circulation
the Hb concentration does not precisely reflect the total amount
of additional Hb because of the simultaneous expansion of
the blood volume. Iron supplementation is essential with the
onset of effective erythropoiesis, as the concentration of iron
in the plasma falls precipitously and any stored iron is rapidly
exhausted.
Megaloblastic anemia recurs rather often in subsequent
pregnancies because of the persistence of dietary inadequacies
or peculiarities in absorption or utilization of folic acid.
Vitamin B12 Supplementation

Vitamin B12 therapy requires 6 weekly injections of 1 mg of
cyanocobalamin. The oral preparations of vitamin B12 have
unreliable absorption and are inadequate for long-term therapy.
Parenteral Therapy
Severely anemic patients especially if they are near delivery
exchange transfusion of packed red cell followed by parenteral
therapy with folic acid (1 mg/day for 1 week) and cyanocoba-
lamin 100 g/day for 1 week may be necessary.
PREVENTION
Routine supplementation with folic acid is advisable in
pregnancy.
Folic acid supplementation of 300 to 400 g per day from
the first booking to cover the second and third trimester is
necessary. For prevention of neural tube defects a dose 400 g/

day is recommended before and during pregnancy. Folate
requirement is usually increased in multifetal pregnancy or overt
hemolytic anemia.
KEY POINTS
Megaloblastic anemia in pregnancy manifests late and is
due to the deficiency of folic acid and vitamin B12.
In the developed world the incidence is 3 to 4% while in
the developing world it is as high as 25%.
The molecular basis for megaloblastic anemia is failure
of the synthesis and assembly of DNA due to the
deficiency of folic acid and vitamin B12.
In adequate intake, increased demand and impaired
absorption are main causes of the deficiency.
The basic workup for vitamin B12 or folate deficiency
includes, peripheral blood smear, serum folate level and
serum B12 estimation.
The diagnostic criteria includes; hemoglobin level below
10 g%, and the presence of at least two of the following
features in the films of the buffy coat layer.
a. More than 4% of neutrophil polymorphs with 5 or more
lobes.
b. Orthochromatic macrocytes with diameters exceeding
12m.
c. Howell-Jolly bodies which are residual nuclear
inclusion bodies within the erthrocytes.
d. Nucleated red cells, that is normoblasts showing
premature hemoglobinization for their stage of nuclear
development.
e. Macropolycytes may be present. These are giant
polymorphs.
Treatment includes folic acid, vitamin B 12 and iron
supplementation either oral or parenteral depending upon
the severity of the deficiency.
BIBLIOGRAPHY
1. Guidotti RJ. Anaemia in pregnancy in developing countries.
Br. J Obstet gynaecol 2000;107:437-8.
2. Kolp R, Blakemore K. Haematologic Diseases of pregnancy.
In: Lambrou NC, Morse AN, Wallach EE (eds). The John
Hopkins Manual of Gynaecology and obstetrics. Baltimore,
USA: Lippincott, Williams and Wilkins, 1999;133-43.
3. Scott J M, Weir DG. Role of folic acid/folate in pregnancy.
Prevention is better than cure. Recent Advances in Obstet
and Gynaecol, 1998;20;1-20.
4. Van den Broek NR, Letsky EA. Etiology of anemia in
pregnancy in South Malawi. Am J Clin Nutr 2000;73(spl);
247-56.
CHAPTER 6
Thalassemia in
Pregnancy
Manju Puri
Anjali Taneja
Introduction
Structure and synthesis of hemoglobin
Genetic control of hemoglobin synthesis
Classification of thalassemias
Pathophysiology of thalassemia
Effect of thalassemia on pregnancy
Diagnosis of thalassemia
Management of pregnancy with thalassemia
Recent advances in the management of thalassemias
Key points
INTRODUCTION
Thalassemia is the commonest single gene disorder of hemo-
globin synthesis. Thomas B Cooley, a physician from USA,1
first described it in 1925. The initial cases were reported in
children of Greek and Italian immigrants who became severely
anemic and developed splenomegaly in the first year of life.
The term Thalassemia is derived from a Greek word Thalessa
meaning sea or in classical sense Mediterranean. The disease
is concentrated mainly in the Eastern Mediterranean, Middle
East, parts of India, South East Asia, Africa and the West
Indies. However, due to immigration of people from these areas
to other countries obstetricians do encounter this problem all
over the world. -thalassemias occur throughout Sub-saharan
Africa, the Mediterranean region, Middle East, the Indian sub-
THALASSEMIA IN PREGNANCY 83
continent and South East Asia and has a incidence varying

from 1 to 15%.2 In India, -gene deletion frequency is 0.05
to 0.98%.3
-thalassemia is found widely in regions ranging from
Mediterranean and parts of North and West Africa, the Middle
East, the Indian sub-continent and South east Asia. Incidence
in these regions variys from 10 to 15%.2 In India, -thalassemia
comprises about 80 to 90% of total thalassemia cases with
frequency ranging from 3.5 to 15% in general population.3
The communities commonly affected by -thalassemia major
include Gujaratis, Maharashtrians, Sindhis, Goaneses, Bengalis,
North West part of India(Punjab, Haryana, UP, Rajasthan).
The importance of recognizing thalassemia lays in the fact
that prenatal diagnosis and timely intervention can prevent
the birth of babies with severe thalassemia and save the families
of emotional, mental and financial distress.
STRUCTURE AND SYNTHESIS OF

HEMOGLOBIN
Hemoglobin is a tetrameric protein composed of two different
pairs of globin chains , each attach to a heme complex .There
are various types of globin chains , , , , , etc. In humans
there are six distinct types of normal hemoglobin. Different
types of hemoglobins are synthesized in the embryo, fetus and
adult depending on their oxygen requirements.
During embryonic stage, three hemoglobins that predo-
minate are Hb Gower 1 (22), Hb Portland (22) and Hb
Gower 2 (22). The remaining three hemoglobins are present
in fetal and adult stages of development (Table 6.1).
Table 6.1: Type of hemoglobin and fetal development

Developmental stage Type of hemoglobin
Embryonic Hb Gower 1 (2 2)
Hb Portland (2 2)
Hb Gower 2 (2 2)
Fetal HbF (2 2)
Adult HbA (2 2)
HbA2 (2 2)
HbF (2 2)
Adult and fetal hemoglobins have chains combined with

chains (HbA), and chains (HbF) respectively. During the
first, second and early third trimesters HbF predominates fetal
environment. After 32 weeks of gestation the and chain
genes become active and increasing amounts of adult
hemoglobins HbA and HbA2 are synthesized. The proportion
of adult hemoglobin increases from 0% at 26 weeks gestation
to 30% at term.4 Infants slowly become dependent on HbA
synthesis within 4 to 6 months after birth. Thus the disorders
of globin synthesis may manifest in utero or at birth compared
to disorders of globin synthesis that usually manifest after
4 to 6 months of age. In adults 95% of circulating hemoglobin
is HbA (2 2), 2 to 3% is HbA2 (2 2) and < 2% is HbF
(2 2).5
GENETIC CONTROL OF HEMOGLOBIN

SYNTHESIS
The genes controlling the synthesis of various types of globin
chains forming the hemoglobin molecule are located on
chromosomes 11 and 16. The arrangement of the two main
families of globin genes and of adult hemoglobin (Hb A)

is on two separate chromosomes. The production of globin
chain is under the control of four genes located on chromosome
16, two inherited from each parent whereas that of globin
chain is by 2 genes located on chromosome. The activation
and deactivation of these different globin genes result in the
synthesis of different types of hemoglobins during various stages
of fetal development.
thalassemia is usually a mutation disorder where as
thalassemia is a deletion disorder.
CLASSIFICATION OF THALASSEMIAS
Thalassemia is a heterogeneous group of genetic disorders of
hemoglobin synthesis characterized by lack of or decreased
synthesis of one or more globin chains. They are divided into
, , or thalassemia according to the affected globin
chain. Of these thalassemia is the most common type.
Depending upon whether there is no synthesis or reduced
synthesis of a particular globin chain, these are known as
or thalassemia or + or + thalassemia respectively (Table
6.2).
Table 6.2: Classification of thalassemia

A. -Thalassemia Syndrome
Phenotype Genotype No of genes
1 Silent carrier / 3
Heterozygous +
2. Thalassemia trait a. / 2
Heterozygous o
b. / 2
Homozygous +
Cont...
3. HbH disease / 1
Heterozygous + / o
4. Hb Barts disease / 0
Homozygous o
4 (Hb Bart)
B. -Thalassemia
1. Thalassemia minor o/ Heterozygous
+/ Heterozygous
2. Thalassemia major o/ o Homozygous
+/ + Homozygous
Aster JC. Red blood cell and bleeding disorders. In: Kumar V, Abbas
AK, Fausto N (Eds). Robbins and Cotran Pathologic Basis of Disease,
7th Ed. Elsevier Publishers 2004:634.
PATHOPHYSIOLOGY OF THALASSEMIA
The basic defect in thalassemia is absent or reduced synthesis
of globin chains. In thalassemia there is reduced or absent
production of globin chains and a relative excess of free
globin chains as their synthesis is unaffected. This results
in inadequate hemoglobin in red blood cells with resultant
microcytic hypochromic anemia. The free chains accumulate
and precipitate in the red cell precursors as large intracellular
inclusions. These inclusions are highly toxic to erythroblasts
causing intramedullary destruction of red cell precursors and
consequently ineffective erythropoiesis. The precursors that
mature into red cells with inclusions the inclusions interfere
with their passage through microcirculation, especially spleen
thus shortening their life span. Moreover the degradation
products of excess chains especially heme and iron have
harmful effects on red cell membrane making the red cells
Flow chart showing pathophysiology of thalassemia

rigid with a shorter life span. The damage to the red cell
precursors and their progeny is both mechanical and toxic.
Hence the anemia associated with thalassemia is due
to ineffective erythropoiesis and hemolysis. Anemia stimulates
erythropoietin production. Increased erythropoietin results in
an increased absorption of iron with subsequent iron overload
and resultant hepatic, endocrine and cardiac complications.
Erythropoietin also causes increased production of erythrocytes,
which cause expansion of bone marrow manifesting as skull
and long bone deformities, increased BMR, wasting, folate
deficiency, etc. The spleen enlarges as a result of a large number
of abnormal cells being destroyed in it. Both splenomegaly
and bone marrow expansion cause an increase in plasma
volume, which further contribute to anemia.
Persistence of fetal hemoglobin into adult life is also
common in thalassemia. It provides an alternative source
( chains) to combine with excess chains. As the synthesis
of chains is also unaffected there is an increase in levels
of HbA2 (22). In thalassemics if the anemia is corrected the
increase in production of erythropoietin and associated bone
marrow expansion consequent to anemia is prevented.
However, with each unit of blood transfusion 200 mg of iron
is added to the body leading to a steady accumulation of iron
in liver, myocardium and endocrine glands. So, iron-chelating
therapy with desferrioxamine is given to prevent complications
due to iron overload.
EFFECT OF THALASSEMIA ON PREGNANCY

The various types of thalassemia show a wide variation in
clinical presentation ranging from severe life threatening anemia
to an extremely mild condition.
THALASSEMIA AND PREGNANCY

Thalassemia Minor
In thalassemia minor the obstetric complications and
pregnancy outcome do not differ from that in general popula-
tion. There is an increase in the incidence of mild anemia and
a doubtful increase in neural tube defects consequent to relative
folate deficiency.6
Thalassemia Major
On the contrary women with thalassemia major have a high
mortality and morbidity. Despite this more than 100 pregnancies
have been reported in women with thalassemia major and
intermedia in literature.7
The women with thalassemia major are usually subfertile
due to delayed onset of menarche, primary or secondary
amenorrhoea, chronic anovulation consequent to multiple
endocrinopathies due to iron deposition. These women usually
require the support of ovulation inducing drugs to conceive.8
Some workers have reported a relatively high incidence of
early pregnancy losses, IUGR and prematurity due to maternal
anemia and associated chronic placental hypoxia.9
Increased plasma volume associated with maternal anemia
and myocardial hemosiderosis predisposes these women to heart
failure. The reported incidence of cephalopelvic disproportion
and cesarean delivery is high in these women as they are small
built.
The frequency of hypersplenic crisis manifesting as anemia,
leucopenia and thrombocytopenia occurring singly or in
combination is increased during pregnancy in thalassemics,

especially in the last weeks of pregnancy. In splenectomised
women there is predisposition to venous thrombosis due to
thrombocytosis during pregnancy.
The perinatal morbidity and mortality is increased due to
prematurity, IUGR and adverse effects of iron chelating agents.
The various teratogenic effects of iron chelating agents used
during pregnancy are retardation of bone ossification, vertebral
aplasia and bifurcation or fusion of ribs.8 Long-term use of
desferrioxamine has been associated with ricket like bone
alterations in adults.10
Thalassemia and pregnancy

In thalassemia the adverse effects in pregnancy are not related
to decrease or no production of adult hemoglobin but to
accumulation of abnormal hemoglobins like HbH and Barts
Hb. The pregnancy is well tolerated in carrier state. However
profound fetal and neonatal adverse effects are associated with
the presence of abnormal hemoglobins.
Silent Carrier State and Pregnancy

The individuals with deletion of one globin gene have no
clinical symptoms or RBC alterations. This condition can be
diagnosed only by DNA analysis.
Thalassemia Trait and Pregnancy

Pregnant women with thalassemia trait are asymptomatic
but their peripheral smears show microcytic hypochromic
anemia.
HbH Disease and Pregnancy

This condition is generally associated with mild hemolytic
anemia. The clinical presentation varies from no symptoms
to severe anemia with hemolysis and hepatosplenomegaly.
Cholelithiasis is common. The pregnant women are predisposed
to hemolytic crisis in conditions like fever, infections, use of
drugs, etc.
Although the condition is usually diagnosed after birth but
in rare cases it may be associated with hydrops foetalis with
intrauterine death.7
Hb Barts Disease and Pregnancy

This condition results in serious fetal and perinatal problems
like hydrops, stillbirths, early neonatal deaths, etc. The surviving
infants have limb reduction defects, hypospadias and other
urogenital abnormalities.
Maternal complications like pre-eclampsia, polyhydramnios,
placentomegaly and retained placenta are also increased in
this condition.11
DIAGNOSIS OF THALASSEMIA
Thalassemia should be suspected in pregnant women with the
following clinical features:
1. History of transfusion dependent anemia with or without
iron chelation therapy in self or family.
2. Women with mild to moderate microcytic hypchromic
anemia not responding to oral iron supplements.
3 Thalassemia trait should be suspected in pregnant women
with mild anemia with low MCV, not responding to oral
iron supplements and thalassemia excluded.
The thalassemia screening program in pregnant women as

implemented by Delhi Government includes subjecting all
pregnant women to NESTROFT naked eye single tube rapid
osmotic fragility test with 0.36% buffer solution. A positive
result is evident by a hazy solution and is followed up by Hb
electrophoresis of the pregnant woman and husbands blood
for NESTROFT.
INVESTIGATIONS
Complete blood count and peripheral smear
Complete blood count and peripheral smear show a low level
of hemoglobin and decreased mean corpuscular volume. The
peripheral smear shows microcytes, hypochromia, anisocytosis

and poikilocytosis. In thalassemia, target cells and basophilic
stippling may be seen on peripheral smear (Fig. 6.1).
Thalassemia in pregnancy has to be differentiated from other
causes of microcytic hypochromic anemia like iron deficiency,
chronic infections, etc. (Table 6.3).
Fig. 6.1: Thalassemia major (marked aniso poikilocytosis)

1. nRBC (nucleoted RBC) 2. Neutrophil 3. Target cell
4. Microcytic hypochromic cell (For colour version see Plate 3)
Hemoglobin Electrophoresis
The serum level of various types of hemoglobins is assessed
by electrophoresis. This helps in clinching the diagnosis of
thalassemia and its severity. Table 6.4 shows the levels of
different types of hemoglobins in normal and thalassemic
pregnant women.
Table 6.3: Differential diagnosis of microcytic

hypochromic anemia12
Parameter Normal Iron Thalassemia Chronic
range deficiency infections
anemia
Red cell indices

MCV cumm 80-96 N or
MCH pg 27.5-33.2 N or
MCHC gm/dl 33.4-35.5 N or N or
Serum Iron g/dl 60-150 N or

TIBC (g/dl) 250-435 N or
Serum ferritin g/L 12-150 N or N or
Transferrin saturation 30-80 N
Serum transferrin N N
receptors %
Bone marrow Fe +ve ve +ve +ve
Automated High Performance Liquid Chromatography

It is highly efficient, rapid and automated technique and has
currently replaced the former Hb electrophoretic and manual
evaluation of the HbA2 and HbF. The technique is capable
of separating more than 40 frequently encountered human
hemoglobins in a short span of time (as short as 12 minutes).
It has a high sensitivity and superior resolution. Some variants
of hemoglobin unresolved by conventional electrophoretic
techniques can be diagnosed by HPLC.
Table 6.4: Distribution of hemoglobin

in normal and thalassemic pregnant women
Clinical condition HbA HbA2 HbF
(22) (22) (22)
Normal adult 95% 2-3% < 2%
Thalassemia minor 80-95% 4-10% 1-5%
Thalassemia major 0 4-10% 90-96%
Thalassemia trait cannot be diagnosed by hemoglobin

electrophoresis or HPLC and requires molecular genetic testing.
Molecular Genetic Testing
This is indicated in pregnant women suffering from microcytic
hypochromic anemia not responding to iron therapy with
thalassemia excluded on electrophoresis and iron studies.
Molecular genetic testing is carried out to detect globin gene
deletion.
Genetic counseling and prenatal diagnosis
Genetic counseling and prenatal diagnosis is indicated in
thalassemic pregnant women (major/ trait) carrying a pregnancy
from a carrier spouse. The various methods of prenatal
diagnosis are:
1. Chorionic villous sampling (CVS)
2. Amniocentesis
3. Cordocentesis
4. Obstetric ultrasound (USG)
Chorionic villous biopsy is carried out at 10 to 12 weeks

of pregnancy by transcervical or transabdominal route.
Chorionic tissue provides a large amount of fetal DNA. It is
associated with a complication rate of 1 to 2%. Increased
incidence of limb reduction defects is associated with CVS.
Amniocentesis is performed at 15 to 20 weeks and subjected
to karyotyping. The complication rate is 0.5 to 1%. 13
Cordocentesis at 12 to 14 weeks for diagnosis of Hb Barts
disease has been suggested as an alternative at centers not
equipped with facilities for molecular genetics.14
USG is not useful in the prenatal diagnosis of thalassemia
but may be useful in thalassemia. The various findings
suggestive of severe forms of thalassemia are hydrops fetalis,
placentomegaly, cardiomegaly, increased cardiac output, and
forward velocities in ductus venous and middle cerebral artery
on Doppler. Hydrops fetalis is a classical sign of Hb Barts
disease but appears late usually after 20 weeks of gestation.
Cardiovascular changes on Doppler flow studies and increased
placental thickness are early signs and can be detected in early
second trimester.15,16
MANAGEMENT OF PREGNANCY WITH

THALASSEMIA
The management depends on the type of thalassemia and
its severity.
THALASSEMIA
Thalassemia Trait
Pregnancy is well tolerated in individuals with thalassemia
trait. Folate supplementation is recommended. Iron supplemen-
tation should be done in the presence of documented iron

deficiency. Parentral iron is contraindicated.
Genetic screening is important. If both parents are carriers
of heterozygous thalassemia trait ( /) there is a 25%
risk of the fetus being affected by Hb Barts disease. Prenatal
diagnosis should be offered in this situation. Medical termination
of pregnancy should be offered if the pregnancy is affected.
If the couple chooses to continue an affected pregnancy,
close monitoring of the pregnant women for early detection
and timely management of obstetric complications is indicated.
If both the parents have a homozygous + thalassemia trait
(/ ) there is no risk of HbH and Hb Barts disease and
fetal testing is not required.
HbH Disease ( / )
Women with HbH are likely to have an acute exacerbation
of chronic anemia during pregnancy. The treatment is primarily
aimed at preventive and supportive preconception evaluation.
The partner should be screened for a carrier state. If the partner
is a silent carrier of heterozygous + thalassemia (/) or
homozygous + thalassemia trait (/) there is a 25%
chance of the baby being affected with HbH. If partner is
heterozygous o thalassemia trait (/ ), there is 25% chance
of HbH and 25% chance of Hb Barts. Prenatal diagnosis
should be offered to these couples.
Periconceptional high dose folic acid supplementation
5 mg/day is recommended. Iron supplementation is indicated
only in the presence of documented iron deficiency. Blood
transfusion is indicated in the presence of severe anemia. These
women should be assessed for iron load status and end organ
damage as in patients with thalassemia major.
Prompt recognition and treatment of infections, and

avoidance of ingestion of oxidative compounds should be done
to prevent hemolytic crisis.
Close antenatal surveillance for early detection and
management of complications like pre-eclampsia and preterm
labor is done.
THALASSEMIA MINOR
Screening of the partner with MCV and hemoglobin electro-
phoresis is indicated to determine the fetal risk for thalassemia
major. Genetic counseling is advised if the partner is screen
positive. Couples who are heterozygous carriers for
thalassemia have a 25% chance of having a child who is
thalassemia major and 50% chance of having a child who
has thalassemia minor.
Periconception high dose folic acid supplementation
5 mg/day with iron supplementation only to women with
documented iron deficiency is indicated. Parentral iron is
contraindicated. Blood transfusion in indicated for correction
of anemia, if Hb<8 gm% near term. Some workers have used
erythropoietin in the treatment of severe anemia during
pregnancy in these pregnant women.17
THALASSEMIA MAJOR
Preconception Considerations
Preconception Evaluation
Preconception evaluation is recommended for all women with
thalassemia major planning a pregnancy. The preconception
evaluation includes assessment of the following:
1. Transfusion needs of the patient

2. Compliance with chelation therapy
3. Iron load assessment
4. End organ damage from iron overload
5. Endocrine and hormonal functions
6. Indirect Combs test
7. Screening for transfusion related chronic infections like
Hepatitis B, Hepatitis C, and HIV, etc.
A detailed history and physical examination should be
followed by genetic counseling and evaluation of end organ
damage. The investigations should be targeted to assess the
functional status of various organs likely to be damaged by
iron overload (Table 6.5).
Table 6.5: Iron overload and various end organ damage

1. Investigations to assess end organ damage due to iron overload
Organ Investigation
Heart ECG, Echocardiography
Liver Liver function tests, USG
Gallbladder USG for any evidence of cholelithiasis
Spleen USG for enlargement
Endocrine
Pancreas Fasting blood sugar, Hb A 1c, GTT
Thyroid Thyroid function tests
Kidneys RFT
Urine complete and C/S
2. Investigations to rule out transfusion related infections and
isoimmunization
ICT
VDRL
Elisa HIV
HBSAg
HCV
3. Investigations to assess the iron load status
Serum ferritin levels.
Pre conception evaluation of a woman with thalassemia major
Preconception Counseling
Preconceptional counseling follows a detailed initial assessment.
The partner is screened for thalassemia and genetic counseling
and prenatal diagnosis is offered if found to be positive.
Chelation with desferrioxamine should be stopped as soon
as pregnancy is diagnosed or in midcycle when ovulation therapy
is being used. However, in patients with myocardial dysfunction
the risk of stopping chelation therapy outweighs the risk of
teratogenicity on continuing the drug.7,8 In these cases chelation
therapy is continued. Pregnancy termination can be offered
to women who are worried about the possible risk of congenital
malformations. The various teratogenic effects reported with
iron chelation therapy are retardation of bone ossification,
vertebral aplasia, bifurcation or fusion of ribs, EEG abnormalities,
ricket like bone abnormalities, cataract formation, etc.
There is an increased need for ovulation induction and
ART in these women.
Preconception high dose folic acid supplementation (5 mg/
day) is recommended.
Antenatal and Intranatal Considerations

All pregnant thalassemic women are continued on high dose
of folic acid supplementation. Chelation therapy is stopped
except in patients with cardiac dysfunction. Vitamin C should
be stopped as it increases iron absorption. In patients who
are asplenic Hepatitis B and Pneumococcal vaccines are given.
At the initial visit the baseline evaluation of cardiac,
endocrine and hepatic functions should be carried out if not
done in the preconception period. These are repeated in the
second and third trimesters.
The patients are subjected to complete blood count every

two weeks and transfusion therapy is continued with the aim
of maintaining a hemoglobin level of 10 gm%. It is observed
that the need for transfusion increases during pregnancy.
Prompt recognition and management of factors that
precipitate hemolytic crisis like fever, infection and ingestion
of oxidative compounds should be avoided.
Careful fetal monitoring is done to detect intrauterine growth
restriction in antenatal period. The mode of delivery is
individualized and caesarean delivery is done only for obstetric
indications. The overall incidence of cesarean delivery is high
in these patients due to cephalopelvic disproportion.
Postpartum Considerations
Lactation is not contraindicated in these patients. Blood
transfusion therapy is continued as per requirement and iron
chelation therapy is restarted after 3 weeks when the first blood
transfusion is required in the postpartum period.
The cardiac, endocrine and hepatic evaluation is repeated
at 4 to 6 months postpartum. There is no contraindication
to any type of contraception however the oral contraceptive
pills are avoided in splenectomised patients due to the risk
of thrombosis.
RECENT ADVANCES IN THE MANAGEMENT OF

THALASSEMIAS
Couples at risk of hemoglobinopathy can be offered
preimplantation genetic diagnosis in order to help them give
birth to an unaffected child. DNA analysis is done on a single
blastomere aspirated from a embryo prior to transfer. PGD

has also been sought by couples to give birth to a stem cell
donor for an affected sibling.18 DNA analysis can be combined
with foetal HLA typing,19 in order to determine the availability
of HLA matched donors with in the family and also to assess
if the fetus will be a suitable umbilical cord blood donor for
an affected sibling.
Bone marrow transplant is the only curative procedure for
thalassemia. However, stem cell transplant using umbilical cord
blood as a source of stem cells is being explored as a useful
source of donor cells.
KEY POINTS
Commonest single gene disorder of hemoglobin syn-
thesis, characterized by lack of or decreased synthesis
of one or more globin chains.
Two most common types are:
b thalassemiaMutation disorder, diagnosed by Hb
electrophoresis.
a thalassemiaDeletion disorder, diagnosed by
genetic testing.
Clinical presentation varies from extremely mild to severe
life threatening anemia.
In thalassemia minor, obstetric outcome is not affected.
However folic acid supplementation is recommended.
Screening of partner and prenatal diagnosis if required
should be offered.
thalassemia major:
A. Preconception period
Hypogonadismhigh demand for ovulation induction
Evaluation for end organ damage from iron overload
Screening of partner and genetic counseling
FA supplementation.
B. During pregnancy
Stop chelation and vitamin C
High dose folic acid supplementation
Repeated blood transfusions with the aim to maintain
Hb at 10 gm%
Prenatal diagnosis to be offered if required
Fetal monitoring for IUGR
Mode of delivery to be individualized.
C. Postpartum period
No contraindication to lactation
Chelation therapy restarted at 3 weeks postpartum.
OCPs are avoided.
Thalassemia:
Adverse effects in pregnancy are due to accumulation of
abnormal hemoglobins like HbH and Barts Hb.
Silent carrier state Asymptomatic.
thalassemia trait Mild anemia
Pregnancy well tolerated
FA supplementation
recommended
HbH disease Anemia exaggerated
Increased incidence of hemolytic
crises
FA supplementation is recommended
Blood transfusion for severe anemia
Screening of partner and genetic counseling is recom-
mended for women with thalassemia trait/ HbH disease.
Prenatal diagnosis should be offered to detect affected
fetus.
Close antenatal surveillance and management of
complications like preterm labor and preeclampsia.
REFERENCES
1. David J Weatherall. Hemoglobin and the inherited disorders
of globin synthesis. In: postgraduate hematalogy 5th edition.
ed. Hoffbrand AV, Catovsky D, Tuddenham EGD, Blackwell
Publishing 2005;88.
2. Edward J Ben. Hemoglobinopathies. In: Harrisons Principles
of Internal Medicine, 16th Ed. McGraw Hill. 2005; 594.
3. Ambedkar SS, Phadke MA, Mokashi GD et al. Pattern of
hemoglobinopathies in Western Maharashtra. Indian
Pediatrics. 2001;38(5):530-4.
4. Ross MG, Ervin MG, Novak D. Placental and fetal physiology.
In: Gabbe SG, editor: Obstetrics: and problem pregnancies.
4th edition. New York: Churchill Livingstone Inc. 2002:38-
62.
5. Steinberg MH, Benz EJ. Pathobiology of the human
erythrocyte and its hemoglobins. In: Hoffman J Editor.
Hematology: basic principles and practice. 3rd edition. New
York. Churchhill Livingstone. Inc 2000;356-66.
6. Ibba RM, Zoppi MA, Floris M et al. Neural tube defects in
the offspring of thalassemia carriers. Fetal Diagn Ther.
2003;18:5-7.
7. Rappaport VJ, Velazquez M, Williams K. Hemoglobino-
pathies in pregnancy in Obstet Gynecol Clin N America.
2004;31:287-317.
8. Jensen CE, Tuck SM, Wanke B. Fertility in thalassaemia
major: a report of 16 pregnancies, preconceptual evaluation
and a review of the literature. British Journal of Obstetrics
and Gynecology 1995;102:625-9.
9. Warwood M, Hoffbrand AV. Iron metabolism, iron deficiency
and disorders of hemsynthesis. In: postgraduate hematology
5th edition ed. Hoffbrand AV, Catovasky D, Tuddenham
EGD, Blackwell Publishing, 2005:26-43.
10. Daskalakis GJ, Papageorgiou IS, Antsaklis AJ, Michalas SK.
Pregnancy and homozygons beta thalassaemia major. British
Journal of Obstelrics and Gynaecology 1998;105:1028-32.
11. Wheatherall DJ, Clegg JB. The thalassaemia syndromes.
Oxford, Blackwell Science, 1972.
12. Liang ST, Wong VCM, So WWK et al. Homozygous -thalass-
emia: clinical presentation, diagnosis and management. A
review of 46 cases. Br J Obstet Gynecol 1985;92:680-4.
13. Warwood M, Hoffbrand AV. Iron metabolism, iron deficiency
and disorders of hem synthesis. In: postgraduate hematalogy
5th edition. ed. Hoffbrand AV, Catovsky D, Tuddenham EGD,
Blackwell Publishing, 2005:26-43.
14. Old JM. Prenatal diagnosis of the hemoglobinopathies. In:
Milunsky A, ed. for Genetic disorders and the fetus. Baltimore
(MD): John Hopkins, University Press 1998:581-611.
15. Lam YH, Tang MH. Prenatal diagnosis of hemoglobin Barts
disease by cordocentesis at 12-14 weeks gestation. Prenat
Diagn 1997;17:501-4.
16. Ghosh A, Tang MH, Lom YH et al. Ultrasound measurement
of placental thickness to detect pregnancies affected by
homozygous alpha-thalassaemia-1. Lancet 1994;344:988-
9.
17. Lam YH, Tang MH, Tse HY. Ductos venosus doppler study
in fetuses with homozygous alpha-thalassemia-1 at 12 to 13
weeks of gestation. Ultrasound Obstet Gynecol 2001;17: 30-
3.
18. Breymann C, Fibach E, Visca E et al. Induction of fetal
hemoglobin synthesis with recombinant human erythro-
poietin in anemic patients with heterozygous beta-thalassemia
during pregnancy. J Matern Fetal Med 1999;8:1-7.
19. Gavaghon C. Use of preimplantation genetic diagnosis to
produce tissue donors: an irreconcilable dichotomy? Hum
fertil 2003;6:23-5.
20. Orofino MG, Argiolu F, Sanna MA et al. Fetal HLA typing
in beta thalassaemia: implications for hemopoietic stem cell
transplantation. Lancet 2003;362:41-8.
CHAPTER 7
Hemolytic
Anemia in
Pregnancy
Kiran Aggarwal
Introduction
Pathophysiology
Classification of hemolytic anemia
History and examination
Laboratory Investigations
Hemolytic anemia caused by inherited erythrocyte
defects
1. Membrane defects of red blood cells
Hereditary spherocytosis
Hereditary elliptocytosis
2. Red cell enzyme deficiencies
Glucose- 6 phosphate dehydrogenase deficiency
Pyruvate kinase deficiency
Acquired hemolytic anemia
1. Immune hemolytic anemia
2. Mechanical hemolytic anemia
Microangiopathic hemolytic anemia
Cardiac hemolytic anemia
Miscellaneous
1. Hemolysis due to infections
2. Drugs induced hemolysis
3. Paroxysmal nocturnal hemoglobinuria
Pregnancy induced hemolytic anemia
HEMOLYTIC ANEMIA IN PREGNANCY 109
INTRODUCTION
Hemolytic disorders are conditions where the life span of red
blood cells is shortened and they are removed from the
circulation prematurely. Red blood cells normally survive in
circulation for 90 to 120 days. Normal marrow is capable of
increasing the production of red blood cells six to eight times
in response to destruction. When loss is more than compen-
satory erythrocytosis, anemia develops. The presentation of
patient with hemolytic anemia may vary from being
asymptomatic to features of severe anemia depending on the
degree and rate of onset of hemolysis. In this chapter hemolytic
anemia is discussed in reference to pregnancy and its
management.
Hemolysis may be intravascular or extravascular.In
extravascular hemolysis red blood cells with membrane
alterations are destroyed by macrophages of reticuloendothelial
system in liver, spleen and bone marrow.1 In intravascular
hemolysis the erythrocytes sustain direct trauma from damaged
endothelium, complement fixation and activation on the cell
surface or infectious agents.1
PATHOPHYSIOLOGY
Hemolysis causes breakdown of red blood cells with release
of hemoglobin and lactate dehydrogenase.The hemoglobin in
plasma is proportionate to the degree of hemolysis . This binds
to serum haptoglobin and once haptoglobin is saturated
hemoglobin passes through renal glomeruli, reabsorbed in
proximal renal tubule where it is catabolised in situ and
incorporated as storage iron ferritin and hemosiderin.
Hemosiderin is excreted through kidneys. Hemosiderinuria
indicates that significant amount of hemolysis has occurred.

When absorption capacity of proximal tubule has been
exceeded hemoglobinuria is seen which indicates severe
intravascular hemolysis.2
Some of the free plasma hemoglobin is oxidized to met-
hemoglobin which is dissociated into ferriheme and globin.
Ferriheme binds to plasma hemopexin and on saturation of
hemopexin it binds to albumin forming methemlbumin which
is seen on spectrophotometry of plasma as a band which is
the basis of Schumms test. Liver removes haptoglobin and
hemoglobin complex, hemoglobin and hemopexin complex and
remaining free hemoglobin.3
Fate of hemoglobin released in plasma after hemolysis3

CLASSIFICATION OF HEMOLYTIC ANEMIA

Hemolytic Anemias due to Intracorpuscular (Intrinsic)
Defect
A. Membrane defects
1. Hereditary spherocytosis
2. Hereditary elliptocytosis.
B. Enzyme defects
1. Due to deficiency of glucose-6-phosphate dehydrogenase
or other enzymes of the pentose phosphate pathway
2. Due to deficiency of pyruvate kinase or other enzymes
of the Embden-Meyerhof pathway.
C. Hemoglobin defects
1. Thalassemia syndrome
-thalassemia major
Hb-H disease.
2. Hemoglobinopathies
Sickle cell disease
Other abnormal hemoglobin (Hb-C , Hb-E, Hb-D, etc)
Unstable hemoglobin disease.
Hemolytic Anemia due to Extracorpuscular (Extrinsic)

Defect
A. Immune mechanisms
Autoimmune hemolytic anemia
1. warm antibodies
2. cold antibodies.
Alloimmune hemolytic anemia
Incompatible blood transfusion.
B. Non-immune mechanisms
Mechanical hemolytic anemia:
1. Micro-angiopathic hemolytic anemia

Pre-eclampsia and HELLP syndrome
Thrombotic thrombocytopenic purpura
Hemolytic-uremic syndrome.
2. Cardiac hemolytic anemia.
C. Miscellaneous
1. Hemolytic anemia due to infections and burns
2. Hemolytic anemia due to drugs
3. Paroxysmal nocturnal hemoglobinuria (an intrinsic but
acquired defect)
4. Pregnancy induced hemolytic anemia.
HISTORY AND EXAMINATION

In all cases of anemia a careful detailed history and
examination may lead to a suspicion of hemolysis. Patients
with minimal or long standing anemia may be asymptomatic
and hemolysis may be an incidental finding. Patients may
complain of fatigue and other symptoms of anemia. . There
may be history of pain abdomen due to gallstones and leg
ulcers as seen in sickle cell anemia.
There may be complaints of dark colored urine because
of hemoglobinuria. Acute hemolytic episodes may mimic an
acute febrile illness with fever, chills, headache, vomiting,
backache and abdominal pain.4 A complete drug history and
toxin exposure is important. Family history of splenomegaly,
jaundice or enzyme deficiencies is important.
On physical examination features of anemia like pallor,
tachycardia, tachypnea, anoxia, etc. may be seen. Jaundice
occurs because of increased indirect bilirubin but levels are
rarely greater than 4 mg/dl in hemolysis unless complicated
by liver disease.
Splenomegaly occurs in hereditary spherocytosis. It may

also indicate underlying disorder like chronic lymphocytic
leukemia, lymphoma and systemic lupus erythrematosus.
Bleeding, petechiae with neurological signs may indicate
thrombotic thrombocytopenic purpura. Butterfly malar rash
with arthritis point towards SLE.4
LABORATORY INVESTIGATIONS
COMPLETE BLOOD EXAMINATION WITH
PERIPHERAL SMEAR
Fall in hemoglobin level with reticulocytosis implies erythroid
hyperplasia and is a significant finding in hemolytic anemia.
Reticulocytosis occurs three to five days after the destruction
of red blood cells. However, increase in reticulocyte count may
also occur as a bone marrow response to hematinic therapy
and recent blood loss.
Peripheral smear showing red blood cells morphology may
indicate hemolysis and point towards the possible etiology.
Spherocytosis is seen in congenital spherocytosis and
immune hemolytic anemia (Fig. 7.1).
Schistocytes which are fragmented red blood cells suggest
traumatic injury to the membrane of red blood cells associated
with Microangiopathic hemolytic anemia and prosthetic cardiac
valves.
Heinz bodies which are precipitates of hemoglobin are seen
in unstable hemoglobin disease and oxidant stress.
Polychromasia may be seen which implies red blood cell
immaturity.
Fig. 7.1: Hereditary spherocytosis 1. Spherocyte

(For color version see Plate 3)
Coexisting hematological or malignant diseases can be

identified by examination of white blood cells and platelets.
Thrombocytopenia may be associated in conditions like systemic
lupus erythematosus, chronic lymphocytic leukemia.
BIOCHEMICAL INVESTIGATIONS
Blood Tests
Unconjugated bilirubin levels are raised in hemolysis and levels
are usually low less than 4 to 5 mg/dl unless liver function is
deranged when higher levels may be seen. Unconjugated bilirubin
levels may also be raised in Gilberts syndrome.
In the absence of tissue damage in other organs elevated
levels of serum lactate dehydrogenase especially type II is a
criteria for diagnosis of hemolysis though it is not specific.5
Other cells like neoplastic liver cells also secrete it. LDH type I
is also elevated in megaloblastic anemia.6
Serum haptoglobin is an alpha-globulin which binds with

hemoglobin and resultant complex is rapidly cleared by
macrophages and liver. Thus levels of haptoglobin fall in
moderate to severe intravascular hemolysis where hemoglobin
is released in circulation.7
Serum AST (SGOT) levels may be slightly elevated whereas
ALT levels are normal.
Change in LDH and serum haptoglobin levels are most
sensitive general tests for hemolysis because indirect bilirubin
may not always be increased.
Urinary Tests
Hemoglobinuria causes red brown urine and is indicated by
a positive reaction for heme in the absence of red blood cells
suggesting intravascular hemolysis.8 Dark urine may also be
seen in myoglobinuria, porphyria. Hemosiderinuria may be
demonstrated by Prussian blue staining of sloughed tubular
cells in urinary sediment.9 In hemolysis there is a rise in urinary
urobilinogen which may also occur in liver dysfunction.
Imaging Studies
Ultrasound may show splenomegaly and evidence of other
chronic diseases.
ECG and X-ray chest for cardio pulmonary status are
important.
Specific Tests
Certain special tests may be needed in specific conditions
i. Direct antiglobulin test is positive in autoimmune hemolytic
anemia.
ii. Red blood cells survival studies (chromium Cr 51) are

rarely used but demonstrate shortened erythrocyte life
span.
iii. Polyacrylamide gel electrophoresis (PAGE) to define
abnormalities of membrane proteins.
iv. Cold agglutinin titer may show high titer of anti I antibody
in mycoplasma infection and in hemolysis associated with
Infectious mononucleosis.4
v. A G6PD screen detects enzyme deficiency.
vi. Tests for abnormal hemoglobin: Electrophoresis, HbA2
by microcolumn chromatography, HbF by alkali
denaturation, Quantification of alpha and beta chains
by electrophoresis, HbS by sickling test, solubility test and
DNA analysis for detection of mutations.
INHERITED HEMOLYTIC ANEMIA

HEMOLYTIC ANEMIA CAUSED BY
INHERITED ERYTHROCYTE DEFECTS
Inherited hemolytic anemia is due to inborn defect in red blood
cells either at the level of surface membrane, enzymes or
hemoglobin. The normal erythrocyte is a biconcave disk and
destabilization of the membrane lipid bilayer causes a surface
area deficiency and makes it prone to hemolysis.10
Membrane Defects of Red Blood Cells

Hereditary Spherocytosis
Hereditary spherocytosis is characterized by inherited molecular
defects in erythrocyte membrane proteins. It is usually
autosomal dominant. Autosomal recessive condition and de
novo gene mutations may also be seen.11 This may be caused
by deficiency of surface proteins of red cells called spectrin,

ankyrin, protein 4.2 and moderate band 3, or combinations
of them.12 This membrane defect causes spherocytosis and
makes the red blood cells prone to sequestration by spleen.5
Clinical features: Varying degrees of anemia are seen with
jaundice and splenomegaly. Some patients may present with
cholelithiasis in young age. Direct antiglobulin test is negative.
Spherocytes and reticulocytes are seen on the peripheral smear.
Increased red blood cell osmotic fragility can be demonstrated.
Pregnancy: Patients do well in pregnancy Increased fetal loss
may be seen in the first trimester.13 An aplastic or hemolytic
crisis may be the first manifestation of the disease in pregnancy.5
Folic acid supplementation should be done .Splenectomy is
a definite cure of the disease.14 Infections should be treated
in time. If neonate has inherited hereditary spherocytosis jaundice
and anemia may be seen and exchange transfusion may be
needed.
Hereditary Elliptocytosis
This is also inherited as an autosomal dominant trait but is
a milder hemolytic state. There is a structural defect in the
red cell wall. Most cases detected during pregnancy have been
successfully treated with supportive therapy.15
Red Cell Enzyme Deficiencies

The enzyme system of the red blood cells is very important
for viability and function of the cells. This is especially important
to have energy for maintaining the biconcave shape of the
cell and for integrity of sodium and potassium pumps to
maintain osmotic equilibrium. The enzyme systems responsible
for producing energy and reducing power are:
1. Glycolytic (Embden-Meyerhof) pathway in which glucose

is metabolized to pyruvate and lactic acid with production
of ATP (Adenosine triphosphate). Pyruvate Kinase is an
enzyme of this system.
2. The hexose monophosphate pathway which provides
reducing power for the red cell in the form of nictonamide
adenine dinucleotide phosphate(NADPH) which maintains
glutathione in reduced form. Glucose-6-phosphate dehydro-
genase is an enzyme of this system.
A deficiency of red blood cell enzymes causes hereditary
non-spherocytic anemia.
Glucose-6-Phosphate Dehydrogenase Deficiency

This is the most common metabolic disorder of the red blood
cells. Glucose-6-phosphate dehydrogenase (G6PD) is required
for production of glutathione which protects the red blood cells
from oxidative damage. There are more than 400 variants of
G6PD deficiency which are known. It affects millions of people
around the world especially in Africa , around Mediterranean,
the Middle East and South East Asia. The gene for G6PD
is localized on chromosome Xq28. It is a X-linked disorder
and predominantly affects males. In the A variant both
X-chromosomes are affected and enzyme activity of
erythrocytes is markedly deficient. In the heterozygous variant
only one X-chromosome is deficient.27 The female heterozygotes
can also have clinical problems due to lyonization (inactivation
of one X-chromosome randomly).16
Clinically Intravascular hemolysis is seen when patients are
exposed to certain drugs and infections. Anemia is episodic
and in the absence of bone marrow depression, recovery occurs

after stoppage of drug or recovery from infections.10
Investigations show a normal blood count. During an episode
of hemolysis peripheral smear would show irregularly contracted
cells, Heinz bodies and reticulocytes.
G6PD deficiency can be detected using screening tests
demonstrating decreased ability of G6PD deficient cells to reduce
dye as in methylene blue reduction test. The levels of the enzyme
can be directly assayed. DNA analysis may be done to define
mutations.
Drugs causing hemolysis in G6PD deficiency
Analgesics: Aspirin Antibacterial: sulphonamides
Phenacetin nitrofurantoin
Furazolidine
Ciprofloxacin
Chloroamphenicol
Antimalarials: Miscellaneous drugs:
Pyrimethamine vitamin K
Primaquine Probencid
Quinine nalidixic acid
quinidine
Chloroquine
Pamaquine
Treatment is to stop the offending drug, treat the underlying
infection and supportive therapy with blood transfusion.
In pregnancy G6PD deficiency has a variable effect. Activity
of the enzyme may decrease further in second and third
trimester. Increased rate of spontaneous abortions, stillbirths
and low birth weight babies may be seen.17 Prenatal diagnosis

is possible by direct DNA analysis of chorionic villus sampling.5
Pyruvate Kinase Deficiency

It is uncommon. It is inherited as autosomal recessive trait.
Its deficiency results in impaired glycolysis and poor power to
generate adenosine triphosphate(ATP), so the energy
requirements of red blood cells are not met with. They get
distorted and are destroyed by the reticuloendothelial system.5
Clinical presentation may be varied from asymptomatic
to a patient with jaundice. Transfusions are rarely needed.
Investigations would reveal anemia of varying severity, blood
smear would show distorted cells called prickle cells with
reticulocytosis and low pyruvate kinase activity.
Treatment is supportive with blood transfusions especially
during pregnancy and infections. Splenectomy may be helpful
in patients requiring frequent blood transfusions
Pregnancy is well tolerated 18but hemolysis may be
precipitated by stress. Pyruvate Kinase deficiency can cause
nonimmune hydrops fetalis and early neonatal death.19 There
may be a history of recurrent abortions.
ACQUIRED HEMOLYTIC ANEMIA

IMMUNE HEMOLYTIC ANEMIA
Immune hemolytic anemias are caused by antibodies against
antigens on red blood cells. This can be autoimmune, drug
induced or alloimmune based on antigen that stimulates
antibody or complement mediated destruction of red blood
cells. Positive direct antiglobulin test and microspherocytes on
peripheral smear are diagnostic.1
Autoimmune Hemolytic Anemia

This is caused by autoantibodies which can be warm IgG type
(80-90%) and bind to red blood cells at the body temperature
and cold antibodies which are IgM type and bind to red blood
cells at lower temperature (0-4 degree centigrade).1 These
syndromes may be associated with underlying disorders like
lymphomas, leukemias and connective tissue diseases,
infections.1 Drugs like penicillin and alpha methyl dopa cause
immune hemolytic anemia. Cold agglutinin disease may be
induced by Mycoplasma pneumoniae or infectious mono-
nucleosis.20
Investigations reveal spherocytosis and reticulocytosis on
peripheral smear examination. Hyperproliferative macrocytic
anemia is seen. Autoimmune thrombocytopenia and
neutropenia may be present Leucocytosis is seen because of
marrow hyperactivity. Positive direct Coombs test is seen.
Pregnancy may cause marked increase in hemolysis. IgM
antibodies do not cross placenta and thus fetus is unaffected
in cold agglutinin disease.
Treatment: Steroids are effective in 80% of the patients
Prednisolone 1mg/kg/day is needed. Splenectomy may be consi-
dered in patients not responding to steroids. At times immuno-
suppression, plasmapheresis may be needed in refractory cases.
Thrombocytopenia may need correction. Transfusion of
red blood cells is difficult because of presence of anti erythrocyte
antibodies. Warming the blood to the body temperature
decreases hemolysis with cold antibodies.1
Alloimmune Hemolytic Anemia

The most severe alloimmune hemolysis is that caused by
transfusion reaction of ABO incompatible blood. Intravascular
hemolysis is seen and fever, chills, dyspnea, hypotension and

shock may be seen. Delayed reactions occur after three to ten
days and cause extravascular hemolysis usually caused by low
titer antibodies to minor red blood cell antigens.21
MECHANICAL HEMOLYTIC ANEMIA

Red cells may be injured due to physical trauma because of
direct injury as they circulate through the vascular system. The
distorted red blood cells are seen on the peripheral blood film
as fragmented, contracted, triangular, and helmet shaped forms
or microspherocytes. These are destroyed prematurely and
evidence of both intravascular and extravascular hemolysis is
seen.1
Causes of Mechanical Hemolytic Anemia

1. Microangiopathic Anemia
a. Eclampsia
b. Thrombotic thrombocytopenic purpura
c. Hemolytic-uremic syndrome
d. Autoimmune disordersSLE, scleroderma, polyarteritis
nodosa, acute glomerulonephritis.
2. Cardiac Hemolytic Anemia
Microangiopathic Hemolytic Anemia

This is also called fragmentation hemolysis. There is mechanical
trauma to the membrane of red blood cells in circulation.1
Damaged vascular endothelium with associated fibrin and
platelet deposits causes hindrance to the flow of blood and
causes hemolysis.
Direct Coombs test is negative and features of intravascular

hemolysis like hemoglobinemia and hemoglobinuria with
thrombocytopenia may be seen. Haptoglobin levels are low
and LDH levels are elevated. Intravascular devices as prosthetic
cardiac valves can also lead to microangiopathic hemolytic
anemia.9 Pre-eclampsia with HELLP syndrome and hemolytic
uremic syndrome are common causes in pregnancy.
Pre-eclampsia: Severe preeclampsia is often accompanied by
evidence of hemolysis resulting in HELLP syndrome (Hemolysis,
Elevated Liver Enzyme, Low Platelets). The incidence of
HELLP varies from, 4 to 14% of pre-eclampsia cases.22 It
is a severe manifestation of severe pre-eclampsia. Red blood
cell fragmentation is secondary to formation of microthrombi
in small arterioles or to peripheral vasospasm.
Investigations reveal elevated serum lactate dehydrogenase,
thrombocytopenia, reticulocytosis and schistocytosis on
peripheral smear.5 Concurrent DIC may be seen. Abnormal
values of unconjugated bilirubin, creatinine, fibrinogen and
FDPs may be seen.
The treatment is to terminate pregnancy. General measures
include strict control and monitoring of blood pressure, control
of coagulation status, acid base balance and prophylaxis
against seizures. In few patients if mother is stable conservative
management can be done in presence of fetal immaturity with
very careful monitoring. Plasma exchange may be needed at
times.22
Hemolytic-uremic syndrome and thrombotic thrombo-
cytopenic purpura: Thrombotic thrombocytopenic purpura
(TTP) and hemolytic uremic syndrome(HUS) are both
thrombotic microangiopathic diseases with intravascular

platelets aggregation, thrombocytopenia, and hemolytic anemia
and can cause multiorgan failure. It may be difficult to distinguish
both of them from each other.23 Pathological effects are
confined largely to kidneys in HUS and are more generalized
in TTP.
Thrombotic thrombocytopenic purpura: TTP usually presents
with a pentad of clinical and laboratory manifestations which
include hemolytic anemia thrombocytopenia, neurologic
symptoms, renal abnormalities and fever and is usually a
multiorgan disease.
Young females are generally affected in the age group of
20s and 30s. In many cases it is associated with other conditions
like neoplasia, connective tissue disorders, infections, pregnancy
and puerperium but the etiology is unknown.24 Lately it has
been shown that multimers of von Willebrand factor (vWF)
are increased in these patients because of deficiency of a
protease called ADAMTS 13 which cleaves them . This is not
seen in HUS.
Clinically patients may present with abnormal bleeding from
mucous membranes, vaginal bleeding jaundice and fever.
Neurological symptoms like altered consciousness, syncope,
headache, seizures, etc. are more common than HUS. Clinically
pallor, jaundice, purpura and neurologic abnormalities are
present . The clinical picture is severe with high mortality. DIC
is unlikely as seen in severe pre-eclampsia and abruption.
Investigations reveal moderate to severe anemia with
thrombocytopenia. Arteriolar lesions with fibrin and platelets
deposits are seen. Fragmented red blood cells, thrombocytopenia
and intravascular hemolysis is seen. Peripheral smear reveals
fragmented red cells, polychromatophilia (reticulocytosis) and

leukocytosis. Platelet count may be below 20,000 per cu mm
in almost half of the patient.23
The indirect bilirubin, LDH levels are raised and renal
functions are deranged. The Coombs test is negative.
In pregnancy or puerperium when microangiopathic
hemolysis is diagnosed some women with severe toxemia or
eclampsia have similar picture of fragmentation hemolysis and
thrombocytopenia and renal failure . Treatment of eclampsia
should take precedence over that for TTP unless there is positive
evidence that TTP preceded pregnancy or occurred without
evidence of toxemia.25
Treatment: Although pregnancy is the most common condition
associated with TTP it is not clear whether pregnancy aggravates
or initiates it and thus it is not clear whether termination is
useful in managing this condition. Without treatment TTP is
fatal in 90% of cases and plasmapheresis brings down the
mortality from 80 to 10%.26 Treatment of choice is total plasma
exchange with fresh frozen plasma. In patients who do not
respond glucocorticoids, vincristine should be condisered.27
Hemolytic-uremic syndrome: HUS has many common clinical
and laboratory features of TTP and it occurs primarily in
children. Sporadically it may occur in adults and is related
with pregnancy and puerperium.5 It may occur days to weeks
after normal pregnancy. There may be a history of diarrheal
illness.
Neurological manifestations are rare but renal dysfunction
and failure is more common. Bleeding and thrombocytopenia
are generally more severe in TTP.
Treatment of choice is plasmapherisis. Renal dialysis may
be needed Fetal and neonatal outcome is poor.28
TTP HUS DIC
CNS complaints +++ +/ +/

Renal dysfunction +/ +++ +/
D-dimers May be increased Normal Increased
vWF Increased Normal Normal
ADAMTS13-protease Decreased Normal Normal
Plasma exchange Very helpful May be No effect
helpful
Differential diagnosisTTP HUS AND DIC.
Prosthetic heart valves: Significant hemolytic anemia is seen

in 5 to 25% of patients with valvular prosthesis.29 Majority
of valves with hemolytic anemia are aortic but mitral valve
may be implicated.30 Extreme turbulence and flow across
pressure gradients causes macrovascular hemolysis. Supportive
therapy with bed rest, iron supplementation is needed during
exacerbations.5
MISCELLANEOUS
HEMOLYSIS DUE TO INFECTIONS
Infections may cause hemolysis by:1
a. Autoantibody induction as in Mycoplasma pneumoniae
infection.
b. Glucose-6-phosphate dehydrogenase deficiency.
c. Antimicrobial drugs, by direct action.
d. Infections agents may be directly toxic.
Malaria is an example where Plasmodium species enter
red blood cells and cause lysis and splenic sequestration of
red blood cells.31 Anemia and intravascular hemolysis is seen.
Anemia may also occur in malaria because of depression of
marrow erythropoiesis and immunological damage.
Clostridium perfringens infection which may occur in

septic abortions and causes hemolysis when bacteria releases
alpha toxin a phospholipase that degrades the membrane of
erythrocytes due to the direct action of the toxin on the red
cells1. Group A beta hemolytic streptococcus and gram-negative
bacterial endotoxin especially seen with pyelonephritis may also
cause hemolysis.5
DRUG-INDUCED HEMOLYSIS
Drugs cause hemolytic anemia by direct toxic action on the
red cells or cause hemolysis of red cells with hereditary enzyme
deficiency or by immunological mechanisms.
Drug-induced Hemolytic Anemia

1. Direct toxic action
2. Red cell metabolic abnormalities
a. Hereditary enzyme deficiencies
b. Unstable hemoglobin.
3. Immune mechanisms
Immune hemolytic anemia
Auto immune hemolytic anemia.
Drugs and Toxins cause direct injury to red cells by interfering
in their metabolism because of their powerful oxidants. Heinz
bodies are seen on the peripheral smear. Red cells are contracted,
fragmented and spherocytic in appearance.This is seen in
patients with G6PD deficiency.
Drug induced immune hemolysis may be caused by drug
absorption (hapten induced), immune complex or autoantibody
formation.1 Positive direct antiglobulin test is seen. Hemolysis
is mild and settles on withdrawing the drug and the drug should
be stopped. Hemolysis occurring by Penicillin is an example

of drug absorption mechanism. Penicillin bound to red blood
cells stimulates IgG antibodies formation which bind to
erythrocytes and causes extravascular destruction of this
complex.
Alpha methyl dopa causes production of antierythrocyte
antibody induction and causes extravascular hemolysis.32
PAROXYSMAL NOCTURNAL HEMOGLOBINURIA

It is a hemopoietic stem cell disorder where defective formation
of platelets, granulocytes, and erythrocytes occurs. Red blood
cells are lysed by complement mediated intravascular hemolysis
because of presence of abnormality on their surface mem-
brane.33 Red cells are deficient in several proteins like leucocyte
alkaline phosphatase, erythrocyte acetylcholine esterase which
are attached to cell membrane by an anchor called glycosyl
phosphotidylinositol(GPI).Due to a defect in PIG-A gene this
anchor is absent. It is acquired and arises from one abnormal
clone of cells, like a neoplasm.34 CD-55 a complement
regulatory protein also called Decay accelerating factor is also
absent. Resultant abnormal anchor proteins of the erythrocyte
and granulocyte membrane makes the red cells susceptible to
hemolysis by complement.18
Clinically patients present with mild to severe hemolysis
which may be precipitated by surgery, infections, delivery or
iron therapy. It was termed nocturnal hemoglobinuria because
initially it was thought to occur at night. Hemolysis can occur
at any time and concentrated urine overnight produces alteration
in the color of the urine.33
Hypercoaguable state is present Venous thrombosis is major

cause of death. Renal dysfunction, hypertension and Budd-
Chiari syndrome may be associated.
Investigations would reveal intravascular hemolysis. Blood
film shows normocytic normochromic anemia. There is pan-
cytopenia. Hemosiderinuria is a constant feature. Flow
cytometric analysis of red cells with anti-CD55 and anti-CD59
is done which shows abnormality of membrane proteins. Bone
marrow is hypoplastic inspite of hemolysis. Median survival
after diagnosis is 10 years however, long-term remissions may
be seen.35
Treatment: There is no specific treatment for PNH. Supportive
measures like blood transfusions are needed for severe anemia.
New anti complement agent eculizumab a monoclonal antibody
has been found to be effective to decrease hemolysis.36 Bone
marrow transplantation is the definitive treatment.
Effect on Pregnancy: Paroxysmal nocturnal hemoglobinuria
is a serious disease and pregnancy may be dangerous. Very
few pregnancies have been reported. Chronic anemia,
Postpartum Thrombosis and hepatic vein thrombosis are most
common complications.37 Maternal mortality is very high
(10%). Supportive therapy with folic acid and iron
supplementation is helpful. Anticoagulation should be done
in postpartum period.38 Prednisolone 0.3 to 0.6 mg /kg/day
may be needed at the time of acute episode of hemolysis
PREGNANCY-INDUCED HEMOLYTIC ANEMIA

Unexplained hemolytic anemia during pregnancy is a distinct
entity where severe hemolysis develops early in pregnancy and
resolves within months after delivery. Infant may also show
transient hemolysis. Maternal corticosteroid treatment is usually
effective.39
KEY POINTS
Hemolytic disorders are conditions where life span of red
blood cells is shortened and they are destroyed prema-
turely resulting in hemolysis.
Breakdown of red blood cells causes release of hemo-
globin and lactate dehydrogenase with rise in unconju-
gated bilirubin. Free hemoglobin binds to serum hapto-
globin whose levels fall. With significant hemolysis
hemoglobinuria and hemosiderinuria occur.
Detailed history of symptoms of anemia, jaundice, gall-
stones, leg ulcers, infections and intake of drugs is
important. Family history of splenomegaly, jaundice and
enzyme deficiencies should be taken.
Other underlying conditions like chronic lymphocytic
leukemia, lymphoma and SLE should be ruled out.
Fall in hemoglobin with reticulocytosis, raised unconju-
gated bilirubin, elevated lactate dehydrogenase levels
with fall in serum haptoglobin levels are most sensitive
tests for hemolysis.
Inherited hemolytic anemias are due to inborn defects in
red blood cells at membrane level, enzyme deficiencies
or defects in hemoglobin.
Hereditary spherocytosis is an inherited autosomal defect
in synthesis of surface membrane proteins resulting in
change of biconcave shape of erythrocytes to spherocytes
which are prone to extravascular hemolysis by macro-
phages. Pregnancy is usually well tolerated but episodes
of hemolytic crisis may be precipitated. Infections should
be treated and folate supplementation done.
A deficiency of red blood cells enzyme causes loss of
function and shape thus making them prone to hemolysis.
G-6PD deficiency is an X linked disorder. G-6PD protects
RBC from oxidative damage of infections and drugs.
Treatment is supportive with withdrawl of offending drug
and treatment of infections.Increased rates of spon-
taneous abortions, stillbirths and lowbirth weight babies
may be seen with increase incidence of neonatal

jaundice.
Pyruvate kinase deficiency is uncommon. It is an auto-
somal recessive disease resulting in lack of ATP that is
energy for the cell. Pregnancy and stress can precipitate
hemolysis. Non-immune hydrops fetalis is seen. Treatment
is supportive.
Immune hemolytic anemia is caused by antibodies
against red blood cells which can be warm IgG type and
cold that is IgM type. Underlying conditions like auto-
immune disease should be ruled out. Direct Coombs test
is positive. Microspherocytes are seen on peripheral
smear. Pregnancy may precipitate hemolysis . Steroids are
effective.
Mechanical injury to red blood cells by damaged endo-
thelium with fibrin and platelet aggregates or by improper
prosthetic valves can occur causing intravascular
hemolysis.Schistocytes are seen on peripheral smear.
HELLP, TTP and HUS are important thrombotic micro-
angiopathic diseases which cause hemolytic anemia and
may cause multi-organ failure. Neurological manifes-
tations are more common in TTP whereas renal
derangement is common in HUS. Plasmapheresis is
helpful in management of TTP.
Malarial parasite causes direct lysis of red blood cells
whereas clostridium perfringens acts by toxins and causes
severe hemolysis. This is commonly seen in septic
abortion cases.
Drugs can cause hemolysis by direct injury to the red
blood cells. Drug induced hemolysis can occur by
stimulation of antierythrocyte antibody formation as in
alpha methyl dopa or by hapten induced damage as seen
in hemolysis caused by Penicillin. .
Paroxysmal nocturnal hemoglobinuria is a hemopoietic
stem cell disorder with defective production of platelets,
granulocytes and erythrocytes resulting in complement

mediated intravascular hemolysis. Patient may present
with severe hemolysis precipitated by surgery, infections,
delivery or iron therapy. It is a hypercoaguable state and
mortality may occur because of venous thrombosis and
Budd-Chiari syndrome.
Pregnancy-induced hemolytic anemia develops during
pregnancy and resolves after delivery.
Infant may also show transient hemolysis.
REFERENCES
1. Gurpreet Dhaliwal MD, Patricia A. Cornett, Lawerence M
Tierney, JR Hemolytic Anemia. Am Fam Physician
2004;69:2599-606.
2. Bunn HF, Rosse W: Hemolytic anemia and acute blood loss.
In Braunwald E, Fauci AS, Kasper DL, et al (Eds): Harrisons
Principles of Internal Medicine, 15th edn. New York McGraw-
Hill 2001:681.
3. Kumar and Clark, Hematological disease. In Kumar and Clark
(Eds): Practices of Medicine. 2005;424-39.
4. Paul Schick. E-medicine- Hemolytic Anemia, www. Emedicine.
Com/med/ topic 2005.
5. Line Leduc, MD Hemolytic anemias in pregnancy. Clin Ob
Gynae 1995;38(3):463-71.
6. Winston RM, Warburton FC, Stott A. Enzymatic diagnosis of
megaloblastic anemia. Br J Haematol, 1970;19:587-92.
7. Marchand A, Galen S, Vanleute. The predictive value of serum
haptoglobin in hemolytic disease. JAMA 1980;243:1909-11.
8. Crosby WH, Dameshek W. The significance of hemoglo-
binemia and associated hemosiderinuria, with particular
reference to various types of hemolytic anemia. J Lab Clin
Med 1951;38:829-41.
9. Tabbara IA. Hemolytic anemias. Diagnosis and management.
Med Clin North Am 1997;76:649-68
10. Palek J, Jarolim P. Hereditary spherocytosis, elliptocytosis and
related disorders. In Beutler E, Lichtman MA, Coller BS,
Kipps TJ, (Eds): Williams Hematology, 5th edn. New York:

McGraw-Hill 1995:536-57.
11. Agre P. Hereditary spherocytosis JAMA 1989;262:2887-90.
12. Rosse W, Bunn HF, Hemolytic anemias. In Isselbacher KJ,
Braunwald E, Wilson JD, Martin JB, Faucil AS, Kasper DL
(Eds): Harrisons Principles of Internal Medicine, 13th edn,
New York, McGraw-Hill, 1994;1743.
13. Pajor A, Lehoczky D, Scakacs Z. Pregnancy and hereditary
spherocytosis. Arch Gynecol Obstet.
14. Ho-Yen Do. Hereditary spherocytosis presenting in pegnancy.
Acta Haematol 1984;72:29-33.
15. Breckenridge RL, Riggs JA. Hereditary elliptocytosis with
hemolytic anemia complicating pregnancy. Am J Obstet
Gynecol 1968;101:861.
16. Beutler E: Glucose-6-phosphate dehydrogenase deficiency.
N Engl J Med 1991;324:169.
17. Vergnes H, Clerc A. Erythrocyte enzyme activity in pregnancy
Lancet 1968;2:834.
18. Amankwah KS, Dick BW, Dodge S. Hemolytic anemia and
pyruvate kinase deficiency in pregnancy. Obstet Gynecol
1980;55:42-4.
19. Gilsanz F, Vega MA, GomezCastillo E, Ruiz- Balda JA,
Omenaca F. Fetal anemia due to Pyruvate Kinase deficiency.
Arch Dis Child 1993;69:523-4.
20. Schwartz RS, BerkmanEM, Silberstein LE. Autoimmune
hemolytic anemias. In: Hoffman R, Benz EJ Jr, Shattil SJ, Furie
B, Cohen HJ, Silberstein LE, et al. (Eds): Hematology: Basic
Principles and Practice, 3rd ed. Philadelphia: Churchill
Livingstone 2000:624.
21. Perotta PL, Synder EL. Non-infectious complications of
transfusion therapy. Blood Rev 2001;15:69-83.
22. Sibai BM, Taslinie MM, EL Naazer A, et al. Maternal perinatal
outcome associated with the syndrome of hemolysis,
elevated liver enzymes and low platlets in sever pre
eclampsiaeclampsia. Am J Obstet Gynecol 1986;155:501-
9.
23. Esplin MS, Branch DW. Diagnosis and management of
thrombotic microangiopathies during pregnancy. Clin Obstet
Gynecol 1999;42:360.
24. Bukowski RM. Thrombotic thrombocytopenic purpura: a
review. Prog Hemost Thromb 1982;6:287.
25. Schwartz ML, Brenner WE: The obfuscation of eclampsia by
thrombotic thrombocytopenic purpura. Am J Obstet Gynecol
1978;131:18.
26. Watson WJ, Katz VL, Bowes WA. Plasmapheresis during
pregnancy. Obstet Gynecol 1990;76:45.
27. Bell WR, BraineHG, Ness PM, et al. Improved survival in
thrombocytopenic purpura-hemolytic uremic syndrome. N
Engl J Med 1991;325-98.
28. Martin JN Jr, Files JC, Morrison JC. Peripartal adult throm-
botic thrombocytopenic purpura and hemolyticuremic
symdrome. In: Clark SL, Cotton DB, Hankins GDV, Phelan
JP (Eds): Critical Care Obstetrics 2nd ed. Boston: Blackwell
Scientific Publications 1991:464-83.
29. Marsh G, Lewis SM. Cardiac hemolytic anemias. Semin
Haematol 1969;6:133-49.
30. Lopez JA, Schnee M, Gaos CM, Wilansky S. Left ventricular
outflow tract obstruction and hemolytic anemia after mitral
valve repair with a Duran ring. Ann Thorac Surg
1994;58:876-8.
31. Bakowitz FE. Hemolysis and infectio. Categories and
mechanisms of their interrelationships. Rev Infect Dis 1991;
13:1151-62.
32. Petz LD. Drug induced autoimmune hemolytic anemia.
Transfus Med Rev 1993;7:242-54.
33. Packham CH. Pathogenesis and management of Paroxysmal
nocturnal hemoglobinuria. Blood Rev 1998;12:1.
34. Emmanuel C Besa, MD, Ulrich Woermann MD;Paroxysmal
nocturnal hemoglobinuria. www.emedicine. com / med/topic
2696. htm9816 (2006)
35. Hillmen P, Lewis SM, Bessler M, et al. Natural history of
Paroxysmal nocturnal hemoglobinuria. New Engl J Med
1995;333:1253.
36. Hillmen P, Hall C, Marsh JC, et al. Effect of eculizuamb in

patients with Paroxysmal nocturnal hemoglobinuria. New
Engl J Med 2004;350:552.
37. Spencer JA. Paroxysmal nocturnal hemoglobinuria in
pregnancy. Case report. Br J Obstet Gynecol 1980;87:246-
8.
38. Hurd WW, Modobnik M. Stys SJ. Pregnancy associated with
paroxysmal nocturnal hemoglobinuria. Obstet Gynecol
1982;60:742-6.
39. Schrier S. Extrinsic non immune hemolytic anemia. In:
Holfman R, Benz EJ Jr, Shattil SJ, Furie B, Cohen HJ,
Silberstein LE, et al. (Eds): Hematology Basic principles and
Practice. 3rd edition. Philadelphia: Churchill Livingstone,
2000:630-8.
CHAPTER 8
Sickle Cell
Anemia in
Pregnancy
Ratna Biswas
Introduction
Prevalence and geographic distribution
Pathogenesis of sickling
Diagnosis and laboratory findings
Effect of pregnancy on sickle cell disease
Effect of sickle cell disease on pregnancy
Management of pregnancy with sickle cell disease
Antepartum care
Prenatal diagnosis
Intrapartum management
Postpartum management
Specific problems during antepartum period and
their management
Transfusion therapy in pregnancy
Neonatal screening
Contraceptives
Future therapy
Key points
INTRODUCTION
Sickle cell anemia is an inherited chronic hemolytic anemia.
Its clinical manifestations are a result of polymerization of the
sickle hemoglobin and deformation of red blood cells into
characteristic sickle shape. This property is due to substitution
of valine for glutamic acid at position 6 of the -globin chain.
The homozygous state (HbSS) is the commonest form of sickle
SICKLE CELL ANEMIA IN PREGNANCY 139
cell disease but interaction with other hemoglobins also lead

to sickling. The term sickle cell disease (SCD) is used to denote
all entities associated with sickling of hemoglobin within red
cells (Table 8.1).
Table 8.1: The sickling syndromes1
Hemoglobin SS disease
Hemoglobin SC disease
Hemoglobin S- thalassemia
Hemoglobin S- thalassemia
Hemoglobin S/Hereditary persistence of fetal hemoglobin
Hemoglobin SE disease
Hemoglobin SD disease
Hemoglobin SO Arab disease
Hemoglobin S Lepore
Sickle cell trait (asymptomatic)
Early in the 1960s and 1970s the maternal mortality was

very high and thromboembolic events were the major cause
of death. With the advent of early integrated prenatal care
not only has the maternal mortality reduced to 1% but there
has been a significant improvement in prenatal outcome too.
In general pregnancy outcome depends on the severity of
patients anemia, frequency of occurrence of sickle cell crises,
thromboembolic events, infections and pre-eclampsia.
Pregnancy with sickle cell disease is a high risk pregnancy and
management should be multidisciplinary to give optimal
maternal and neonatal outcome.
PREVALENCE AND GEOGRAPHIC

DISTRIBUTION
It has the highest prevalence in tropical Africa. It is also found
in northern Greece and southern Italy. In the United States
it is seen in the population of African ancestry. It is also
distributed in the Caribbean island and in the non-white
population in Brazil. In India it is common in the tribal
population of Central India. The dissemination of sickle
mutations to different areas of the world took place through
trade routes and the slave trade.2
Sickle trait provides survival benefit in areas endemic for
falciparum malaria and distribution of sickle cell disease
paralleled this disease. The sickle hemoglobin containing red
cells inhibit proliferation of Plasmodium falciparum and the
infected cells are more likely to become deformed and removed
from circulation.2
PATHOGENESIS OF SICKLING2
Red cells acquire the sickle or elongated shape upon deoxy-
genation as a result of polymerization of HbS. The polymeri-
zation of HbS is influenced by oxygenation status, intracellular
hemoglobin concentration and presence of other hemoglobins.
Both HbA and HbF inhibit polymerization. Acidosis and
elevated 2,3-diphosphoglycerate enhances polymerization by
reducing oxygen affinity.
Sickling is associated initially with reversible membrane
changes but multiple cycles of sickling and unsickling results
in irreversible fixation of the membrane in the sickled
configuration. The sickle cells have a low mean cell volume
(MCV) and a high mean corpuscular hemoglobin concentration
(MCHC) as a result of dehydration.
Irreversible sickle cell has increased amount of intracellular

Ca2+, as much as fourfold. The two pathways responsible for
alteration of cation permeability is the Ca2+ activated K+
channel (Gardos) and KCl cotransport channel. The overall
loss of K+ from irreversible sickle cells exceeds Na+ gain and
there is overall loss of cell water thereby leading to cell
dehydration and increase in concentration of intracellular Hb.
Sickle red cells exhibit an abnormal adherence to vascular
endothelium and to monocytes, macrophages and model lipid
membranes. This property is imparted in the deformable sickle
cells rather than the ISCs, because of the fact that the rigid
cells are unable to form multiple surface contacts whereas
deformable sickle cells enters capillaries readily and adhere
strongly to the endothelium and compromise blood flow.
Sickling induced membrane fragmentation and compliment
mediated lysis causes intravascular hemolysis of red cells. The
entrapment of poorly deformable cells extravascularly and their
uptake by macrophages and monocytes is the dominant
mechanism of extravascular hemolysis2.
Adherence of sickle cells to the endothelium causes vaso-
occlusion. Risk factors for vaso-occlusion are HbS polymeri-
zation, sickle cell deformability, sickle blood viscosity, fraction
of dense cells, sickle cell endothelial cell adherence, endothelial
cell activation, hemostatic activation, vascular tone, contribu-
tion from white cells and platelets, local and regional environ-
mental factors and psychosocial factors.2
A decrease in vasodilator substances like prostacyclin and
nitricoxide and an increase in vasoconstrictors including
endothelin 1 and prostaglandins also leads to vaso-occlusion.2
Clinical manifestations of sickle cell anemia are secondary

to hemolysis, vaso-occlusive crises and increased predisposition
to infection.Vaso-occlusion results in tissue infection and pain
in the affected part.
DIAGNOSIS AND LABORATORY FINDINGS2

Average hemoglobin is around 8 gm/dl. Anemia is normocytic
normochromic and is moderately severe. The MCV is
approximately 90 fl and MCHC is 34 gm/dl.
Blood smears shows sickle cells, target cells, cigar shaped
cells and ovalocytes (Fig. 8.1). Polychromatophilia, basophilic
stippling and normoblastosis are suggestive of accelerated
erythropoiesis. Howell-Jolly bodies and Pappen-heimer bodies
are present in asplenic patients. Mean reticulocyte count is
10% with average ranging between 4 to 24%. WBC count
is raised as a result of increase in number of mature granulocytes.
Mean leucocyte count is 12 to 15 109/L. This increase in
leucocyte count results from shifting of leucocytes from
marginated to circulating compartment. Segmented leucocytes
increase during episodes of vasoocclusion and infection. Platelet
count increases due to reduced or absent splenic sequestration
but the count may be reduced during vaso-occlusive crises.
The clotting factors like factor VIII and fibrinogen concentration
increases and fibrinolytic activity also rises. These alterations
are due to endothelial damage inflicted by the sickling process.
The erythrocyte sedimentation rate is low as a result of
failure of sickled cells to undergo rouleax formation. Serum
lactate dehydrogenase increases during hemolytic and vaso-
occlusive episodes. Serum alkaline phosphatase also increased
during symptomatic crises.
Fig. 8.1: Sickle cell anemia 1. Sickle cell

(For color version see Plate 4)
The final diagnosis lies on electrophoretic or chromato-

graphic separation of the various hemoglobins in the hemoly-
states prepared from peripheral blood. The HbS is the
predominant hemoglobin seen although HbF is also present
in varying amounts. HbA2 levels are normal and HbA is absent.
The heterozygous states are diagnosed by Hb separation by
isoelectric focusing or high performance liquid chromatography
(HPLC) globin-chain electrophoresis or structural analysis of
Hb by protein chemistry, mass spectrometry or sequencing of
polymerase chain reaction amplified DNA.
There are certain simple tests for detection of HbS. A drop
of blood can be put under cover slip to cause deoxygenation
or sodium metasulphite 2% solution can be added to
deoxygenate HbS. Deoxy HbS is insoluble and precipates in
solution rendering it turbid whereas other hemoglobins remain
clear. Hyperglobinemia or other sickling hemoglobins can cause

false positive results. But these cannot be used as primary
screening tests because differentiation from sickle cell trait or
Hb variants that interact with HbS is not possible.
EFFECT OF PREGNANCY ON SICKLE

CELL DISEASE
Physiological changes in the cardiovascular system in pregnancy
leads to increased cardiac output because of reduced systemic
vascular resistance. Due to increased left ventricular end-
diastolic volume there is a decompensation of cardiac function.
Similarly because of increase in tidal volume, minute ventilatory
volume, minute oxygen uptake and total pulmonary resistance
and reduced functional lung capacity and residual volume there
are increased chances of cardiopulmonary dysfunction in
pregnant woman with sickle cell disease. Previously asympto-
matic women may become symptomatic and worsening of
symptoms may occur with advancing pregnancy.
EFFECT OF SICKLE CEEL DISEASE

ON PREGNANCY
Miscarriage rate is significantly high as reported in literature.
In two prospective studies, the rate of spontaneous abortion
ranged from 35 to 65% as compared to 35 to 41% in controls.3
Other complications include placental abruption, pre-
eclampsia and preterm labor. In a recent prospective study
in Jamaica, the risk of pre-eclampsia and abruption were not
increased but pre-term labor was noted in 38 to 45% of patients
of HbSS as compared to 20% in controls. It was also observed
that preterm labor and toxemia were higher in those patients
who required blood transfusion for sickle cell complications.

This probably reflects that the risk of obstetric complications
is higher in patients with severe acute and chronic vascular
injury with sickle cell disease. The mode of delivery and cesarean
rates were consistent with normal controls.3
Antepartum and postpartum hemorrhage rates are not
increased. Retained placenta was slightly more prevalent in
a Jamaican study.4 Postpartum endometritis was reported to
be significantly high in one study.5
Although the overall complication rate in the ante-intra-
and postpartum period is not significantly high, however an
integrated approach of multispeciality antenatal supervision
along with patient education and follow-up will prevent much
of the morbidity and mortality associated with the disease.
Earlier studies quoted a very high perinatal mortality rate
of almost 53%. However, over the last three decades there
has been a dramatic improvement in perinatal outcome. With
improved obstetric and neonatal care neonatal mortality has
ranged from 0 to 10%.6
Intrauterine growth retardation and low birth weight is
common owing to chronic anemia and placental damage
because of vaso-occlusion. Doppler flow studies have shown
a positive correlation between reduced uterine flow and birth
weight.7 However, pain episodes have not been associated with
apparent change in umbilical flow despite increased uterine
vascular resistance. Use of opiates during pain episodes
may transiently alter the non stress test and biophysical profile
so caution in interpretation is required in absence of other
findings.
MANAGEMENT OF PREGNANCY WITH

SICKLE CELL DISEASE
ANTEPARTUM CARE8,9
As mentioned earlier at first antenatal visit a detailed history
particularly in context to prior crises, their nature, frequency
and management details are noted. Any associated medical
problems or long term complications of sickle cell disease like
renal failure, hypertension, liver or cardiac involvement should
be noted so as to be vigilant for any further deterioration of
functional status. Pregnancy may be contraindicated or
associated with significant complications owing to end organ
damage. The past obstetric history is evaluated in detail. Special
emphasis is put on adequate dating since intrauterine growth
retardation is a commonly seen in sickle cell disease. A baseline
complete blood count including reticulocyte count, serum iron
levels, and liver and renal function test is obtained. Screening
for HIV and hepatitis is important because of earlier trans-
fusions.
All women should take folic acid supplements of 1mg/day.
If there is no evidence of iron overload then routine iron
supplements should be prescribed like in any pregnant women.
An oral intake of penicillin 250 mg twice daily is recommended
because of a common association of asplenism in sickle cell
disease, to prevent infection by encapsulated organisms. Patients
are counseled for maintaining adequate hydration and are
warned to report any signs of infection at the earliest. Vigilance
is maintained for early diagnosis of preterm labor, pre-eclampsia,
abruption, IUGR and sickle cell disease activity. At every visit
signs and symptoms of these complications are looked for.
In the first and second trimester, 2 weekly visits are recommen-
ded and supervision by both obstetrician and hematologist is

beneficial. Weekly visits are recommended in the third trimester.
At each visit in addition to the routine assessment of blood
pressure and urine analysis a complete blood count and urine
microscopy and culture are done. Gestational age is confirmed
by ultrasound.
After 24 weeks, monthly ultrasonography is recommended
to assess fetal growth and fetal movement count is to be
maintained daily by the patient. Weekly non-stress test and
biophysical profile is started after 32 weeks. Doppler ultrasound
is performed at 28 to 30 weeks to determine umbilical artery
flow and systolic-diastolic ratios for early detection of IUGR.3
Baseline blood pressure is lower in sickle cell disease as
compared to general population and hence a moderate increase
in blood pressure may be an early indication of pregnancy
induced hypertension. A specific threshold value has not been
established but some authorities have given a reference value
of 125/75 mmHg.10
PRENATAL DIAGNOSIS2
The most important aspect is the screening of the womens
partner so that the couple can be advised appropriate tests
for diagnosis of affected fetus. Screening procedure includes
examination of red cell indices, hemoglobin electrophoresis and
HbA2 and HbF estimation wherever indicated. If a hemoglobin
variant is found then the partner is screened.
Prenatal diagnosis is offered to women at risk of affected
baby. Initially the fetal blood sampling was the preferred method
for prenatal diagnosis. But recent developments in molecular
biology allows DNA prepared from amniotic fluid cells obtained
at 15 to 20 weeks gestation or from a biopsy of chorionic
villus obtained at 10 to 12 weeks of gestation. Chorionic villus

sampling provides earlier diagnosis thereby allowing first trimester
medical termination. The least invasive method of prenatal
diagnosis uses fetal cells from maternal circulation isolated by
a variety of techniques such as multiparameter flow cytometry.
Preimplantation diagnosis can be done in in vitro fertilization
techniques and unaffected embryos implanted into the uterus.
Methods of analysis include restriction fragment length
polymorphism for the analysis of fetal DNA. The use of PCR
to amplify -globin sequences before restriction enzyme
increases the sensitivity and speed of procedure. The dot and
blot method of allele specific hybridization uses fixation of PCR
amplified target -globin DNA to filter and hybridization of
the filters with labeled probes complementary of A and S
sequences.
INTRAPARTUM MANAGEMENT6
Supportive measure to reduce stress of labor has a beneficial
effect. Intravenous fluid supplementation with balanced salt
solutions helps in preventing vaso-occlusive crisis. Oxygen
supplementation by mask improves cardiac function and
prevents sickling. To reduce cardiac demand which increases
during labor adequate intrapartum pain relief by narcotics or
epidural anesthesia is advocated. Nitrous oxide mixed with 50%
oxygen can be given for inhalation for short term pain relief.
Continuous intrapartum fetal monitoring is highly recom-
mended to detect fetal hypoxia. Vaginal delivery is preferred
unless there is an obstetric indication for cesarean section. For
cesarean delivery blood should be cross-matched and arranged
before hand. Regional anesthesia is preferred to general
anesthesia to avoid the risk of iatrogenic hypoxia.
POSTPARTUM MANAGEMENT9
Early ambulation is advised to prevent venous thrombosis.
Adequate hydration and usage of thromboembolic deterrent
stocking is encouraged. Analgesics drugs should be given for
pain relief. Breast feeding is encouraged. Patients caloric and
fluid intake should be adequate in postpartum period.
Prophylactic antibiotic is generally not needed but any source
of infection should be adequately treated. Cord blood is sent
for electrophoresis and repeated after 6 weeks in case of
equivocal results. Babies with sickle cell anemia should be given
prophylactic penicillin therapy by the beginning of third month.
SPECIFIC PROBLEMS DURING ANTEPARTUM

PERIOD AND THEIR MANAGEMENT3
Urinary Tract Infection
Asymptomatic bacteria, lower urinary tract infection and
pyelonephritis all are exacerbated in pregnancy. Lower urinary
tract infection is seen in 30 to 40% and pyelonephritis in 7
to 9% in SCD. Adequate treatment with antibiotics according
to culture sensitivity report should be instituted.
Sickle Cell Pain Episode3

These may increase in frequency and severity during pregnancy.
Treatment principles are same as in nonpregnant women, that
is to reduce sickling and adherence of red blood cells to vessel
wall. Intravenous fluids and oxygen therapy should be started
to maintain intravascular volume and oxygenation. If there
is a precipitating infection, it should be detected and treated
promptly. Pain should be controlled adequately by analgesics.
Opiates may be needed and its use has not been associated
with teratogenecity or toxic effects but transient suppression

in fetal heart variability and movements have been noted.
Chronic exposure can lead to neonatal abstinence syndrome
after birth.
Acute Chest Syndrome3

It is reported in 7 to 10% of pregnancies. Treatment consists
of blood transfusion, bronchodilators and improved oxyge-
nation.
Sequestration Crises
It may occur in milder forms of sickle cell disease where splenic
function is maintained till adulthood. Acute multiorgan failure
may occur with rapid deterioration of renal, hepatic and
pulmonary function. It should be recognized early and supportive
therapy should be started. Transfusion therapy helps in halting
disease progression.
TRANSFUSION THERAPY IN PREGNANCY3

Blood transfusion is given for acute severe anemia (Hb
< 6 gm/dl) or certain complications of sickle cell disease during
pregnancy. Prophylactic transfusions do not result in significant
reduction of obstetric complications or improvement, in the
fetal birth weight. The only beneficial effects that have been
seen is the reduction in number of pregnancies complicated
by pain events from 42 to 9% and a decrease in acute chest
syndrome from 25 to 5%. The use of transfusion therapy is
generally limited to patients who experience a significant increase
in sickle cell disease activity with severe complications including
acute chest syndrome, acute severe anemia and in anticipation
of surgery. Matching of minor antigen should be done for the

full Rh blood group (C/c/D/E/e) and kell antigens. Alloantibody
formed may cause hemolytic disease of the newborn. In women
with prior transfusions in pregnancy, almost 20 to 26% develop
alloantibodies.
Indications for Transfusion11

Acute Anemia
When the hemoglobin levels falls by more than 20% from
baseline or patient is symptomatic and presents with
breathlessness, intolerance to minimal exertion or has dizziness
on standing, then blood transfusion is given. Acute blood loss
is another indication for transfusion. Acute anemia requires
only simple blood transfusion.
Splenic Sequestration
The acute anemia develops as a result of trapping of blood
in the spleen. Anemia is associated with thrombocytopenia.
Sometimes due to massive splenic sequestration, hypotension
and death may follow, hence it is a medical emergency and
rapid transfusion of red blood cells is life saving. At the same
time overtransfusion is to be avoided as entrapment of sickled
red blood cells may be reversible once blood is infused and
patient may become polycythemic. Therefore, in absence of
hypotension, transfusion should be given over several hours
and about 5 ml/kg should be infused initially. This way
hyperviscosity caused by release of previously entrapped cells
can be avoided thereby reducing the chance of sludging of
the sickled cells in various organs and thus preventing end organ
damage.
Aplastic Crises
Acute anemia due to reduced production is usually precipitated
by infection especially parvovirus B19. A decrease in erythro-
poiesis leads to severe anemia since sickle cell patients are
dependent on overproduction of RBCs at baseline to
compensate for the short life span of the cells in the circulation.
They become symptomatic if hemoglobin falls by 20% or more
and such situations warrant blood transfusion.
Acute Chest Syndrome

This condition tends to be more severe and sometimes fatal
in adults and requires urgent exchange transfusion. While in
children it is sometimes associated with bacteremia, systemic
infection is unlikely in adults and evidence of fat embolism
is found in minority of cases. Most often it is preceded by
acute painful episodes. Whatever the cause, transfusion is
helpful. In patients with more severe presentation, with a normal
pretreatment hemoglobin level, an exchange transfusion is
preferable to improve hemoglobin A levels to 70 to 80%, while
keeping hematocrit of less than 30% to avoid hyperviscosity.
In patients who are anemic or in whom the presentation is
milder, a simple transfusion can be given.
Other Indications
When there is sludging in the liver, hepatic necrosis can ensue
but this can be reversed by simple or exchange transfusion.
When there is multiorgan failure hepatic, renal and CNS
abnormalities develop and exchange transfusion is required to
lower hemoglobin S to less than 30% and maintain hematocrit
at less than 30%. Exchange transfusion is achieved by apheresis
and leads to rapid clinical improvement as evident by improved

oxygenation in acute chest syndrome or neurologic function
in stroke.
Sickle Cell Disease Associated Chronic Complications3

Blood transfusion prevents damage to the organs either during
the course of an acute episode or prevents their recurrence.
Infarctive strokes can be prevented by blood transfusion. In
chronic osteomyelitis transfusion helps to attain a complete
response to antibiotics. In chronic renal failure transfusion
therapy delays disease progression. Leg ulcers healing may be
augmented by blood transfusion. Recurrent transfusion therapy
requires iron chelating agents like desferoxamine to prevent
hemosiderosis. It is a category C drug and should be withheld
in pregnancy. Serum ferritin levels should be monitored and
iron intake should be avoided in patients with iron overload.
NEONATAL SCREENING2
Neonatal screening program was first introduced in New York
in 1975. The incentive for universal screening came from the
fact that early diagnosis reduces mortality and morbidity in
infants particularly by prevention of pneumococcal sepsis with
penicillin prophylaxis. A National Institute of Health Consensus
conference concluded that every child should be screened early
for sickle cell disease.
A cord blood sample or heel prick sample can be taken
but both are subject to small error rate primarily involving carrier
phenotypes but cord blood samples are more prone to
inconclusive results. Isoelectric focusing and high performance
liquid chromatography are the techniques used in screening.
These techniques allow detection of minor hemoglobin
components in presence of HbF. In infants having sickle cell

anemia the Hb components comprise of HbF, a relative small
amount of HbS and no HbA. Neonates doubly heterozygous
for HbS and thalassemia and HbS and hereditary persistence
of fetal hemoglobin have a hemoglobin pattern indistinguishable
from HbSS. They may be differentiated by hemoglobinopathy
screening of parents or repeat testing of infants at later stage.
PCR based techniques are used for reliable confirmatory testing
for distinguishing HbS thalassemia from HbSS.
CONTRACEPTIVES9
Oral contraceptives have a theoretical risk of thromboembolic
event but use of low dose oral contraceptive is not contra-
indicated. Progesterone based contraception like depot medroxy
progesterone acetate is a safe alternative and it also has
beneficial effect of decreasing sickling due to stabilization of
erythrocyte membrane. IUCDs are relatively contraindicated
because of risk of pelvic infection but can be used in selected
cases where other methods are contraindicated. Levonorgestrol
containing devices are associated with lower risk of pelvic
infection than copper IUCD. Barrier method is widely used
but risk of failures is high. Permanent method is advised on
completion of family.
FUTURE THERAPY
Therapeutic agents which act at molecular level such as
cytotoxic drugs increase the percentage of hemoglobin F or
hemoglobin A and form the mainstay for future treatment.
The first drug to be used was 5-azacytidine which stimulates
y-globin gene activation. Hydroxyurea has generated great
interest because it is relatively nontoxic and its myelosuppressive

effects are readily reversible. It acts by induction of F cell
formation in the bone marrow as a result of rapid erythroid
regeneration that is stimulated after myelosuppression by
hydroxyurea. Hemoglobin F production results in reduced rate
of intracellular polymerization and sickling. Erythropoietin has
also shown to stimulate the production of fetal hemoglobin
when used in combination with hydroxyurea. Although use
of hydroxyurea throughout pregnancy has not been associated
with birth defects but it is a teratogen in animals and hence
should not be used in pregnancy.12
KEY POINTS
Clinical manifestation of sickle cell anemia is a result of
polymerization of sickle hemoglobin and deformation of
red cells into sickle shape.
Diagnosis is by electrophoretic or chromatographic
separa-tion of the various hemoglobins.
Obstetric complications like pre-eclampsia and preterm
labor are higher in patients with severe acute or chronic
vascular injury with sickle cell disease.
Important aspect of antenatal management is screening
of the partner and prenatal diagnosis, if both partners are
affected.
Chorionic villus sampling, amniocentesis and fetal blood
sampling are the important methods of prenatal diagnosis.
Pre-implantation diagnosis can be carried out in in-vitro
fertilization techniques.
Antenatal visits should be every 2 weeks in first and
second trimester and at each visit a complete blood count,
urine microscopy and culture should be done in addition
to blood pressure and urine analysis.
Monthly ultrasound after 24 weeks is essential to monitor
fetal growth. Weekly nonstress test and biophysical profile
is recommended after 32 weeks. Doppler ultrasound
should be done at 28 to 30 weeks.
Special emphasis is laid on prompt detection and

management of urinary tract infection, sickle cell pain
episodes and acute chest syndrome.
Prophylactic transfusion offers no additional benefit and
hence transfusion is recommended in the management
of acute anemia, splenic sequestration crisis, aplastic
crisis or acute chest syndrome. Exchange transfusion
leads to rapid clinical improvement in acute chest
syndrome and in neurological manifestation like stroke.
Intrapartum management aims at reducing stress of labor
by adequate pain relief and maintaining adequate hydra-
tion and oxygenation.
Cord blood should be sent for electrophoresis and repeat
neonatal blood analysis should be done at 6 weeks in
equivocal cases.
Therapeutic agents like hydroxyurea have great potential
but its use in pregnancy is not recommended.
REFERENCES
1. Lal A, Vinchinsky EP. Sickle cell disease. In Postgraduate
Hematology 5th edn. Blackwell Publishing 104-18.
2. Wang WC. Sickle cell anemia and other sickling syndromes.
In Wintrobes Hematology. 11th edn. Lippincott Williams and
Wilkins 2004:1263-331
3. Hassel K. Pregnancy and sickle cell disease. Hematol Oncol
Clin N Am 2005:903-16.
4. Serjeant GR, Lookloy L, Crowther M, et al. Outcome of
pregnancy in homozygous sickle cell disease. Obstet Gynecol
2004;103(6):1278-85.
5. Seoud MF, Cantwell C, Nobles G, et al. Outcome of
pregnancies complicated by sickle cell and sickle C
hemoglobinopathies. Am J Perinatol 1994;11(3):187-91.
6. Rust OA, Perry KG. Pregnancy complicated by sickle
hemoglobinopathy. Clin Obstet Gynecol 1998;38:472-84.
7. Billett HH, Langer O, Regan OT et al. Doppler velocimetry
in pregnant patients with sickle cell anemia. Am J Hematol
1993;42:305-8.
8. Anyaegbunam A, Gauthier Morel M, Merkatz I. Antepartum
fetal surveillance tests during sickle cell crisis. Am J Obstet
Gynecol 1991;165(1):1081-3.
9. Ntim EO, Lupton M, Mensah S et al. Sickle cell disease and
pregnancy. Progress in obstetrics and gynecology. 16th edn.
Churchill Livingstone 73-82.
10. Koshy M, Burd L. Management of pregnancy in sickle cell
syndrome. Hematol Oncol Clin North Am 1991;5(3):585-
96.
11. Telen MJ. Principles and problems of transfusion in sickle
cell disease. Semin Hematol 2001;38(4):315-23.
12. Diav-Citrin O, Hunnisett L, Sher G, et al. Hydroxyurea use
during pregnancy: a case report in sickle cell disease and
review of literature. Am J Hematol 1999;60:148-50.
CHAPTER 9
Aplastic Anemia
in Pregnancy
Abha Singh
Varsha Parakh
Introduction
Etiology
Pathogenesis of aplastic anemia during pregnancy
Pathophysiology
Clinical features
Differential diagnosis
Workup of a patient of aplastic anemia
Management
Prognosis
Conclusion
Key points
INTRODUCTION
Aplastic anemia is a disease of the hemopoeitic system
characterized by insufficient production of the marrow cells
leading to peripheral pancytopenia and marrow hypoplasia.The
concept of aplastic anemia was first introduced by Paul Ehrlich
in 1888 when he studied the case of a pregnant woman who
died of bone marrow failure. In 1904 Chauffard termed this
disorder as aplastic anemia1.
Pregnancy complicated by aplastic anemia is rare. It is
usually associated with significantly high maternal and fetal
morbidity and mortality.1, 2 It is still not known whether
pregnancy plays a pathogenic role in the development of the
disease or it is a chance occurrence. It has been postulated
that pregnancy induces erythroid hypoplasia.3 It was observed
APLASTIC ANEMIA IN PREGNANCY 161
that in one third of patients the aplasia resolves spontaneously

soon after delivery, to recur with subsequent pregnancies.4
However, there is no definite evidence to suggest that pregnancy
aggravates aplastic anemia. 1,2 In literature 80 cases of
pregnancy-associated aplastic anemia have been reported by
various authors.5 Since, this disease is quite rare its etiology
remains an enigma.
ETIOLOGY
The basic defect in aplastic anemia is failure of production
of all the three types of blood cellserythrocytes, leucocytes
and platelets. Aplastic anemia occurs because of either
qualitative defect of common stem cell population (seed or
stem cell deficiency), or as a result of defective marrow
environment (soil or microenvironment deficiency) or because
of immune suppression.6 This defect may either be inherited
or acquired.7,11 In acquired aplastic anemia clinical and
laboratory observations suggest that this is an autoimmune
disease.
1. Inherited (20%)
Fanconis anemia
DiamondBlackfan syndrome
Familial aplastic anemia and others.
2 Acquired (80%)
Nutritional depletion, e.g. folate or cobalamin (vitamin
B12) deficiency.
Infectious causes
Non-A, Non-B hepatitis, EBV, HIV, CMV,
Parvovirus, mycobacterial infections, etc.
Toxic exposure to marrow suppressive substances, e.g.

alcohol, radiation and chemicals such as benzene, etc.
Drugs such as chloramphenicol, phenylbutazone, gold,
etc.
Paroxysmal nocturnal hemoglobinuria (PNH) caused
by acquired genetic defect limited to stem cell
compartment affecting the PIGA gene.
Transfusional graft versus host disease (GVHD)
Orthotopic liver transplantation for fulminant hepatitis
Pregnancy
Eosinophilic fascitis.
PATHOGENESIS OF APLASTIC ANEMIA

DURING PREGNANCY
During pregnancy, usually there is erythroid hyperplasia and
leucocytosis with normal or decreased platelet count. The
pathogenesis of pregnancy-associated aplastic anemia is
multifactorial.8
IMBALANCE OF FACTORS INFLUENCING

ERYTHROPOIESIS
Hormonal changes that occur secondary to pregnancy have
been attributed to play a role in the pathogenesis of aplastic
anemia. Fleming suggested following factors as the main cause
of aplastic anemia:
i. The imbalance between erythropoietin and human
placental lactogen is disturbed, which decreases blood
production,
ii. Increase in estrogen level, which inhibits erythropoiesis.8
PRODUCTION OF AN INHIBITOR OR ABSENCE OF

A STIMULATOR OF HEMATOPOIESIS
A study by Kiss and Szemere showed that when serum from
12 pregnant patients with refractory anemia was injected into
mice, it did not stimulate erythropoiesis. However, when the
serum from healthy pregnant and iron deficient pregnant women
was injected into mice, it stimulated varying degrees of
erythropoiesis.5 These observations suggest that there is either
a presence of a hemopoiesis inhibitor or absence of a stimulator
of hemopoiesis which may be responsible for aplastic anemia
during pregnancy.
MARROW DYSFUNCTION DURING PREGNANCY

Camitta et al hypothesized that since there pre-exists a mild
degree of marrow dysfunction in patients who develop aplastic
anemia during pregnancy, the bone marrow is not able to
respond to the stress of pregnancy and thus results in a total
failure of marrow function.9,15
TEMPORAL RELATIONSHIP
It has been observed that aplastic anemia resolves spontaneously
after delivery in one third of cases.5,8,12-15. However, relapse
in subsequent pregnancies has been reported in women with
disease remission, either after a spontaneous delivery or
termination of pregnancy.5,8,12-15 Keskin and Soysal15 reported
a case in which the blood cells decreased throughout pregnancy
and which improved spontaneously after termination of
pregnancy.15
A COINCIDENCE
Aplastic anemia in pregnancy is merely a coincidence as
predilection for a specific gestational age is not reported and
hematological recovery after termination of pregnancy occurs
in only one third of cases.
PATHOPHYSIOLOGY
Morphologically, the bone marrow is devoid of hematopoietic
elements, but shows presence of large number of fat cells.
Flow cytometry shows that there is a reduction in CD 34-cell
population which contains the stem cells and early progenitors.
In vitro colony culture assays suggest significant functional loss
of hematopoietic progenitors, which are unresponsive to even
high doses of hematopoietic growth factors. There is little
evidence to suggest that defective microenvironment is a cause
of aplastic anemia. In severe aplastic anemia (SAA), stromal
cells have normal function (including growth factor production)
which is essential for success of bone marrow transplantation
(BMT) as the stromal elements are usually of host origin.
Immune dysfunction was suggested in 1970, when
autologous recovery was proved in a patient of aplastic anemia
in whom engrafting failed after BMT. Immunosuppressive
regimen promoted the return of normal marrow function,
(Mathe) which was also proved by various studies in 70% of
cases. Immunity is genetically regulated (by immune response
genes) and also influenced by environment (nutrition, aging,
previous exposure). The inciting antigens that weaken the
immunity are unknown but Human Leukocyte Antigen (HLA)
DR2 is over represented among European and American
patients with AA. Suppression of hematopoiesis may possibly

be mediated by increased cytotoxic T lymphocytes (CTLS):
CD8 and HLA-DR+, which are detectable in both blood and
bone marrow of patients with AA. These cells produce inhibitory
cytokines as gamma-interferon and tumor necrosis factor, which
can suppress progenitor cell growth and affect the mitotic cycle
and cell killing by inducing Fas-mediated apoptosis. These
cytokines induce nitric oxide synthase and nitric oxide production
by marrow cells which cause immune mediated cytotoxicity
and elimination of hematopoietic cells.
INCIDENCE
The incidence of aplastic anemia among normal population
in various countries as reported in literature is as follows:7
USA 0.6-6.1 cases/million population
Europe 2.0 cases/million population
Bangkok 4.0 cases/million population
Thailand 6.0 cases/million population
Japan 14.0 cases/million population
Environmental factors like increased exposure to toxic
chemicals rather than genetic factor may be responsible as
no increase in incidence has been found in people of Asian
origin living in USA.
CLINICAL FEATURES
HISTORY
The onset is insidious and symptoms are related to decrease
in production of hematopoietic cells by the bone marrow.10,11
The initial symptoms may be related to anemia or bleeding,
but later fever or infections may be the presenting symptoms.
Anemia may manifest as pallor, headache, palpitations,

dyspnea, fatigue or swelling of feet.
Thrombocytopenia may present as mucosal and gingival
bleeding or petechial rashes.
Neutropenia may manifest as overt infections, recurrent
infections or mouth and pharyngeal ulcerations, fever with
chills and sweating, chronic skin infections and recurrent
chest infections. Pneumonia and septicemia are frequent
causes of death.10
History of exposure to solvent or radiation may be present
Family history of AA, exposure to marrow suppressive
substances and infectious disease in the past is important.
EXAMINATION
The main feature on physical examination is the absence of
objective findings and overt signs of infection. Physical signs
resulting from anemia as pallor and tachycardia, or thrombo-
cytopenia such as petechiae, purpura or ecchymoses may be
present. Usually there is no icterus but a small subset of patients
with aplastic anemia may present with jaundice. The spleen
is rarely palpable. Liver is palpable only as a complication
of severe anemia. Lymph nodes are not enlarged, though the
regional nodes draining infected lesions may become
palpable.10 If lymphadenopathy or organomegaly are present
an alternative diagnosis should be considered. Physical stigmata
of inherited marrow failure syndromes, like skin pigmentation,
short stature, microcephaly, hypogonadism, mental retardation
and skeletal anomalies may be present in cases of AA.
DIFFERENTIAL DIAGNOSIS
Acute myelogenous leukemia
Acute lymphocytic leukemia
Myelofibrosis
Myelodysplastic syndrome
Non-Hodgkins lymphoma
Agranulocytosis
Pure red cell aplasia
Fanconis anemia
Megaloblastic anemia
Systemic lupus erythematosus
Hypersplenism
Human herpes virus type 6
Infections such as HIV, mycobacterial infections, cyto-
megalovirus (CMV), EBV.
WORKUP OF A PATIENT OF APLASTIC ANEMIA

LAB STUDIES
CBC Count and Peripheral Smears
Patients with Aplastic anemia usually show normocytic
normochromic anemia or slightly macrocytic anemia with
leucopenia, particularly neutropenia with relative lympho-
cytosis and thrombocytopenia.
The degree of cytopenia is useful in assessing the severity
of aplastic anemia. The corrected reticulocyte count is
uniformly low in aplastic anemia.
(Reticulocyte index < 2). Erythrocyte sedimentation rate

is elevated.11
The peripheral blood smear is helpful in differentiating
aplasia from infiltrative and dysplastic causes. The presence
of teardrop poikilocytes and leucoerythroblastic changes
are suggestive of an infiltrative process.
Patients with MDS (Myelodysplastic syndrome) often show
certain characteristic abnormalities, which include dysery-
thropoietic red blood cells and neutrophils with hypogranu-
lation, hypolobulation, or apoptotic nuclei reaching to the
edges of the cytoplasm. Monocytes are also hypogranular,
and their nuclei may contain nucleoli.11
A leukemic process may show evidence of blast cells on
the peripheral smear which are absent in AA.
Blood Tests
Blood group testing and hemoglobin electrophoresis may
show red cell I antigen and elevated fetal hemoglobin
suggesting stress erythropoiesis, which is observed in both
aplastic anemia and MDS and often is proportional to the
macrocytosis.11
Biochemical profileevaluation of serum transaminase,
bilirubin, lactic dehydrogenase, Coombs test, and kidney
function tests are useful in evaluating etiology and differential
diagnosis.
Serologic testing for hepatitis and other viral diseases as
EBV, CMV, and HIV.
Autoimmune disease evaluation for evidence of collagen-
vascular disease.
Serum B12 and folate levels should be done to exclude

megaloblastic anemia.
Diepoxybutane test (DEB) is performed to assess chromo-
somal breakage for diagnosing Fanconis anemia. This test
should be done in absence of phenotypic features of
Fanconis anemia because 30% of patients may not have
any clinical stigmata.
The Ham test or sucrose hemolysis test is performed, but
at present fluorescence-activated cell sorter (FACS) profile
of PIGA anchor proteins, such as CD55 and CD %, may
be more accurate for excluding PNH.
Histocompatibility testing should be performed early to
identify potential related donors, especially for young patients.
It has been observed that extent of previous transfusion
affects the outcome of patients undergoing BMT for aplastic
anemia so these tests should be carried out as early as
possible.
Bone Marrow Examination

Both bone marrow aspirate and trephine biopsy should be
done to confirm the diagnosis.
Characteristic findings of aplastic anemia include hypo-
cellular bone marrow with fatty replacement and relatively
nonhematopoietic elements such as plasma and mast cells.
Careful examination should be performed to exclude tumor
foci on biopsy.7
Imaging Studies
Imaging studies are not usually required to establish a diagnosis
of aplastic anemia.
A Skeletal Survey
Skeletal survey is useful in diagnosing inherited marrowfailure
syndromes, which may present as skeletal abnormalities.
Classification of severity of disease

The failure of stem cells to produce mature cells can vary from
partial to almost complete, thus producing a disease of varying
severity in different people.
Based on International Aplastic Anemia Study Group
(Camitta, 1983), the disease can be divided into three groups.9,12
Severe AA BM cellularity <25%, or 25 to 50% with <30%

residual hemopoietic cells.
2/3 of the following:
1. Neutrophils <0.5 109/l
2. Platelets <20 109/l
3. Reticulocytes <1% corrected (percentage
of actual [Hct] to normal Hct)
Very Severe AA As for severe AA but neutrophils <0.2 109/l.

Non Severe AA Patients not fulfiling the criteria for severe or very
severe AA.
Clinical Course
Spontaneous improvement without treatment occurs in up to
one-third of patients after delivery. Patients with mild AA have
a better prognosis and often do not require therapy4 as compared
to severe AA
Previously more than 80% of patients with severe aplastic
anemia, if left untreated died from complications of infection
and bleeding.6 Good supportive care with more effective
antibiotics and safe blood transfusions has improved the short
term prognosis of these patients.
The disease usually progresses during pregnancy and there

is a significant risk of relapse in subsequent pregnancies in
patients who have previously responded to immunosuppressive
therapy.12 In contrast, after successful allogenic bone marrow
transplantation, pregnancy does not appear to trigger relapse
of the disease.
A recently reported European Blood and Marrow Trans-
plantation Severe Aplastic Anemia study14 has evaluated
outcome of pregnancy and disease course among 36
pregnancies in women with severe aplastic anemia previously
treated with immunosuppression. Almost half the pregnancies
had a complication either in the mother or baby or both. There
were 34 live births (including one set of twins) 5 premature
births and 3 abortions (one spontaneous). All infants born alive
had normal postnatal development. There were two cases of
eclampsia and two maternal deaths after delivery. Relapse of
aplastic anemia occurred in 7 pregnancies (19%) and a further
5 patients without relapse required transfusions during delivery.
Three out of 7 women recovered spontaneously, 3 recovered
after retreatment while 1 did not recover and died. Most patients
with relapsed aplastic anemia or progressive thrombocytopenia
during pregnancy were delivered by cesarean section. During
pregnancy, blood counts changed significantlyhemoglobin
levels and platelet counts decreased while neutrophil counts
increased. However, the counts tended to return to prepregnancy
values within 1 to 6 months of delivery. Normal blood counts
before conception did not guarantee freedom from relapse of
aplastic anemia. Women with uneventful pregnancy had a better
prepregnancy remission status (8 complete and 11 partial
remission and higher median platelet count (146 109 cells
/ L) than did women with complicated pregnancy (2 complete

and 8 partial remission and 4 cases of paroxysmal nocturnal
hemoglobinuria) and median platelet count of 92 104 cells/
L. Thus, this study concluded that successful pregnancy with
normal outcome is possible in women with aplastic anemia
previously treated with immunosuppression. Complications are
more likely in patients with low platelet count and paroxysmal
nocturnal hemoglobinuria but less likely in women with complete
remission.
COMPLICATIONS
Maternal
Anemia
Infection
Hemorrhage
Fetal
Intrauterine growth restriction
Intrauterine death
Fetal thrombocytopenia
Fetal malformations.
MANAGEMENT
There is still a dilemma regarding the optimal approach for
management of patients with aplastic anemia.
Patients with AA should be counseled against getting
pregnant. If conception has occurred the controversy is whether
pregnancy should be terminated early or allowed to proceed
till term, facilitating a better maternal and fetal prognosis. These
women require prolonged medication and are subjected to
increased risk of fatal hemorrhage and infection during
pregnancy. 4,15 The potential risks to both the mother and baby
should be discussed in detail with the women and her family
and the final decision whether to continue with pregnancy or
opt for a therapeutic abortion lies with the patient.12
Management also depends upon gestational age ,severity
of disease and whether treatment has been given and is
discussed under the following headings:10,11
A. Identification and elimination of exposure to causative
agent.
B. Supportive care
i. Prevention and treatment of infection
ii. Blood transfusion
iii. Psychological and general support.
C. Measures to accelerate recovery from pancytopenia
i. Immunosuppressive agents
ii. Bone marrow transplantation
iii. Growth factors.
A. Identification and elimination of exposure to causative agent
Aplastic anemia is precipitated by ingestion or inhalation of
certain drugs or chemicals.
The exposure should be terminated as soon as possible,
to reduce the severity of the disease. A brief exposure to certain
drugs like benzene and herbal medications containing
phenylbutazone can have a fatal outcome.
B. Supportive Care
i. Prevention and treatment of infections
Several prophylactic measures should be taken for the patients
at risk of infection.
The risk of infection is determined by the neutrophil counts12
in patients blood.
Low risk >0.5 109/l

High risk <0.2 109/l
Moderate riskBetween 0.2 to 0.5 109/l.
Prophylactic measures
Avoidance of areas of microbial contamination such as
hospitals, where antibiotic resistant organisms are common.
Use of topical antiseptic preparation to reduce the load
of nasal and oral bacteria.
Prophylactic antibiotic administration is not recommended
as it tends to alter the microbial flora to resistant organism.
With high dosage of corticosteroids, Candida albicans
infection is common, so concurrent oral administration of
a nonabsorbable anti-fungal agent should be done.
To reduce the load of these organisms in mouth and
gastrointestinal tract.
Treatment of infection and hemorrhage
Oral antibiotics are advised for minor episode of infection in
less severe neutropenic subjects, but intravenous broad spectrum
antibiotics are indicated in patients with severe neutropenia
to avoid overwhelming sepsis. Infection can worsen the degree
of thrombocytopenia and precipitate potentially fatal bleeding.
Repeated platelet transfusion over weeks or months may
lead to the development of isoantibodies to allogenic platelets
rendering random donor platelet transfusions ineffective.
Avoid use of non-steroidal anti-inflammatory drugs as they
may cause severe gastrointestinal bleeding.
ii. Blood Transfusion
Management of aplastic anemia in pregnancy includes maternal
hematological support with blood products and stimulation
of hematopoiesis. For maximal fetal oxygenation, hemoglobin

should be maintained above 8 gm/dl during pregnancy.10, 11
In severe anemia, there may be fetal growth restriction or fetal
death. Therefore, red cell transfusions should be administered
to maintain hematocrit of 20 for adequate fetal growth.
When platelet counts are less than 20 103/L, there is
an increased risk of spontaneous hemorrhage, so platelets
should be administered 10, 11 and women should be delivered
vaginally. Judicious use of blood products is essential
In presence of bleeding, blood donated less than 24 hours
old should be transfused as it contains functionally effective
platelets and coagulation factors. When white blood cell count
is reduced there is an increased risk of infections, especially
chorioamnionitis which can be fatal. It can also induce preterm
labor, thus affect perinatal outcome. White blood cell
transfusions are only indicated in documented cases of severe
infection.5, 10, 11
iii. Psychological and general support
Psychological support for the patient and family is very
important. Aplastic anemia is a rare disease in pregnancy and
requires careful explanation about its nature, potential
seriousness and prognosis.
Preferred route of delivery is still controversial. To minimize
the risk of complications, some authors advise routine vaginal
delivery. If straining and stress during labor leads to intracranial
hemorrhage in mother or if uncontrollable external blood loss
is present the fetus should be delivered by cesarean section
with enough units of blood in hand.
After reviewing the literature which included 41 patients,

Fleming concluded that, if complications of pancytopenia could
be controlled, pregnancy with aplastic anemia should be allowed
to proceed to term preferably for vaginal delivery. However,
with a deteriorating hematological picture and life-endangering
hemorrhage or repeated infections, termination of pregnancy
should be performed with the hope of hematological
improvement in the puerperium.
C. Measures to accelerate recovery from pancytopenia
i. Immunosuppressive agents
Corticosteroids and androgens: Androgens are contra-
indicated during pregnancy as there is a risk of virilization
of female fetus. 14 Very high-doses of glucocorticoid
(prednisolone 10-20 mg/kg)11,12 can induce adverse responses
in a small proportion of patients with aplastic anemia.
Cyclosporine: Immunosuppressive therapy with cyclosporine
has been found to be a suitable alternative to bone
marrow transplant. In patients who were refractory to
antilymphocyte globulin treatment 14, cyclosporine has been
observed to produce 50% response. When used as a first-
line therapy in nonpregnant patients cyclosporine is
comparable to ATG, but there is paucity of data regarding
its use in pregnancy. Experience from pregnancy after organ
transplant shows that cyclosporine is not teratogenic.11,12,13
Though it is excreted in milk, the fetal growth and
development were found to be normal. Cyclosporine can
be combined with granulocyte-macrophage colony-
stimulating factor (GMCSF), but only a few reports regarding
its use during pregnancy are available. If a patient requires
blood transfusion or if the blood counts are falling rapidly
so that patient will soon require transfusion support,

cyclosporine 5 mg/kg/day orally is recommended so that
levels between 150 to 250 u/l are maintained. Response
to cyclosporine is delayed and is usually evident between
6 to 12 weeks.12
Antilymphocyte globulin (ALG): A 5-year survival of up to
61% has been reported with use of ATG or ALG in patients
with aplastic anemia. ALG use is reported in one case only
without any effect on the fetus, so more clinical trials are needed
before it can be declared safe for use during pregnancy.5, 12
These drugs may cause thrombocytopenia therefore; platelet
transfusions should precede their administration. If a
satisfactory hemoglobin level and platelet count is not achieved
with corticosteroids, then immunosuppressive therapy with ALG
should be considered
ii. Bone Marrow Transplantation
In nonpregnant patients with severe aplastic anemia, allogenic
bone marrow transplant from a (HLA) human leukocyte
antigen-matched sibling is the treatment of choice and has
resulted in the long-term survival of 75%.
Bone marrow transplantation can only be performed when
a matching donor is available. For patients lacking a suitable
donor, pregnancy complicated by aplastic anemia represents
a management challenge. Sanders, et al reviewed outcome
in 41 women with 72 pregnancies following bone marrow
transplantation, 52 resulted in live births, however almost half
of these pregnancies were complicated by preterm deliveries
or hypertension. However, during pregnancy, bone marrow
transplantation is contraindicated, as it requires the use of high-
dose immunosuppressive drugs.
iii. Growth Factors

Hemopoietic growth factor such as Human Granulocyte, Colony
Stimulating Factor (G-CSF) is glycoprotein that regulates the
proliferation and differentiation of hematopoietic stem cells
and increases the proliferation and migration of neutrophils.
Treatment with G-CSF has been used extensively to combat
neutropenia in patients with aplastic anemia as it has the
potential to restore a normal neutrophil count and cause partial
marrow recovery in an aplastic marrow. Ohba, et al reported
a case in which G-CSF was used and it was found to be
beneficial and safe in pregnancy and without any serious adverse
effects in either mother or baby.3
It is likely that the patient had some residual normal
hematopoietic progenitor cells and therefore, responded well
to G-CSF therapy. Patients with no neutrophils or very severe
neutropenia do not respond to growth factors. A modest,
transient rise in leukocyte count with eosinophilia has been
noted, but it falls to baseline levels after discontinuation of
the factor.
G-CSF when used in rats was found to cross the placenta
and induce peripheral neutrophilia as well as neutrophil storage
in the marrow and spleen of fetal and newborn rats. In humans,
transplacental passage of G-CSF was found to be in sufficient
quantities so as to elicit biologic effects in the fetus.
In the single case reported in literature, where a patient
with severe congenital neutropenia received G-CSF before
conception and throughout her pregnancy without any adverse
effects.3 GM-CSF may also be used in cases of severe infection.
Deka et al used cyclosporine and GM-CSF in 1 case of severe
aplastic anemia.11 This fetus developed intestinal gangrene
which could not be attributed to the use of these drugs.
Advances in therapy
Advances in cytokine therapy combined with close interdiscip-
linary collaboration have resulted in the development of a
therapeutic regimen as well as conventional transfusion support
and administration of immunosuppressive agents. This
treatment is expected to increasingly contribute to successful
outcomes for pregnant women with aplastic anemia. Finally
it is essential that the patient and their blood counts are
monitored frequently throughout pregnancy and very close
liaison of the obstetric team and hematologist is essential.
PROGNOSIS
Maternal mortality varies from 20 to 60%, depending on the
severity of the disease and the standard of care available. The
outcome of pregnancy and maternal survival were observed
to be better in women who had pre-existing aplastic anemia
before conception as compared to those in whom it developed
during the course of pregnancy.
The prognosis of pregnancy-associated aplastic anemia has
improved significantly. Survival rates for mother and baby have
increased from 43 and 36% respectively, to 81 and 76%,
respectively.5 Hemoglobin level if normal at the time of
presentation is associated with a favorable prognosis only if
aplastic anemia is diagnosed during the first 5 months. However,
white cell counts and platelets do not affect pregnancy outcome.
If diagnosed before pregnancy patients have a better prognosis
than during pregnancy. 90% of the reported mortalities are due
to hemorrhage and sepsis.
After BMT there may be toxicity from the conditioning
regimen and graft versus host disease (GVHD).
With immunosuppression about one-third of patients do

not respond. For the responders, relapse and late- onset clonal
disease, such as (PNH), (MDS) and leukemia may occur.
Some patients who had recovered from aplastic anemia
have been reported to relapse in an unpredictable manner during
subsequent pregnancies.
PATIENT EDUCATION
Maintain good hygiene so as to reduce the risks of infection.
Precaution should be taken to avoid community acquired
infection especially during the period when patient is having
neutropenia.
Reduce activities that can cause trauma especially during
periods of thrombocytopenia.
Emphasis on compliance of therapy.
Dietary adviseAvoid raw meats, dairy products, fruits
and vegetables which can be colonized with the bacteria,
fungus, or molds especially in neutropenics or in those
patients who are on immunosuppressive therapy.10-12
Diet with salt restriction is advised during therapy with
steroids or cyclosporine.
CONCLUSION
Thus, the etiology of aplastic anemia in pregnancy still remains
an enigma and whether pregnancy is a causative agent remains
controversial. Whatever the etiology, the consequences of
aplastic anemia complicating pregnancy can be grave.
Hemorrhage and sepsis are responsible for more than 90%
of the reported mortalities.4, 5, 8
Management strategy depends upon the gestational age

and severity of the disease. Those who present with SAA in
early gestation can undergo therapeutic abortion while those
presenting later in pregnancy should be managed with
supportive measures (transfusion) until delivery. However, if
delivery is not possible for several months, Aitchison et al have
suggested that (ALG) antilymphocyte globulin may be safely
given in pregnancy.
Management of aplastic anemia is debatable because the
role and safety of treatment of aplastic anemia during pregnancy
involving bone marrow transplant or immunosuppressive
therapy, such as cyclosporine, steroids, or antithymocyte globulin
(ATG) is not known. Over the past few decades, great advances
have been made in the treatment of aplastic anemia in
nonpregnant patients. However role of therapy with these agents
in pregnancy remains to be determined.
After delivery, splenectomy, treatment with cyclosporine,
antilymphocyte globulin (ALG) or ATG, infusion of hema-
topoietic cells derived from fetal liver, and allogenic bone marrow
transplantation have been tried, but it is difficult to ascertain
their effectiveness, either because of the rarity of the association
between the 2 entities or the small number of cases recorded.11
Thereafter, they may be offered bone marrow transplantation
or ALG. A combined effort of obstetricians and hematologists
can lead to a successful pregnancy outcome in some patients.
KEY POINTS
Aplastic anemia is characterized by peripheral pancy-
topenia and marrow hypoplasia.
Pregnancy with aplastic anemia is very rare and has high
maternal and fetal morbidity and mortality.
Etiology of aplastic anemia is idiopathic while patho-
genesis is multi-factorial.
The onset of the disease is insidious; symptoms are
related to decrease in the production of hemopoeitic cells.
Physical signs result from anemia, neutropenia and
thrombocyto-penia.
Diagnosis is confirmed by bone marrow examination. The
International aplastic anemia study group classified the
disease into three groups depending upon the severity.
In SAA bone marrow cellularity is <25% or 25 to 50% with
< 30% residual hemopoeitic cells and any two of the
following
- neutrophils < 0.5 x 109 /l, platelets < 20 x 109 /l and
reticulocytes < 1% .
One-third of the patients have spontaneous improvement
after delivery.
Fetal complications may be intrauterine growth restriction,
intrauterine death, fetal thrombocytopenia and fetal
malformations.
Management depends upon gestational age, severity of
the disease and treatment given earlier.
Identification and elimination of the exposure to causative
agents, supportive care to accelerate recovery from
pancytopenia should be considered. Preferred route of
delivery is vaginal but if straining and stress during labor
leads to intracranial hemorrhage or uncontrollable
external blood loss then cesarean section with enough
units of blood in hand is advisable.
Survival rate for mother and baby have increased from
43 and 36% to 81% and 76% respectively with advances
in treatment.
REFERENCES
1. Ang HY, Ho HK, Linn YC. A case of aplastic anemia in
pregnancy. J Obstet Gynaecol 1999;39:102-5.
2. Young NS, Maciejewski J. The pathophysiology of acquired
aplastic anemia. N Eng J Med 1997;336:1365-72.
3. Aitchison RG, Marsh JC, Hows JM. Pregnancy associated
Aplastic anemia, a report of 5 cases and review of current
management. Br J Hematol 1989;73:541-5.
4. Bourantas K, Makrydimas G et al . Aplastic anemia: Report
of a case with recurrent episodes in consecutive pregnancy.J
Reprod Med 1997;42:672-74.
5. Saif MW. Aplastic anemia in pregnancy; An association or
a co-incidence? Resident and Staff Physician 2003,vol 49
6. Stewart FM. Hypoplastic /Aplastic anaemia. The Medical
Clinics of North America 1992;76:684.
7. Bakhshi S, Baynes R.Aplastic anemia. Available at file://D:\e
Medicine/topic 162 htm- Aplastic anemia. Article by Bakhshi
S. last updated jan 6, 2006.
8. Fleming AF. Hypoplastic anemia in pregnancy. J Obstet
Gynaecol Br Commonw 1968;75:138-41.
9. Camitta BM, Storb R, Thomas ED. Aplastic anemia:
Pathogenesis, diagnosis, treatment and prognosis. N Eng J
Med 1982;306:645-52.
10. Firkin F, Chesterman C et al. Pancytopenia; Aplastic anemia
in Firkin F, Chesterman C(eds) De Gruchys Clinical
hematology in medical practice. 5th ed. published by
Blackwell Science 1999;119-36.
11. Young SN. Aplastic anemia and myelodysplasia and related
bone marrow failure syndromes in Kasper D, Braunwald E,
Fauci A, Hauser S (eds) Harrisons principles of Internal
Medicine. 16 th edn. published by Mac Graw Hil
2005;1:617-26.
12. Marsh JCW, Ball SE et al .British Committee for Standards
in Hematology (BSCH) Guidelines for the diagnosis and
management of acquired apastic anemia. Br J Hemat
2003;123:782.
13. Deka D, Malhotra N, Sinha A et al. Pregnancy associated

aplastic anemia: maternal and fetal outcome. J Obstet
Gynaecol Res 2003;29:67-72.
14. Tichelli A, Socie G, Marsh J et al. Outcome of pregnancy and
disease course among women with aplastic anemia treated
with immunosuppression. An Intern Med 2002;137:164-72.
15. Kesin A, Soysal S et al. Aplastic anaemia and pregnancy. Case
report. Hema 2001;4(1):41-4.
16. Sanders JE, Hawlay J, Lavy W. Pregnancy following high
dose cyclophosphamide with or without high dose
busulphan or total body irradiation and bone marrow
transplantation Blood 1996;87:3045.
CHAPTER 10
Severe Anemia
in Pregnancy
Reena Yadav
Introduction
Definition
Causes of severe anemia
Prevalence
Clinical manifestation
Effects on mother
Effects on fetus
Investigations
Treatment
Key points
INTRODUCTION
Anemia is one of the most common disorder in pregnancy.
Severe anemia is associated with increased maternal and
perinatal morbidity and mortality. According to WHO, anemia
contributes to 40% of maternal deaths in third world countries.1
DEFINITION
Anemia is defined as reduction in the circulating red cell mass
and corresponding decrease in hemoglobin mass and oxygen
carrying capacity of blood. According to WHO, a hemoglobin
concentration of less than 11 gm/dl constitute anemia in
pregnancy and anemia is considered severe when hemoglobin
falls below 7 gm/dl2. However some of the studies have taken
hemoglobin less than 7 gm/dl,2,3 others less than 6.5 gm/dl4
or less than 6 gm/dl5 as severe anemia.
SEVERE ANEMIA IN PREGNANCY 187
CAUSES OF SEVERE ANEMIA

Most common cause in cases of severe anemia in pregnancy
is iron and folate deficiency. Other causes are acute blood
loss, hemolytic anemia, and aplastic anemia. Chronic infections
and chronic systemic diseases can lead to chronic severe anemia.
PREVALENCE
Estimate of the prevalence of anemia depends on the method
used for assessing hemoglobin concentration and the cutoff
point applied. Cutoff point is different for different popula-
tions.6,7 Prevalence of anemia as shown in various studies varies
from 40 to 80%.2,3,8 Severe anemia in pregnancy is seen in
5 to 10%.5,9
CLINICAL MANIFESTATION
Manifestation of severe anemia depend on many factors like
the reduction in oxygen carrying capacity of blood, the degree
of change in total blood volume, the rate at which these changes
occur, the capacity of cardiovascular and pulmonary system
to compensate for anemia and associated manifestation of
the underlying disorder that resulted in anemia.
Patients with severe anemia are mostly symptomatic. In
rapidly developing anemia as in acute blood loss, signs and
symptoms like tachycardia, hypotension and syncope are
because of uncompensated hypovolumia rather than anemia.
Slowly developing anemia may initially be asymptomatic but
with increase in severity, signs and symptoms appear consequent
to tissue hypoxia and compensatory mechanisms.
In severe anemia, there is selective perfusion to vital organs

with resultant vasoconstriction and oxygen deprivation in the
subcutaneous tissue. This result in characteristic pallor of the
skin and mucous membrane, nail beds, palmer creases,
platynychia.10
In order to maintain oxygen supply cardiac output increases,
causing palpitation, shortness of breath, exertional dyspnea
and orthopnea, increased capillary and arterial pulsation with
wide pulse pressure. The apex beat is forceful, soft systolic
murmurs and bruits are apparent due to increased flow and
turbulence. Cardiac decompensation usually occurs in women
with hemoglobin at or below 5 gm/dl.Lack of oxygenation leads
to anerobic metabolism of lactic acid which further leads to
cardiac failure, pulmonary edema, and even death.
Headache, light headedness, faintness, lethargy, easy
fatigability, night cramps are because of hypoxia. Atrophy of
the papillae of the tongue might indicate folate deficiency or
iron deficiency. Abnormal gait and other sensory changes are
seen in cobalamine deficiency. Angular stomatitis develops in
iron deficiency.
Increased bone marrow activity in response to increased
erythropoietin can result in sternal tenderness, diffuse bone
aches.10 Hepatosplenomegaly may be seen in infections like
malaria and in hemolytic anemias.
EFFECTS ON MOTHER
The etiology of anemia is important in evaluating its effects
on pregnancy.
As far as obstetric complications are concerned, there are
variable and contradictory reports in literature. Earlier studies
reported an increase in incidence of abruptio placentae but
later reports failed to confirm it.11 Studies published recently

have again reported increased incidence of abruption.4,12
Various studies showed an increase in the incidence of
preeclampsia (17-32%) in severe anemia.4,8.12,13 There is
significant increase in incidence of severe preeclampsia in patients
with sickle cell disease due to blockage of small vessels in vital
target organs.14 Preterm labor is an important complication
of severe anemia.4,12,15,16,17
Occurrence of infections is much more frequent including
urinary tract infections and puerperal sepsis.8,12,13 Immune
suppression due to severe anemia increases chances of infection
and morbidity related to it. Kadyaov et al have provided evidence
that severe anemia influences placental vascularization by
altering angiogenesis.18 Increased incidence of postpartum
hemorrage4,12 and thromboembolism have also been seen in
severe anemia.19
A severely anemic patient is more likely to have cardiac
failure8,12 especially in third trimester, in labor, immediately
after delivery and early in puerperium. Cardiac failure is due
to the added strain of increased cardiac output in the presence
of hypoxic cardiac muscle. The various causes of maternal
death due to severe anemia in pregnancy are cardiac failure,
cerebral anoxia, sepsis, and thromboembolism.
EFFECTS ON FETUS
The opinion regarding the adverse effects of severe anemia
on fetus is controversial.20 Placental hypertrophy accompanies
maternal anemia and provides for increased oxygen extraction
by the fetus to compensate for decrease in hemoglobin.
However, severe anemia is associated with poor perinatal
outcome. There is an increase in incidence of spontaneous
abortion,21 prematurity,4,12,15,16,17 fetal growth restriction3, 12,22

and fetal death.12,23 Infants born to severely anemic mother
are more likely to develop anemia in early infancy and are
more susceptible to infections.9
INVESTIGATIONS
Hemoglobin and hematocrit is done to identify the severity
of anemia and Peripheral blood smear establishes the type
and cause of severe anemia. Red blood cell indices will further
classify anemia. Reticulocyte count: Normally 1 to 2% of red
blood cells are reticulocytes. In anemia there is an increase
in reticulocyte count which implies a normal bone marrow.
In a normal patient, reticulocyte production can increase two
to three times in response to a drop in hemotocrit to 30%
and five to six times in patients with chronic hemolytic
anemias.Thus a reticulocyte response to anemia shows
appropriate erythropoietin release, a normal functioning marrow
and sufficient iron to increase production.10
Other investigations which are indicated for work up of
severe anemia are
Stool examination for ova, cysts and occult blood. Urine
examination for proteinuria, casts, pus cells, RBCs and culture
sensitivity for bacteriuria. Kidney function tests to rule out chronic
renal disease which may be responsible for decreased
erythropoietin production and consequently for anemia.10
Serum Proteins to rule out hypoproteinemia.
Serum bilirubin and LDH for any evidence of hemolysis.
Radiography imaging of chest after shielding abdomen is
indicated in congestive cardiac failure and when chronic lung
infection is suspected. Bone marrow aspirate or biopsy is an
important diagnostic work up in patients with refractory anemia

and in aplastic anemia.
Other specific investigation like iron studies, serum folate,
serum B12, Hemoglobin electrophoresis, etc are only done
according to suspected specific type of anemia.
TREATMENT
All patient of severe anemia in pregnancy should be hospitalized.
A careful history, physical examination and appropriate
investigations should be done. Treatment should be initiated
depending on the general condition of the woman. Irrespective
of period of gestation, in a woman with severe anemia with
clinically significant signs and symptoms, blood transfusion is
recommended. However, most asymptomatic pregnant women
in the last four weeks of pregnancy are recommended blood
transfusion in order to increase their oxygen carrying capacity
so as to with stand the strain of labor. Transfusion is not indicated
for anemia in patients who are well compensated and away
from term.In such cases treatment specific to the cause and

type of anemia should be promptly started.
Aim of blood transfusion is to increase red cell mass and
consequently to increase oxygen carrying capacity while restoring
or maintaining blood volume. The decision to transfuse blood
should be made after careful consideration of the cause,
physiological adjustment to anemia and the patients
hemodynamic status.
TYPE OF BLOOD TO BE TRANSFUSED

Blood transfused should be properly typed and cross matched
and preferably should be fresh. With the development of
component therapy, packed cell transfusion has replaced whole
blood transfusion except in a few clinical situations. Whole
blood can be used to replace the loss of both red blood cells
and plasma volume as in case of a rapidly bleeding patient.
Pregnant woman with chronic severe anemia need only red
blood cells. They may respond adversely to whole blood
transfusion by developing pulmonary edema and heart failure.9
Each unit of red blood cells is expected to increase the
hemoglobin by 1 to 1.5 gm/dl and hemotocrit by 3 to 5%.
Number of packed cells unit to be transfused is determined
by clinical assessment and response to transfusion. The increase
in hemoglobin and hemotocrit become evident more quickly
with red cells transfusion as compared to whole blood.24 Red
blood cells should be transfused slowly under diuretic cover
in a decompensated patient or in congestive cardiac failure.
Preferably not more than one unit should be transfused in
24 hours. Diuretics helps in reducing blood volume and there
by allow the intravascular compartment to accommodate the
added red cells with out causing circulatory over load.
Role of Exchange Transfusion

Exchange transfusion has been used in cases of severely anemia
patients with congestive cardiac failure in pregnancy and when
hematocrit falls below 13%. It is said to be an effective way
to raise hemoglobin concentration with out causing circulatory
overload. Partial exchange transfusion of blood keeping negative
balance is recommended. There are not many reports in
literature on exchange transfusion in severely anemic pregnant
woman. Method of exchange transfusion has been described
mostly in transfusion therapy for sickle cell anemia.
Fresh packed cells(less than three days old) should be used
in exchange transfusion. A complete cross match should be
performed .Blood should be warmed to a temperature of 35C

to 37C. Volume of packed cell transfused is based on the
hematocrit of the packed cells, red cell mass and hemoglobin
of the patient. The desired final hemoglobin level, patients
initial hemocrit and blood volume will determine the volume
of whole blood that needs to be removed. The exchange can
be done using one or two intravenous sites by removing and
transfusing blood adjusted to total blood volume. Initially
250 cc of packed cells are exchanged with 500 cc of whole
blood. Subsequently more packed cell can be exchanged with
whole blood depending upon the need and condition of the
patient.25 On an average 750 to 1000 cc packed cells can
be exchanged with 1500 cc of whole blood.26 The method
is said to be well tolerated and resulted in significant reduction
in maternal mortality. However, with limited use of this
procedure, the competence of physicians for carrying out
exchange transfusion in adults has reduced. This treatment
modality can be used more frequently in referral centers.
Complications of blood transfusion include premature labor,
transfusion reactions, exposure to infections, volume overload
causing cardiac failure.
MANAGEMENT OF WELL COMPENSATED

SEVERELY ANEMIC PATIENT IN LABOR
Induction of labor in patients with severe anemia should be
avoided. Most patients go in to labor spontaneously. In the
event of a preterm onset of labor, steroids should be given
for fetal lung maturity. Tocolysis with betamimetics is
contraindicated .The patient is nursed in propped up position.
Oxygen is kept ready by the bed side and administered
intermittently. Prophylactic antibiotics are started. Adequate

pain relief should be provided. Adequate blood is kept cross
matched and transfused under diuretic cover. Intensive
monitoring of the mother and fetus through out labor is
important. A pulse rate of 100/minute and respiratory rate of
24/minute are early signs of cardiac embarrassment. Periodic
auscultation of lungs for basal crepts should be done. Patient
should not be allowed to bear down. The second stage of
labor can be cut short by use of outlet forceps or vacuum.
Active management of third stage is indicated. Intravenous
fluid is restricted to 15 to 30 drops per minute and concentrated
oxytocin (20 units in 500 cc RL) is administered.
MANAGEMENT OF PATIENTS WITH SEVERE

ANEMIA IN LABOR WITH CARDIAC FAILURE
These patients should be managed jointly by the obstetrician
and the physician. Even if the fetus is severely distressed, cardiac
failure must be treated first as the mother will be compromised
if delivery is effected prior to therapy. Treatment includes prop-
ped up position, sedation with morphine, oxygen by mask,
diuretics and antibiotic prophylaxis and digitalization if required.
Packed cells transfusion should be given under diuretic cover.
Intravenous fluid should be avoided in order to prevent fluid
over load. Intensive monitoring of vitals, periodic auscultation
of chest for basal rales should be maintained through out labor.
Monitor progress of labor and ensure adequate pain
relief.Pervaginal examination should be kept to minimum and
strict asepsis is maintained. Artificial rupture of membranes
is to be avoided. Vaginal delivery is preferred unless there is
an obstetrical reason for caesarean section.
After full dilatation of cervix, forceps or vacuum extraction

is indicated to cut short second stage, so as to avoid further
strain on an already compromised pregnant woman. Injection
methergin should be avoided in a patient of severe anemia
with heart failure. Intravenous diuretics (Injection frusemide
40 mg) should be given after the delivery of the placenta. The
patients with severe anemia do not tolerate the blood loss well.
The normal blood loss in vaginal delivery amounts to
postpartum hemorrhage in severely anemic patients. One has
to be very vigilant and should treat PPH energetically with
all the usual measures like concentrated oxytocin infusion and
packed cells transfusion as required.
DURING POST PARTUM PERIOD

Intensive monitoring is continued in postpartum period. Pulse,
blood pressure, respiratory rate, auscultation of lung bases and
bleeding pervaginum are checked periodically. Adequate rest
and measures to prevent sepsis are important. Antibiotics are
continued for seven days. Since these patients are at high risk
for thromboembolism, early ambulation is advised .Specific
therapy for anemia is continued. Breast feeding is not
contraindicated in patients with severe anemia. Patient should
avoid pregnancy for a minimum of next two years.
In severe anemia in pregnancy, appropriate and timely
treatment can save the life of a patient where as delayed and
inappropriate treatment may be life threatening.
KEY POINTS
Severe anemia is associated with increased maternal and
perinatal morbidity and mortality.
According to WHO anemia contributes to 40% of maternal
death in third world countries.
Prevalence of severe anemia in pregnancy is 5 to 10%
in India.
Various maternal complications of severe anemia are
cardiac failure, infections and thromboembolism. Increased
risk of preeclampsia, abruptio placentae, preterm labor
and postpartum hemorrhage is seen in severe anemia in
pregnancy.
The reported adverse effects on fetus are prematurity, fetal
growth restriction and intrauterine death.
All pregnant women with severe anemia should be admit-
ted.
Blood transfusion is recommended in symptomatic
severely anemic patients irrespective of period of gestation.
Aim of blood transfusion is to increase red cell mass and
consequently to increase oxygen carrying capacity.
Packed cell transfusion is recommended.
In labor, intensive monitoring of vital signs should be done
and prophylactic antibiotics and adequate pain relief are
given.
PPH should be treated energetically with all the usual
measures like concentrated oxytocin infusion and packed
cell transfusion.
Specific treatment for anemia is continued in post delivery
period for minimum of three months and pregnancy should
be avoided for a minimum of next two years.
REFERENCES
1. Viteri FE. The consequences of iron deficiency and anemia
in pregnancy. Adv Exp Med Biol 1994;352:127-39.
2. Meda N, Mandelbrot L, Cartoux B, et al. Anemia during
pregnancy in Burkina Faso, West Africa, 1995-1996:
prevalence and associated factors.Bulletein of WHO
1999;77(11):916-22.
3. Malhotra M, Sharma JB, Batra S, et al. Maternal and perinatal
outcome in varying degree of anemia. Int J Gynaecol Obstet
2002;79(2):93-100.
4. Anamika Awasthi, Thakur R, Dave A, Vanita Goyal. Maternal
and perinatal outcome in cases of moderate and severe
anemia. The J of Obst & Gynae of India 2001;51(6):62-5.
5. Khosla AH, Dahiya P, Dahiya K. Burden of chronic severe
anemia in obstetrics patients in rural north India. Indian J
Med Science 2002;56(5):222-4.
6. Stoltzfus RJ. Rethinking anemia surveillance. Lancet
1997;349:1764-6.
7. Yip R. Iron deficiency; contemporary scientific issues and
international programme issues. Journal of nutrition
1994;124:1479s-1490s.
8. ICMR.Evaluation of national nutritional anemia prophylaxis
programme. An ICMR task study ICMR, New Delhi 1989.
9. Williams MD, Whaky MS. Anemia in pregnancy; Review.
Medical clinics North America 1992;76(3):631-47.
10. Christopher ORG. Anemia.In Complication of pregnancy:
Fifth Ed, edited by W.R Cohen. Lippencott Williams &
Wilkins, Philadelphia 2000;367-87
11. Letsky E. Blood volume, hematinics, anemia. In: de Swiet
M(ed). Medical disorders in obstetrics practice, 4th edition
Oxford: Blackwell 2002;29-60.
12. Patra S, Pasrija S, Trivedi SS, Puri M. Maternal and perinatal
outcome in patients with severe anemia in pregnancy. Int J
Gynaecol Obstet 2005;91(2):164-5.
13. Lops VR, Hunter LP, Dixon LR. Anemia in Pregnancy. Am
Fam Physcian 1995;51:1189-97.
14. Cunningham FG, Gant NF, Kenneth JL. Hematological
disorders. In: Williams obstetrics 22nd edition, 2005;1143-
63.
15. Klebanoff MA, Shions PH, Selky JV, et al. Anemia and
spontaneous preterm birth. Am J Obstet Gynecol
1991;164:59-63.
16. Lieberman E, Ryan KJ, Morson RR, et al. Association of
maternal hematocrit with premature labor. Am J of Obstet
Gynecol 1988;159:107-14.
17. Lieberman E, Ryan KJ, Morson RR, et al. Risk factors for racial
differences in the rate of premature birth N Engl J Med
1987;317:743-8.
18. Kadyrov M, Kosanke G, Kinkdon J, Kaufmann P. Increased
foetoplacental angiogenesis during first trimester in anemia.
Lancet 1998;352:1747-9.
19. Joanne E, Ian AG.Thrombo-embolism in pregnancy:
problems and prevention and treatment. In: Progress in
Obstet & Gynaecol, Ed John Studd, Churchill Livingstone
2003;15:57-74.
20. Klebanoff MA, Shiono PH, Berendes HW, et al. Facts and
artifacts about anemia and preterm delivery. JAMA
1989;162:511-4.
21. Pietrzik K, Prinz R, Reusch K, et al. Folate status and pregnancy
outcomes. Am NY Acad science 1992;66:371-3.
22. Baskar DJP, Bull AR, Osmond C, Simmonds SJ. Fetal and
placental size and risk of hypertension in adult life. BMJ
1990;301:259-63.
23. Murphy JE, ORiordan J, Newcombe RG, et al. Relation of
hemoglobin levels in first and second trimester to outcome
of pregnancy Lancet 1986;1:992-5.
24. Snyder El (ed.): Blood transfusion therapy: A physicians
hand book 2nd Ed .American associations of blood bank,
Arlington VA1987.
25. Alan R Cohen, Marie B Martin, Jeffery H. A modified
transfusion programme for prevention of stroke in sickle cell
anemia by American society of hematology. Blood
1992;79(7)1657-61.
26. Beatrice Gee. Transfusion Therapy. In: Sickle cell information
centre guidelines. Ed. James Eckman and Allan Platt. Atlanta-
Georgia. ablatt@emory.edu. 2nd Edition, March 2002{from
internet}.
APPENDIX*
Hematology Reference Values in Normal

Adult (Female)
Test Conventional Units

Hemoglobin 12.3 15.3 gm%
Hematocrit 36 45
Red cell count 4.5 5.1 million microliter
White cell count 4.4 11.3 106 /l
TLC 4400 11300
MCV 80 96 fl
MCH 27.5 33.2 pg
MCHC 33.4 35.5 gm/dl
Platelet count 150 450 103/mm3
Reticulocyte count 0.5 2.5%
Serum Iron 60 150 g/dl
TIBC 250 435 g/dl
Ferritin 15 150 ng/ml
Serum B12 160 950 pg/ml
Serum folate 2 25 ng/ml
Red cell folate 140 640 ng/ml
Hemoglobin A2 1.5 3.5%
Hemoglobin F < 2%
*Perkins SL. Normal blood and bone marrow values in humans.

In Greer JP, Foerster J, Lukens JN, Rodgers GM, et al (Eds)
Wintrobes Clinical Hematology 11th ed. Lippincott-Willams and
Wilkins, 2004.
INDEX
A eradication of anemia 8
Acquired hemolytic anemia prevalence 2
120 preventive strategies 8
immune hemolytic food fortification 11
anemia 120 genetically modified
alloimmune hemolytic foods 12
anemia 121 improving diet 9
autoimmune hemolytic iron and folic acid
anemia 121 supplementation 10
mechanical hemolytic multiple micronutrient
anemia 122 supplement 11
causes 122 other measures 13
drug-induced strategies to eliminate
hemolysis 127 severe anemia 13
Anemia in pregnancy 1 Aplastic anemia 159
anemia common in clinical features 165
pregnancy 5 complications 172
chronic and acute differential diagnosis 167
blood loss 7 etiology 161
deficient intake of iron management 172
and other hemato- pathogenesis 162
poietic factors 6 imbalance of factors
deficient iron stores 6 influencing
increased demands of erythropoiesis 162
iron in pregnancy 5 marrow dysfunction
infections 7 during pregnancy
other causes of 163
anemia 7 production of an
controversies and inhibitor or absence
concerns 14 of a stimulator of
high hemoglobin 15 hematopoiesis 163
effect of anemia on temporal relationship
obstetric outcome 4 163
pathophysiology 164 classification 111

patient education 180 due to extracorpuscular
prognosis 179 (extrinsic) defect 111
workup of a patient 167 due to intracorpuscular
lab studies 167 (intrinsic) defect 111
history and examination
112
D laboratory investigations
Drug-induced hemolytic 113
anemia 127 complete blood exami-
nation with peripheral
E smear 113
Erythropoiesis 21 pathophysiology 109
erythroid precursors 23 I
stages of normoblastic Inherited hemolytic anemia
differentiation 23 116
erythroid progenitors 22 hemolytic anemia caused
burst-forming unit by inherited erythrocyte
erythroid 23
defects 116
colony-forming unit
glucose-6-phosphate
erythroid 23
dehydrogenase
deficiency 118
G membrane defects of
Genetic control of red blood cells 116
hemoglobin synthesis 84 red cell enzyme
deficiencies 117
H Iron deficiency anemia 45
Hematopoiesis 19 clinical features 49
regulation of drug treatment 53
hematopoiesis 20 calculation of iron
Hemolytic anemia 107 requirement 59
biochemical investigations newer iron preparations
114 54
blood tests 114 oral iron therapy 53
imaging studies 115 parenteral iron therapy
specific tests 115 57
urinary tests 115 preparations 58
INDEX 205
technique of giving lymphocyte 31
parenteral iron 60 plasma cell 31
therapeutic iron prolymphocyte 31
therapy 56 monocytemacrophage
etiopathogenesis 47 series 29
blood loss 48 monoblast 29
dietary deficiency 47 monocyte 29
increased demand of promonocyte 29
iron 48 stages of myelopoiesis 25
infections 48 band forms 28
poor absorption 48 metamyelocyte 28
laboratory diagnosis 49 neutrophil granule
management 51 development 28
myeloblast 27
M myelocyte 27
promyelocyte 27
Management of patients with
segmented
severe anemia in labor with
granulocytes 28
cardiac failure 195
Management of well compen-
sated severely anemic P
patient in labor 194 Paroxysmal nocturnal
Megakaryopoiesis 31 hemoglobinuria 128
Megaloblastic anemia 67 Pregnancy-induced
diagnosis 73 hemolytic anemia 129
clinical features 73
differential diagnosis 74 R
laboratory work-up 75 Recent advances in the
morphological changes management of
76 thalassemias 101
etiology 70
folic acid deficiency 71
incidence 68 S
pathogenesis 69 Severe anemia 185
prevention 78 causes 187
treatment 77 clinical manifestation 187
Myelopoiesis 25 effects on fetus 189
lymphopoiesis 30 effects on mother 188
lymphoblast 30 investigations 190
prevalence 187 silent carrier state and

treatment 191 pregnancy 90
Sickle cell anemia 137 thalassemia trait and
antepartum care 146 pregnancy 90
intrapartum thalassemia and
management 148 pregnancy 89
postpartum thalassemia major 89
management 149 thalassemia minor 89
prenatal diagnosis 147 management of pregnancy
transfusion therapy in with thalassemia 96
pregnancy 150 thalassemia 96
contraceptives 154 thalassemia major 98
diagnosis and laboratory thalassemia minor 98
findings 142 pathophysiology 86
effect of pregnancy on
SCD 144 W
effect of SCD on Work-up of a pregnant woman
pregnancy 144 with anemia 33
management 146 clinical diagnosis of anemia
35
neonatal screening 153
clinical examination 37
pathogenesis of sickling
history 35
140 hematological diagnosis
prevalence and geographic 38
distribution 140 hemoglobin estimation
Structure and synthesis of 38
hemoglobin 83 peripheral blood smear
examination 39
T other investigations 39
Thalassemia 81 bone marrow
examination 43
classification 85
free erythropoietin
diagnosis 91
protoporphyrins 41
investigations 92 Nestroft test 41
effect of thalassemia on serum ferritin 41
pregnancy 88 serum iron 41
Hb Barts disease and serum iron binding
pregnancy 91 capacity 41
HbH disease and serum transferrin
pregnancy 91 receptors 41

Anemia in Pregnancy

Încărcat de

Informații document

Drepturi de autor

Formate disponibile

Partajați acest document

Partajați sau inserați document

Opțiuni de partajare

Vi se pare util acest document?

Este necorespunzător acest conținut?

Drepturi de autor:

Formate disponibile

Anemia in Pregnancy

Încărcat de

Drepturi de autor:

Formate disponibile

Anemia

JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD

Abha Singh Manju Puri

Shashi Narayanan Usha Gupta

Anemia is recognized as a major public health problem

edition is most welcome in the field of Obstetrics and

Anemia is the commonest medical disorder in pregnancy, with

1. Anemia in Pregnancy: Magnitude of Problem ........ 1

3. The Work-up of a Pregnant Woman with Anemia 33

4. Iron Deficiency Anemia of Pregnancy ................... 45

5. Megaloblastic Anemia in Pregnancy ..................... 67

6. Thalassemia in Pregnancy .................................... 81

7. Hemolytic Anemia in Pregnancy ......................... 107

8. Sickle Cell Anemia in Pregnancy ....................... 137

9. Aplastic Anemia in Pregnancy ............................ 159

10. Severe Anemia in Pregnancy .............................. 185

Appendix ......................................................................... 201

Index ............................................................................... 203

Health Survey-2 in 1998 to 99 shows that 54% of women

Fig. 1.1: Hemoglobin levels in 10,267 antenatal women

EFFECT OF ANEMIA ON OBSTETRIC OUTCOME

be associated with preterm and low birth weight babies. A

WHAT CONSTITUTES ANEMIA?

WHY IS ANEMIA COMMON IN PREGNANCY?

INCREASED DEMANDS OF IRON IN PREGNANCY

850 mg of extra iron is required during pregnancy. Diet alone

DEFICIENT IRON STORES

DEFICIENT INTAKE OF IRON AND OTHER

rare cause of anemia during pregnancy, is sometimes seen in

CHRONIC AND ACUTE BLOOD LOSS

OTHER CAUSES OF ANEMIA

infections like hookworm and malaria and iron folic acid

IRON AND FOLIC ACID SUPPLEMENTATION

the adolescents has been included in anemia prevention

MULTIPLE MICRONUTRIENT SUPPLEMENT

Rice in the Philippines is fortified with a standard ferrous

GENETICALLY MODIFIED FOODS

Benefits and risks, if any of biomanipulations are being eva-

STRATEGIES TO ELIMINATE SEVERE ANEMIA

Although all efforts must be made to detect and intensively

CONTROVERSIES AND CONCERNS

Some of the earlier studies questioned the routine administration

with moderately increased iron stores18 and increased ferritin

15. Guidotti RJ. Anemia in pregnancy in developing countries.

are being discovered everyday. The receptors for these cytokines

Erythropoietin is the major hormone regulating red cell

been recognized. Under the influence of EPO, these progenitors

Colony-forming Unit Erythroid

Burst-forming Unit Erythroid

Stages of Normoblastic Differentiation

cytoplasm. Prominent nucleoli may be present. At this stage,

that have been termed reticulum. The amount of reticulum

MYELOPOIESIS (Fig. 2.1)

Fig. 2.1: Myelopoiesis

to cytoplasm, fineness of nuclear chromatin, nuclear shape,

Neutrophil Granule Development

granules of the neutrophil lack peroxidase and sulphated

nuclear chromatin is delicate and nucleoli are not visible.

MEGAKARYOBLAST/ STAGE I MEGAKARYOCYTE

STAGE III/IV MEGAKARYOCYTE

Hb level should be maintained at or above 11 gm/dl in pregnancy

CLINICAL DIAGNOSIS OF ANEMIA

Age and parity of the patient are important as young

The obstetric record of abortions, repeated child births and