Clinical evaluation of severe anemia in pregnancy with special reference to macrocytic anemia


Dr Reva Tripathi, Department of Obstetrics and Gynaecology, Maulana Azad Medical College, New Delhi 110002, India. Email:


Aims:  Anemia in pregnancy has been almost synonymous with iron-deficiency anemia but there appears to be a changing trend with emerging evidence of macrocytic anemia. The aim of this study was to evaluate the clinical profile of patients having severe anemia in pregnancy.

Methods:  This study included all antenatal patients presenting with severe anemia (hemoglobin < 7 gm%) over a period of 2 years from January 2008 to December 2009 in the Department of Obstetrics and Gynaecology, Maulana Azad Medical College and Lok Nayak Hospital, New Delhi.

Results:  Although iron-deficiency anemia remains the most important cause of anemia (48.1%) there is also a high prevalence of macrocytic anemia (40%) amongst these cases of severe anemia in pregnancy. The maternal and fetal morbidity and mortality is higher in macrocytic anemia as compared to iron-deficiency anemia.

Conclusion:  There is an emerging trend of macrocytic anemia among antenatal patients with severe anemia. Both maternal and fetal morbidity appears to be higher in these cases. This has important implications in terms of diagnosis and therapy to optimize both maternal and perinatal outcomes. Once clinicians and health administrators recognize the magnitude of this problem it may be considered relevant to start public health interventions by way of requirement of appropriate food fortification.


Anemia is one of the most important public health problems leading to significant maternal and perinatal morbidity and mortality. The World Health Organization (WHO) reported an association of anemia in 64.4% of maternal deaths in India during 1992–1994.1 Pregnancy itself leads to anemia by causing a state of hydremic plethora. There is disproportionate increase of plasma volume as compared to red blood cell mass during pregnancy leading to apparent reduction of red blood cells, hemoglobin and hematocrit value. The dilution picture is normochromic and normocytic. This is so-called physiological anemia of pregnancy.

This physiological situation can be further complicated by acquired nutritional problems, which include iron, folic acid, vitamin B12 and protein deficiency. Anemia may also be consequent to other causative factors, namely hemolytic or hemorrhagic conditions, due to acute or chronic blood loss. Conventionally, iron-deficiency anemia has been synonymous with anemia of pregnancy and this has been well documented in literature and also in recent studies2,3 though other causes of anemia are also present. Of late, an increasing prevalence of macrocytic anemia was observed in our patients, which prompted this analysis.

Materials and Methods

The study was a retrospective observational study involving 185 pregnant women with severe anemia, that is, hemoglobin (Hb) < 7 gm%, who were admitted to the maternity ward during a period of 2 years from January 2008 to December 2009 in the Department of Obstetrics and Gynaecology, Maulana Azad Medical College and Lok Nayak Hospital, New Delhi. Case files of pregnant patients with severe anemia admitted to the antenatal ward of the Department of Obstetrics and Gynaecology were accessed from the medical record department of the hospital. These records were thoroughly reviewed to document relevant information pertaining to history, including details of dietary intake. Findings on general clinical and obstetric examination together with details of investigations performed and treatment given were also noted. All patients had peripheral smear examination to diagnose microcytic and macrocytic anemia. Macrocytic anemia was diagnosed in the presence of macrocytes, macro-valocytes and hypersegmented neutrophils in peripheral smear.4 All data was compiled and analyzed. The following clinical situations were specially noted:

  • • Dyspnea – New York Heart Association Grade 2 and more
  • • General anasarca – swelling all over the body
  • • Hypertension – Blood pressure >130/90 mmHg
  • • Hepatosplenomegaly – clinically palpable liver and spleen
  • • Decreased platelet count – below 100 000/mL
  • • Deranged liver function tests – serum bilirubin >1 mg%, serum glutamic oxaloacetic transaminase / serum glutamic pyruvic transaminase >40 U/mL, alkaline phosphatase – >400 U/mL
  • • Congestive heart failure – raised jugular venous pressure together with presence of fine crepitations at lung bases
  • • Postpartum hemorrhage – Blood loss >500 mL
  • • Prematurity – delivery prior to 37 weeks of gestation
  • • Low Apgar score at birth – <9 at 1 and 5 min.


A total of 185 patients with severe anemia (Hb < 7 gm%) were studied over a period of 2 years. They were divided into three groups based on peripheral smear report. Microcytic hypochromic anemia was most common (89 patients, 48.1%) but a significant number of patients were found to have macrocytic anemia (74 patients, 40%). Dimorphic anemia was present in only a small number of women amongst these cases of severe anemia (22 patients, 11.9%).

Of these 185 patients, 26 patients had very severe anemia, that is, Hb of less than 5 gm% at the time of presentation. In this subgroup of very severely anemic women, as many as 20 (76.9%) were found to have macrocytosis.

The patients presented in all trimesters but the majority of them presented late in gestation, at 28–36 weeks. Seventy-seven patients were given blood transfusions in view of severe anemia, as they were very advanced in pregnancy with no time to build their Hb by other methods prior to delivery. The other therapeutic modalities used in these patients included high-protein diet, parenteral and oral iron preparations, vitamin B12, vitamin C and folic acid supplementation along with antihelminthics.

Maternal complications were seen in the form of congestive heart failure and postpartum hemorrhage. There were three maternal deaths due to severe anemia. Fetal complications like prematurity and fetal growth restriction were associated with severe anemia. The incidence of these morbidities was higher in macrocytic anemia.

The clinical details of the patients are depicted in Table 1 and maternal and fetal outcomes are shown in Table 2. The P-values presented in the tables below relate to the comparison between microcytic and macrocytic anemia. The number of cases showing a dimorphic picture was relatively small and hence comparison with this did not result in any statistically significant differences.

Table 1.  Clinical presentation in relation to various types of anemia
 Microcytic anemiaDimorphic anemiaMacrocytic anemiaP-value*
[n = 89] number (%)[n = 22] number (%)[n = 74] number (%)
  • *

    P-value as calculated between microcytic and macrocytic anemia. Value < 0.05 is taken as significant.

Period of gestation at presentation    
 <28 weeks11 (12.3)3 (13.6)6 (8.1) 
 28–36 weeks59 (63.9)10 (45)44 (59.4) 
 >36 weeks19 (21.3)9 (40)24 (32.4)0.24
 Easy fatigability44 (49.4)8 (36.3)34 (45.9)0.66
 Dyspnea11 (12.3)3 (13.6)9 (12.1)
Diet pattern    
 Vegetarian68 (76.4)15 (68)67 (90.5) 
 Non-vegetarian (occasionally)21 (21.3)7 (18.1)7 (9.4)0.02
Physical examination    
 General anasarca20 (22.4)3 (13.6)33 (44.5)0.003
 Hypertension10 (11.2)2 (9)24 (32.4)0.03
 HepatosplenomegalyNil3 (13.6)25 (33.7)
Severity of anemia    
 Very severe anemia (<5 gm/dL)7 (7.9)1 (4.5)18 (24.3)0.004
Associated abnormal investigations    
 Decreased platelet count1 (1.1)3 (13.6)19 (25.6)0.00
 Deranged liver function tests3 (3.3)2 (9)15 (20.2)0.001
Table 2.  Maternal and fetal outcome in patients
 Microcytic anemiaDimorphic anemiaMacrocytic anemiaP-value*
n (%)n (%)n (%)
  • *

    P-value as calculated between microcytic and macrocytic anemia. Value < 0.05 is taken as significant.

Congestive heart failure11 (12.3)3 (13.6)9 (12.1)1
Postpartum hemorrhage4 (4.4)6 (8.1)0.51
Maternal mortality1 (1.1)2 (2.7)
Prematurity10 (11.2)2 (9)16 (21.6)0.07
Fetal growth restriction12 (13.4)3 (13.6)22 (29.7)0.01
Low Apgar at birth4 (4.4)5 (6.7)0.73
Intrauterine death2 (2.7)

From this data it is obvious that both maternal and perinatal outcome is worst with macrocytic anemia. The main perinatal problem with macrocytic anemia was a higher extent of intrauterine growth restriction. However, detailed analysis of case record data revealed that those patients in whom an early diagnosis (prior to 30 weeks of gestation) was made and treatment was started immediately showed catch up in fetal growth parameters to overcome the lag that was evident earlier.


Anemia is an important health problem in many countries worldwide, especially in pregnant women. According to a survey conducted by the WHO–Federation of Obstetric and Gynaecological Societies of India between 1993 and 2005, Asian countries have 80.9% prevalence of anemia among pregnant women.1

Macrocytic anemia forms an important component of the anemia spectrum, although the prevalence and cause may be variable across populations. With increasing prevalence in the general population, it is expected that the prevalence of macrocytic anemia in pregnant patients should also show an increasing trend. Surprisingly, few studies are available to confirm this fact or to report on patient profile and pregnancy outcomes in these patients.

Studies in the general Indian population showed up to 60% prevalence of vitamin B12 deficiency and 2.4% of anemic patients to have macrocytic picture,5,6 but surprisingly no studies report it during pregnancy – probably the high prevalence of iron deficiency has overshadowed it.

A study conducted in Venezuela showed prevalence of folic acid and B12 deficiency in pregnant women of up to 36.32% and 61.34%.7 This was the only study that could be identified in the literature dealing with the problem of macrocytic anemia in pregnancy. In this study the overall prevalence of severe anemia was 1.2%, out of which 41.6% of patients had macrocytic anemia. In the present study, also, it was observed that the macrocytic picture was present to a similar extent (40%). This may be because dietary intake amongst both these groups of patients could be similar. In this study there is further increasing incidence of macrocytic anemia as the severity of anemia increases, as is shown by the fact that 75% of patients with very severe anemia (Hb < 5 gm/dL) had macrocytosis.

In contrast, only 3–4% of pregnant women with anemia have macrocytic anemia in the American population. Folic acid and vitamin B12 deficiency form a major cause of macrocytic anemia and the reason for this low incidence could be an abundance of vitamin B12 and folate in the American diet.8

On the other hand, our population predominantly consumes a lacto-vegetarian diet, which is naturally deficient in vitamin B12. Thus, a higher prevalence of macrocytic anemia in general and in the pregnant population is expected in our setup as compared to a Western population. It can also be concluded that macrocytic anemia will form a significant component of pregnancy-related anemia in future studies in India, which is underscored in the present study.

Studies have shown that macrocytic anemia is also an important differential diagnosis in the general population as well as in pregnant patients presenting with bicytopenia and pancytopenia.9–11 One previous study from Delhi itself6 has shown the prevalence of macrocytic anemia in anemic patients, however that study reported anemia in both sexes across all age groups, including pediatric cases and few pregnant women. Those authors also showed an associated mild hyperbilirubinemia in up to 32% of patients with macrocytic anemia.6 Vitamin B12 and folate deficiency may lead to ineffective erythropoiesis, which may be accompanied by intramedullary hemolysis leading to mild elevations in bilirubin and levels of lactate dehydrogenase. In the present study also, deranged liver function tests and thrombocytopenia were seen to be significantly associated with macrocytic anemia but not in other types of anemia.

Folic acid and vitamin B12 deficiency is also considered an independent risk factor for neural tube defect besides being an important cause of macrocytosis. Severe B12 deficiency can also produce a cluster of neurological symptoms in infants, including irritability, failure to thrive, apathy, anorexia and developmental regression, which respond remarkably rapidly to supplementation.12 Maternal vitamin B12 and folic acid status is also important in lactation as the effect on the infant is exacerbated by low levels of these nutrients in human milk. This further reiterates the importance of treating macrocytic anemia during pregnancy.

Incidence of maternal and perinatal morbidity was higher in the patients with macrocytic anemia in the present study. General anasarca, hypertension, thrombocytopenia and deranged liver function tests were present in a significantly higher number of cases of macrocytic anemia and contributed to increased maternal morbidity in these cases. Perinatal morbidity was manifested by increase in fetal growth restriction and prematurity, although the latter did not achieve statistical significance. This statistically significant association of maternal and perinatal morbidity may be a reflection of both severity and type of anemia. It is difficult to determine a cause-and-effect relationship in a retrospective study and it is possible that a detailed prospectively conducted study would be able to establish with greater accuracy whether these problems occur as a result of severity of anemia or may be attributed to the type of anemia. As both maternal and perinatal hazards increase with maternal anemia, the importance of timely management cannot be disregarded.13 In addition, identifying the correct cause followed by appropriate treatment needs to be further underscored. It is essential for clinicians to be aware of this problem as treating all cases of pregnancy-related anemia as microcytic and due purely to iron deficiency may have serious implications as patients of macrocytosis will show suboptimal response to therapy and lead to persistence of problems, even with advancing gestation. Inadequate treatment coupled with successive pregnancies will further add to the morbidity for both mother and baby. Detailed analysis of the case records showed that the period of gestation at which the diagnosis is made and treatment instituted also appears to be important as patients who had initial evidence of suboptimal fetal growth showed improved growth parameters after institution of treatment but the same could not be observed in those patients where interval between initiation of therapy and delivery was short, that is, less than 4–6 weeks.

It would have been ideal to have estimated serum values of the various parameters to confirm the diagnosis of vitamin B12 or folate deficiency but this could not be done due to economic constraints. This could be considered an area of future research. It may also be worthwhile to initiate similar analyses at other centers, as anemia with pregnancy is a ubiquitous problem in our country.

In summary, macrocytic anemia is an important cause of severe anemia during pregnancy contributing to 40% of cases in this study. It causes significant maternal and fetal morbidity. The prevalence and problems of macrocytic anemia are much higher in pregnant women than initially thought. Sufficient data regarding the actual magnitude and effects of the problem is still lacking and more research is needed. It is suggested that the problem of macrocytosis should be suspected by clinicians and then accurately identified by a pathologist in order to institute immediate and appropriate therapy. Awareness among medical personnel, diet counseling and appropriate food fortification can play an important role in tackling the problem and such measures can go a long way in changing the epidemiology of anemia in pregnancy.


The help of Mrs Renuka Saha, Assistant Professor, Department of Community Medicine, Maulana Azad Medical College, New Delhi for statistical analysis is gratefully acknowledged.