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Cite this article: Tripathi R, Verma V, Singh T, Kaushik S, Mala YM, et al. (2018) Correlation of Biochemical Parameters in Paired Maternal and Umbilical Cord Sera in Pregnancies Complicated with Severe Anaemia. J Hematol Transfus 6(2): 1081.

*Corresponding authorNilanchali Singh, Department of Obstetrics and Gynaecology, Maulana Azad Medical College and Associated Hospitals, New Delhi, India, Pin: 110002, Tel: 91-9968-604-340; Email:

Submitted: 23 July 2018

Accepted: 29 August 2018

Published: 31 August 2018

ISSN: 2333-6684

Copyright© 2018 Singh et al.

OPEN ACCESS

Keywords•Cord blood•Iron•Ferritin•Folate•Cobalamin•Anemia

Research Article

Correlation of Biochemical Parameters in Paired Maternal and Umbilical Cord Sera in Pregnancies Complicated with Severe AnaemiaReva Tripathi1, Vertika Verma1, Tejinder Singh2, Smita Kaushik3, Mala YM1, and Nilanchali Singh1* 1Department of Obstetrics and Gynaecology, Maulana Azad Medical College, India2Department of Pathology, Maulana Azad Medical College, India3Department of Biochemistry, Maulana Azad Medical College, India

Abstract

Objective: To evaluate the biochemical profile of patients with severe anemia in pregnancy and to study relation between maternal and umbilical cord serum levels of iron, ferritin, cobalamin and folate.

Methods: It is a prospective case control study with 200 pregnant women with severe anemia (Hb< 7 gm/dl) and pregnant women with no anemia (Hb>11gm/dl were recruited. Serum ferritin, folate and cobalamin were measured by electro-chemiluminescence method. Cord blood samples were collected for estimating the levels of iron, ferritin, folate and cobalamin.

Results: Cases were divided into three groups, microcytic anemia (47%), macrocytic anemia (37.5%) and dimorphic anemia (15.5%). Mothers with iron deficiency were 37.5%, whereas cobalamin and folate deficiency were seen in 47% and 11% respectively. In women with microcytic anemia, iron and ferritin levels in umbilical cord blood were 5.54 and 19.41 times higher, respectively, than maternal serum values. However, in macrocytic anemia, cobalamin levels were only 1.22 times more in cord blood as compared to maternal serum values.

Conclusion: Cord blood values show that fetus is able to compensate for low levels of maternal iron and folate but not for cobalamin, indicating the absence of preferential transfer of cobalamin to the fetus.

INTRODUCTIONAnemia in pregnancy has been almost synonymous with iron-

deficiency anemia but there appears to be an emerging evidence of macrocytic anemia. Most of the previous studies have reported a lower incidence of macrocytic anemia and hence its importance in pregnancy has been neglected [1,2]. A study evaluating the clinical profile of patients having severe anemia in pregnancy was published earlier where macrocytic picture was seen in 40% of cases of severe anaemia [3]. It also showed that the maternal and fetal morbidity and mortality appears to be higher in macrocytic anemia as compared to iron-deficiency anemia. The prior study mainly dealt with clinical profile and therefore this study was planned to focus on biochemical characteristics and relationship between maternal and umbilical cord hematological parameters in women with severe anemia with reference to type of anemia [3]. The reason to conduct such a study was to assess the differential transfer of nutrients in iron deficiency and megaloblastic anemia; so as to know the impact of type of anemia

on fetal development. There is paucity of literature addressing this issue. It was also done to evaluate the effect of various types of anemia on the fetus as this may subsequently have long term consequences.

MATERIAL AND METHODSThis was a prospective longitudinalstudyinvolving400

pregnant woman (Test=200 and Control = 200) from August, 2010 to February, 2012 in the Department of Obstetrics and Gynaecology of a tertiary care hospital in Northern India. Ethical clearance was taken from Institutional Ethical Committee. The study included 200 pregnant women with severe anemia (Hb< 7gm/dl) who were admitted to the maternity ward as test group together with 200 pregnant women without anemia (Hb>11gm/dl) attending antenatal clinic who served as controls after written informed consent. Only women with singleton pregnancies presenting after 34 weeks of gestation were recruited. Women with twin pregnancies or who were admitted and treated before 34 weeks were not recruited in the study.

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All women underwent a detailed history followed by thorough general physical, systemic and obstetric examination. Blood samples of all subjects were collected before commencement of any treatment and analyzed for routine antenatal investigations (blood grouping and Rh typing, hemoglobin estimation, antibodies against human immunodeficiency virus, Australia antigen, standard test for syphilis, glucose challenge test, urine routine and microscopy, urine culture and sensitivity and Naked Eye Single Tube Red Cell Osmotic Fragility test (NESTROFT) [4]. At enrolment, approximately 4 ml venous blood was taken from each patient and divided into 2 parts. 1 ml of blood was transferred to a vacutainer containing EDTA solution for the estimation of hemoglobin, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and for peripheral blood smear evaluation. Hemoglobin, hematocrit, MCV, MCH and MCHC were estimated by automated counters. (Biologics ACCUCOUNT 1000 Automated Counter) A peripheral blood smear was stained with Leishman’s stain to determine the morphology of the blood cells and to diagnose type of anemia. The other part of the sample (3 mL) was used for the estimation of serum values of ferritin, iron, folate and cobalamin. It was centrifuged at 2000 rpm for 10 minutes. The separated serum was then transferred to aliquots and the aliquots were stored at -80°C for later measurement of above mentioned parameters. Serum ferritin, folate and cobalamin were measured by electro-chemiluminescence method using automated clinical immune-analyzer in a closed system (Elecsys 2010, Roche Diagnostics, Switzerland). Serum iron estimation was done using fully automated clinical chemistry analyzer (Olympus, Japan) by spectrophotometric method using ready to use Randox reagent kits (Randox laboratories, United Kingdom).

Treatment of anemia was done. Reticulocyte count was evaluated after six days of commencing treatment by staining peripheral blood smear with Brilliant Cresyl blue stain to evaluate response to treatment. Monitoring of women in anemia group was done by measuring hemoglobin, hematocrit and red blood cell indices. Routine antenatal care with special importance for treatment of anemia was provided to the anemic women. Non-anemic women were followed up as routine on outpatient basis. All patients were followed till delivery. Delivery was conducted in hospital for all the patients included in the study. Cord blood samples were collected at the time of delivery for all patients for estimation of hemoglobin, hematocrit, red cell indices and serum values of iron, ferritin, folate and cobalamin. The study plan is represented in Figure 1.

RESULTSA total of 200 patients with severe anemia (Hb< 7 gm %)

as cases and 200 controls (Hb>11 gm %) were studied. On the basis of haematological indices and peripheral smear evaluation the cases were divided into three groups. Though microcytic hypochromic anemia was most common (94 patients, 47%), a significant number of patients were found to have macrocytic anemia (75 patients, 37.5%). Dimorphic anemia was present in a smaller fraction of women with severe anemia (31 patients, 15.5%). In Table 1 the demographic profile of the study population is reported. Majority of study population (148 patients, 74%) belonged to lower socioeconomic status according to modified

Kuppuswamy scale and were multiparous (172 patients, 86%). One hundred and thirty five patients (67.5%) consumed vegetarian diet which is deficient in iron and vitamin B12. Further history revealed that only 90 patients (45%) of total study population had taken iron supplementation; this number was significantly less in patients with microcytic anemia (27 of 94 patients, 28.7%). Incidence of multivitamin (28 patients, 14%) and folic acid intake (11 patients, 5.5%) was also very minimal. Out of total anemic population, 110 patients (55%) received blood transfusion.

Table 2 shows the biochemical parameters in different study groups. Deranged liver function test was seen more commonly in macrocytic anemia. Out of 200 women, who were anemic, 94 (47%) patients were iron deficient whereas cobalamin and folate deficiency were seen in 75 (37.5%) and 22 (11%) patients respectively. Table 3 shows comparison of maternal and cord blood biochemical parameters in different types of anemia. Tables 4 clearly shows that there is preferential transfer of all iron, ferritin and folate from mother to fetus but in case of cobalamin, fetal levels mirror maternal levels very closely. The reason for this lack of preferential transfer is not clearly understood. Figures 2-5 show comparison of iron, ferritin, cobalamin and folate levels respectively in maternal and cord serum in different types of anemia. Serum levels of iron, ferritin, cobalamin and folate were low in maternal blood. Cord blood levels showed correspondingly higher values of iron, ferritin and folate (in the lower normal range) but were almost similar to maternal levels in the case of cobalamin indicating the absence of preferential transfer to the fetus.

DISCUSSION Anaemia is the most common nutritional deficiency disorder

in the world. Anemia is of great concern during pregnancy because of its reported association with a number of adverse outcomes on both maternal and neonatal health. Lower socioeconomic status, poor nutritional status, closely spaced multiple pregnancies without supplementation of iron and multivitamins were found to be associated risk factors for anemia [1,2]. In the present study, macrocytic anemia was diagnosed in substantial number of patients (37.5%). This is in accordance with results of a study conducted in the same department three years back which showed 40% of overall patients of severe anemia had macrocytic picture [3]. However, in another Indian study, it was observed that amongst 130 pregnant women with severe anemia (Hb<5 g/dL), prevalence of microcytic anemia was 49%, followed by dimorphic 35% and macrocytic anemia 10% [2]. In western countries, prevalence of macrocytic anemia is comparatively less [5]. Prevalence of vitamin B12 deficiency is much higher in countries like India because majority of individuals consume purely vegetarian diet which is likely to be vitamin B12 deficient [6-8].

The increasing prevalence of vitamin B12 deficiency in different groups of population is highlighted in various studies [9-11], but there is paucity of literature regarding prevalence of macrocytic anemia, caused by B12 deficiency in pregnancy.

Maternal morbidity manifesting as pedal edema, anasarca and hepatosplenomegaly were significantly higher in patients

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Pregnant patients recruited with Hb< 7gm%

Detailed history & examination

Baseline Investigations of anemia with special Investigationsspecial investigations i.e. iron, folate, cobalamine, ferritin

Reticulocyte count after six days of initiation of therapy

Routine antenatal care along with treatment of anemia

Pregnancy followed till

Cord blood sample collected at time of delivery and analyzed for serumiron, ferritin, folate, cobalamin

Maternal & fetal outcomes noted

Figure 1 Study Design.

Table 1: Demograhic profile of the study population.

Parameters

Cases

Total Casesn=200

Controlsn=200

Microcytic anemia

n=94

Macrocytic anemia

n=75

Dimorphic anemia

n=31

Age (years) 26.11 ± 3.49 25.65 ± 2.6624.07 ± 2.79 25.26± 2.58

23.16± 3.19p =0.089

Primiparous pregnanciesMultipare pregnancies

1080

1268 6

2428

172 35165p =0.169

Gestational ageat detection

34.05 ± 3.69 35.38 ± 2.9335.14 ± 3.25 35. 08 ± 3.13 35. 01 ± 2.26p=0.171

DietVegetarian

Nonvegetarian

5634

6218 20

1013862

12971

p =0.308

Supplementation

Iron1

Folic acid2

Multivitamin3

241224

5012 14

00

881326

1308463

p0.0041

0.0402

0.0013

with macrocytic anemia. Hepatosplenomegaly was present in 23(11.5%) out of 200 patients of severe anemia. A preponderance of these (20 patients, 87%) had macrocytosis. Pedal edema and anasarca was observed in about half of patients having macro-cytic anemia but they were much less common in patients of mi-crocytic and dimorphic anemia. In an earlier retrospective study conducted in same department, anasarca and hepatosplenom-egaly were present in 44.5% and 33.7% pregnant women with severe macrocytic anemia respectively, but in microcytic anemia, only 22.4% patients had anasarca while no patient had hepat-osplenomegaly [3]. Similar observations were seen in other stud-

ies conducted in general (but not obstetric) population also [12]. Various authors [13-15], have stated that anemia is associated with obstetric complications such as gestational hypertension, pre-eclampsia, cardiac failure and their incidence increases with severity of anemia but only one study [3] documented statisti-cally significant association of these obstetric complications with macrocytic anemia. In this study, gestational hypertension and intrauterine growth restriction was present in 32.4% and 29.7% patients with macrocytosis respectively, whereas in patients with microcytic anemia this percentage was only 11.2% and 13.4% respectively [3]. In present study also, macrocytic anemia

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Table 2: Biochemical parameters of maternal serum in different study groups.

Parameters

CasesNon-anemic

(Control group)n =200

p(Micro vs Macro)

Dimorphicanemian =31

Macrocytic anemian =75

Microcyticanemian =94

Totaln =200

n (%) n (%) n (%) n (%) n (%)Serum Bilirubin

(>1 mg/dL) 0(0) 18(24) 0(0) 18(9) 0(0) <0.001

Liver enzymes(> 40U/mL) 2(6.5) 21(28) 6(6.4) 29(14.5) 0(0) <0.001

Serum Iron(< 37µg/dL) 15(48.4) 0(0) 60(63.8) 75(37.5) 0(0) <0.001

Serum Ferritin(< 13 µg/L) 11(35.5) 0(0) 57(60.6) 68(34) 0(0) <0.001

Serum Cobalamin(<250 pg/mL) 29(93.5) 65(86.7) 0(0) 94(47) 0(0) <0.001

Serum Folate(< 2ng/mL) 2(6.5) 19(25.3) 1(1.1) 22(11) 0(0) <0.001

Table 3: Comparison of maternal and cord blood biochemical parameters in the study groups.

Biochemical parameters

Non-anemic(Control group)Median Values

Dimorphic anemian=31

Median Values(Range)

Macrocytic anemian=75

Median Values(Range)

Microcytic anemian=94

Median Values(Range)

Maternal Cord Maternal Cord Maternal Cord Maternal Cord

Iron(µg/dL) 75.16 170.48 37.4

(22.4-99)

196.8(140.2-356.6)

221.70134.8-397)

229.9(135.7-350.6)

33.30(19.2-100.2)

183.9(76.0- 253.4)

Ferritin(µg/L) 30.688 222.94 14.67

(9.7-22.7)298.80

(143.6-2264)232.60

(99.9-920.5)283.7

(152-1138)12.60

(3.2-35.6)232.90

(97.6-600.2)

Cobalamin (pg/mL) 224.988 281.32

178.6(110.6-288.5)

257.7(174.4-742.4)

189.90(92.6-478.3)

232.4(119.6-622.6)

478.30 (280.9-2000)

711.9(299.5-1953)

Folate(ng/mL) 8.7292 24.842 7.78

(1.48-20.0)17.43

(5.64-28.60)5.47

(0.64-19.4)14.33

(4.42-32.6)10.09

(1.01-29.00)16.15

(6.9-22.80)

Table 4: Cord blood values expressed as multiples of maternal values.

Biochemical parameters Non anemic(Control group)

AnemicDimorphic Macrocytic Microcytic

Iron 2.26 5.32 1.03 5.54

Ferritin 7.2 19.9 1.23 19.41

Cobalamin 1.24 1.44 1.22 1.48

Folate 2.8 2.12 2.6 1.34

was found to have statistically significant relationship with vari-ous obstetric complications such as gestational hypertension, in-trauterine growth restriction and intrauterine fetal demise.

Severity of anemia also had association with macrocytosis with 68.8% of patients (22/32) of very severe anemia (Hb< 5 g/dL) having macrocytic anemia. Thrombocytopenia, leukopenia and pancytopenia were present only in patients of macrocytic anemia and few patients with dimorphic anemia. Studies have shown that macrocytic anemia is also an important differential diagnosis in general population as well as pregnant patients presenting with bicytopenia and pancytopenia [3,11,12]. Macrocytic anemia occurs because of vitamin B12 and folate deficiency which affects all rapidly growing cells i.e. red cells,

white blood cells and platelets therefore resulting in anemia, leukopenia and thrombocytopenia.

Biochemical parameters of hepatic dysfunction such as serum bilirubin, liver enzymes were found to be more frequently deranged in patients of macrocytic anemia and the finding is also supported by other studies [3,13].

Neonatal morbidity measured in terms of prematurity, low birth weight, low Apgar score, admission to neonatal intensive care unit was significantly higher in patients of macrocytic anemia. A number of studies had reported that anemia in pregnancy even of varying severity is associated with preterm birth, low birth weight babies, intrauterine growth restriction, NICU admissions and neonatal death [3,15,16]. Neonatal morbidity was seen more

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Hemoglobin20 18 16 14 12 10 8 6 4 2

Serum Iron

500

400

300

200

100

Neonatal Maternal

Hemoglobin (gm/dL) 18 16 14 12 10 8 6 4 2

Serum Iron (ug/dL)

400

300

200

100

0

Neonatal Maternal

Dimorphic anemia

Macrocytic anemia

Hemoglobin

20 18 16 14 12 10 8 6 4 2

300

200

100

0

Neonatal Maternal

Serum Iron

Microcytic anemia

Figure 2 Comparison of IRON in maternal and cord serum in different types of anemia.

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Hemoglobin 18 16 14 12 10 8 6 4 2

S_ferritin

3000

2000

1000

0

-1000

Neonatal Maternal

Dimorphic anemia

20 18 16 14 12 10 8 6 4 2

700

600 500

400

300 200

100

0 -100

Neonatal Maternal

Hemoglobin

Serum ferritin

20 18 16 14 12 10 8 6 4 2

1200

1000

800

600

400

200

0

Neonatal Maternal

Hemoglobin

Serum ferritin

Macrocytic anemia

Microcytic anemia

Figure 3 Comparison of FERRITIN in maternal and cord serum in different types of anemia.

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H

20 18 16 14 12 10 8 6 4 2

700

600

500

400

300

200

100

0

Neonatal Maternal

Serum Cobalamin

Hemoglobin

Hemoglobin 18 16 14 12 10 8 6 4 2

Serum cobalamin

800

700

600

500

400

300

200

100

Neonatal Maternal

Dimorphic anemia

Macrocytic anemia

20 18 16 14 12 10 8 6 4 2

3000

2000

1000

0

Neonatal Maternal

Hemoglobin

Serum Cobalamin

Microcytic anemia

Figure 4 Comparison of COBALAMIN in maternal and cord serum in different types of anemia.

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Hemoglobin 18 16 14 12 10 8 6 4 2

Serum Folate

30

20

10

0

Neonatal Maternal

Dimorphic anemia

HB

20 18 16 14 12 10 8 6 4 2

140

120

100

80

60

40

20

0

Neonatal Maternal

Hemoglobin

S. folate

Hemoglobin 20 18 16 14 12 10 8 6 4 2

Serum Folate

40

30

20

10

0

Neonatal Maternal

Macrocytic anemia

Microcytic anemia

Figure 5 Comparison of FOLATE in maternal and cord serum in different types of anemia.

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frequently in patients with macroc anasarca ytosis [3]. Therefore, patients with anemia should be investigated properly to diagnose types of anemia for initiation of appropriate treatment instead of treating all patients of anemia by standard iron therapy which is likely to further aggravate vitamin B12 deficiency.

In previously described studies, cord blood values for all parameters were higher as compared to maternal values irrespective of the fact whether the mothers were anemic or not [17-20]. But none of these studies had studied cord blood parameters in babies of women with severe anemia.

In present study also, levels of all the hematological parameters were significantly higher in cord blood as compared to maternal values. This is not surprising as it appears to be manifestation of increased physiological uptake from mother irrespective of mother’s nutritional status.

Table 4 shows the difference expressed in terms of multiples between maternal and cord blood values of different parameters. Normal, non anemic women, show higher levels of cord blood values for most parameters but not for cobalamin where cord levels are minimally higher. As expected there is a high difference between maternal and cord levels of iron and ferritin in microcytic and dimorphic anemia but difference in macrocytic anemia is minimal possibly due to them being iron replete i.e. not deficient in iron. Regarding cobalamin values irrespective of type of anemia, the difference between cord serum values and maternal serum values is very minimal. This possibly indicates that transfer of cobalamin poses a problem. Further, relation between maternal and cord blood parameters in anemic women is not described anywhere in literature.

This study is conducted in India where most of women are mainly vegetarian making their diet deficient in vitamin B12.Therefore, the results maybe applicable to population having similar dietary habits only.

In women with iron deficiency anemia, iron and ferritin were much higher in cord blood as compared to maternal levels whereas in cobalamin deficient women, increase in cord blood cobalamin levels was only minimally higher (Table 4). Hence, it appears that the fetus is able to extract adequate iron and folate from the mother irrespective of maternal status and achieves levels, in near normal range. However, the cord blood values of cobalamin are a closer reflection of maternal cobalamin values, i.e. in cobalamin replete women cord blood levels are higher whereas in cobalamin deficiency, cord blood levels are lower. The cause of this differential extraction of nutrients by the fetus remains unknown and whether transcobalamins (TCs) play a role needs further elucidation. A study reported that human placenta modulates the asymmetric transfer of vitamin B12 on the basis of release of specific Cobalamin-binding proteins (TCI/III- and TCII-like) [21]. This differential transfer of cobalamin could have serious impact on subsequent neurological development. In these babies, vitamin B12 deficiency can produce a cluster of neurological symptoms, including irritability, failure to thrive, anorexia and developmental regression. A recent study reported the widespread prevalence of folate deficiency among women of child-bearing age and highlighted the possibility that nutritional insult may exacerbate the risk of metabolic disease

in their offspring [22]. This further highlights the importance of treating macrocytic anemia during pregnancy, which may worsen during lactation if left untreated.

Public health interventions should be made by way of appropriate food fortifications to reduce prevalence of anemia in both pregnant and non pregnant women. Efforts should be made to educate women regarding the importance of antenatal care and adequate diet during pregnancy. Macrocytic anemia must be considered and early diagnosis should be made by appropriate investigations and proper therapy should be started as soon as possible according to type of anemia.

CONCLUSIONThe study clearly shows that besides continuing high

prevalence of microcytic anemia, macrocytic anemia is increasingly becoming prevalent and is associated with worse maternal and perinatal outcomes. Expectedly, serum levels of iron, ferritin, cobalamin and folate were low in maternal blood in anemic women. Cord blood levels showed correspondingly higher values of iron, ferritin and folate (in the lower normal range) but were almost similar to maternal levels in the case of cobalamin indicating the absence of its preferential transfer to the fetus. This is of special concern especially in cases of macrocytic anemia which is associated with higher perinatal problems which are likely to continue postnatally and impact infant and childhood development.

CONTRIBUTION TO AUTHORSHIP Details of ethics approval: Institutional Ethical Committee

of Maulana Azad Medical College.

Funding: Kits received from Institutional Research Funds.

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Tripathi R, Verma V, Singh T, Kaushik S, Mala YM, et al. (2018) Correlation of Biochemical Parameters in Paired Maternal and Umbilical Cord Sera in Pregnancies Complicated with Severe Anaemia. J Hematol Transfus 6(2): 1081.

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