Indian Pediatrics 2002; 39:339-346  

Impact of Daily versus Weekly Hematinic Supplementation on Anemia in Pregnant Women

Sunil Gomber, K.N. Agarwal, Charu Mahajan and N. Agarwal

From the Departments of Pediatrics and *Obstetrics and Gynecology, University College of Medical Sciences and Guru Teg Bahadur Hospital, Delhi 110 095, India.

Correspondence to: Prof. Sunil Gomber, F-4(A) Vijay Nagar, Delhi 110 009, India.

E-mail: [email protected]

Manuscript received: May 21, 2001, Initial review completed: June 29, 2001,
Revision accepted: December 12, 2001.

Objective: To compare the effectivity of weekly versus daily iron therapy in reducing maternal anemia and to evaluate the association of maternal hemoglobin and fetal growth. Design: Prospective. Setting: Tertiary care teaching hospital in an urban metropolis. Methods: 40 pregnant women received daily and 40 pregnant women received weekly oral therapy (335 mg of ferrous sulphate and 500 µg folic acid) for a period of 14 weeks. The age of each pregnant woman and their baseline anthropometric data (weight, height and body mass index) were estimated. Hemoglobin and hematocrit estimations were carried out during follow period at 4wks, 8wks and 14 weeks. Serum ferritin values as a marker of iron status were also calculated in both the groups initially, at 14 weeks and at the time of delivery. Fetal anthropmetric indices of 137 full term neonates delivered to mothers included in either of the supplementation groups or admitted to the hospital were also studied in relation to maternal hemoglobin concentration. Results: Forty subjects each were initially randomized into groups I and II. The age of pregnant women along with their baseline anthropometric data were similar in both groups. A total of 29 pregnant women in group I and 27 pregnant women in group II could be regularly followed up. The increase in hemoglobin and hematocrit values were similar in daily and weekly supplemented mothers. An intention to treat analysis also showed similar results. The ferritin values were similar at the start of supplementation and after 14 wks of weekly or daily iron therapy. Birth weight, crown heel length, head circumference of the neonate and placental weight increased significantly with rise in maternal hemoglobin levels. Conclusion: Weekly iron supplementation is an effective mode of treating anemia among pregnant women and maternal anemia during pregnancy is adversely associated with fetal growth.

Key words: Anemia, Fetal outcome, Pregnant women, Supplementation.

ANEMIA is a problem of great magnitude the world over. Among the most affected by this malady are pregnant women. Reports indicate that in India 62%-88% of pregnant women suffer from anemia(1,2). The recommended National Nutritional Anemia Control Program advocating daily hematinic supplementation to pregnant women has not met with great success, the major constraints being irregular availability of hematinics and lack of education and communication of the importance of hematinic supplementation during pregnancy leading to its poor compliance among the subjects. In order to improve the compliance and reduce the cost of therapy, schedules administering hematinics less than once daily have been tried(3,4). Controversy still exists on the efficacy of weekly versus daily hematinic supplementa-tion in raising hemoglobin during preg-nancy(5-7). Furthermore, there is limited information from India on the association of maternal anemia on the various anthropo-metric indices of newborn(8). The present study was, therefore, planned to investigate the impact of daily versus weekly hematinic supplementation on anemia in pregnancy and to evaluate the association between maternal hemoglobin and fetal growth.

This was a prospective longitudinal study with an observational design which was conducted in the Medical College attached to a tertiary care hospital in Delhi. The study period was 15 months. A total of 80 pregnant women were recruited during the second trimester between 16-24 weeks. These women were residing in the urban slums present around the hospital and had a low socio-economic status. These pregnant women were allocated to daily or weekly supplementation groups in a randomized manner. Only apparently healthy mother with singleton pregnancy were included in the study. Mothers with hemoglobin <7.0 g/dl, and suffering from any chronic systemic disorder, pregnancy induced hypertension and/or diabetes were excluded from the study. The age of each pregnant woman and their baseline anthropometric data i.e., weight, height and body mass index (BMI) were estimated.

Group I (Daily supplementation): Mothers were given daily a tablet of 335 mg of ferrous sulphate (100 mg elemental iron) and 500 µg folic for a period of 100 days. They received 7 tablets with the advice to consume one tablet per day and report every week. They were instructed to show the empty blister pack before issuing the drug for next week to ensure proper compliance. Forty subjects were recruited into this group at the start of the therapy.

Group II (Weekly Supplementation): Mothers were given once a week supervised dose of 335 mg of ferrous sulphate and 500 µg folic acid over a period of 100 days. Mothers were called every week and were made to consume the hematinic supplement in the clinic itself. Forty subjects were initially recruited into this group.

These mothers were regularly followed up till 14 weeks. Hemoglobin and hematocrit estimations were carried out during the follow up period to look for the effect of daily versus weekly hematinic supplementation and also to monitor its side effects. Serum ferritin estimation were also carried out before and after supplementation (14 weeks) and at the time of delivery. Fig. 1 depicts the flow chart describing the progress of studied subjects.

For finding out the association between fetal growth and maternal hemoglobin, neonates delivered either to mothers in one of the supplementation groups or born to mothers attending the hospital were included into the second part of the study. A total of 137 full term neonates were studied for fetal growth parameters in relation to maternal hemoglobin concentration.

A verbal consent was taken from all the subjects and the protocol was approved by the ethical committee of our institution.

Hemoglobin (Hb) and hematocrit (Hct) estimations were carried out by cyan-methemoglobin and microcentrifuge methods, respectively(9). Serum ferritin estimation was carried out using an enzyme immunoassy kit (Quarum EIA ferritin – Glaxo INDIA) on human serum.

Pregnancy outcome was recorded in terms of estimation of various neonatal anthropometric indices namely birth weight, crown heel length, crown rump length, mid arm circumference and head circumference in relation to different grades of anemia. The cut off value for defining anemia in pregnant women by hemoglobin was <12 g/dl and hematrocrit <36%(10). Unlike an earlier study in children(11) we did not attempt categorization based on severity of anemia.

Birth weight and placental weight were recorded on an electronic weighing machine (Seca model-727, manufactured in Germany) with the least count of 5 g. Other anthro-pometric indices were measured using standard procedures(12). Gestational age of neonates was estimated by doing the clinical assessment using Dubowitz criteria(13). Neonatal anthropometry and placental weight were analyzed in relation to maternal hemoglobin levels.

Data was analyzed using SPSS/PC+5.0 software. Student’s t-test was used to compare the age and anthropometric data of the two supplementation groups. Hierarchal ANOVA analysis with Tukey test at 5% level of significance was completed for Hb and Hct values at different time points within or between the groups. The analysis was also done on an intention to treat basis. Serum ferritin values were also compared at different time intervals after its log transformation (natural). One way ANOVA with Tukey test was used to find the effect of maternal Hb levels on neonatal anthropometry. Correla-tions of various neonatal anthropometric indices with maternal hemoglobin were calcu-lated by constructing regression equations.

Table I__Maternal Age and Anthropometric Parameters at Registration in Different Study Groups

Forty subjects each were initially randomized into Groups I and II. The age of pregnant women along with their baseline anthropometric data were similar in both groups (Table I).

Twenty nine and twenty seven pregnant women of Groups I and II respectively could be followed up regularly at 4 weekly intervals until 14 weeks of supplementation. The initial Hb and Hct values in Groups I and II were not different at the start of therapy. The rise in Hb and Hct from the start to the end of therapy after 14 weeks was significant in both the groups (p = 0.001). Moreover there was no difference in mean Hb and Hct values of both the groups at different time points (p = 0.097) as shown in Table II. The principle of intention to treat analysis was applied to include all subjects initially allocated to their respective group and were lost to follow up during the course of supplementation. Their last available value was taken for analysis. Table III depicts the mean value of Hb and Hct of 40 subjects in each group at 4 weeks, 8 weeks and 14 weeks of supplementation with this analysis. Similar results were obtained as mentioned earlier. The study had 90% power and 95% confidence to detect a mean difference of 0.75 g/dl change in hemoglobin between the two groups from the initial to the final values. There were no side effects of iron supplementation noticed in either daily or weekly supplementation groups.

Table II__ Hemoglobin & Hematocrit at Various Intervals in Daily and Weekly Supplemented Mothers (mean ±SD)

  Table III__ Intention to Treat Analysis of Hemoglobin and Hematocrit Concentration Among Daily and Weekly Supplemented Mothers

Serum ferritin was estimated in 29 and 27 pregnant women in the daily and weekly supplemented groups. These were estimated initially, at 14 weeks and at the time of delivery. The mean serum ferritin values after log transformation (natural) were compared within and between the groups at different time points and were not found to be statistically different (Table IV).

Neonatal anthropometric indices along with placental weight were studied in relation to maternal hemoglobin concentration in term babies. It was observed that birth weight, crown heel length, head circumference of the neonate and placental weight increased significantly with rise in maternal hemoglobin levels (Table V). All these parameters were significantly correlated with a linear relationship to maternal hemoglobin values except crown rump length and mid arm circumference (Table VI).

Table IV__ Comparison of Serum Ferritin Values (After Logarithmic Conversion)

The present study on pregnant women demonstrated an equal rise of hemoglobin and hematocrit values in the weekly supplemented group as compared to daily supplemented therapy. The rise in hemoglobin concentration depends on the iron absorption which is further dependent on the initial Hb concentration. In the present study the confounding influence of the initial Hb concentration as well as maternal anthropometry in both the supplemented groups was not present as these values were not statistically different. The strategy of national anemia control program advocating daily administration of 100 mg of elemental iron and 500 µg of folic acid to all pregnant women for a period of 100 days(14) has not met with great success as evidenced by the current prevalence of anemia in this vulnerable group. It is mainly due to lack of compliance of daily ingestion of hematinics, its side effects, poor delivery and distribution of folifer tablet, irregular supply and high cost of treatment. In order to improve compliance, a novel approach of supplementation either weekly or twice weekly was conceived. The strategy is based on intestinal mucosal turnover time. It has been suggested that saturation of iron binding protein, apoferritin, in the mucosal cell is the rate limiting step of further absorption of iron ("mucosal block theory"). A study in rats also demonstrated more efficient iron absorption if iron is given every 3rd day, the mucosal removal time, rather than daily(15). Since the mucosal turnover time in humans is 5-6 days, the strategy of weekly supplementation has been strongly suggested by few workers. The approach has successfully been used in Indonesian pregnant women(3,4) and in Indian adolescent girls of poor community(16). However, the issue has been contentious(6). In order to provide some of the answers the results of the present study though smaller in sample size also prove that weekly supplementation is equally efficacious as compared to daily iron-folate supplementation.

Table V__Neonatal Anthropometry and Placental Weight at Term in Relation to Maternal Hemoglobin Levels

Group	Hemoglobin	Birth weight		Length				Circumferences
	g/dl	(g)		Crown heel  (cm)		Crown rump  (cm)		Head  (cm)		Mid arm  (cm)		Placental  weight(g)
		Mean	SD	Mean	SD	Mean	SD	Mean	SD	Mean	SD	Mean	SD
I (n = 11)	7–9	2509	428	49.3	0.95	33.7	0.54	34.4	0.70	10.3	0.71	504	55.93
II (n = 51)	9–11	2670	351	49.3	0.87	33.7	0.74	34.4	0.86	10.2	0.96	532	72.66
III (n = 75)	> 11	2803	342	49.9	0.67	33.0	0.78	34.7	0.56	10.4	0.80	555	71.79
F value	4.51			10.81		3.09		5.16		3.52		7.80
P value (ANOVA)	0.01			0.00		0.30		0.07		0.41		0.02
Tukey test at 5% level	Group III significantly different from group I			Group III significantly different from group I & II		ns		ns		ns		Group III significantly different from group I

(ns = not significant).  

Table VI__ Correlation and Regression Equations of Maternal Hemoglobin with Neonatal Anthropometry and Placental Weight

Serum ferritin values continue to be remain low during pregnancy irrespective of supplementation since the demand for iron outstrips the supply(17). Supplementation helps in preventing the depletion of iron stores. The effectivity of weekly hematinic supplementation was also being substantiated by the maintenance of iron stores. During pregnancy, the iron from stores is mobilized to be utilized for production of increased red cell mass and for fetal and placental requirements occurring during pregnancy(17,18).

Neonatal growth of term babies in relation to maternal hemoglobin was also assessed. Only term babies were included to prevent the well known effect of period of gestation on fetal growth. The parameters of fetal anthropometry namely birth weight, crown heel length and head circumference were affected and were significantly co-related to the maternal hemoglobin concentration. Multiple regression analysis between maternal hemoglobin and neonatal growth parameters was not carried out as all the neonatal anthropometric indices are dependent on each other. A linear relationship of all the parameters of neonatal growth with maternal hemoglobin has been documented earlier(8). The evaluation of effects of maternal anemia on neonatal anthropometric measurements requires multi-centric studies particularly to establish the differential effects and the level of maternal hemoglobin necessary to avoid these. The findings of linear relationship of decrease in placental weight with increasing severity of maternal anemia could be due to morphological abnormalities especially villous fibrosis secondary to placental hypoxia(19,20).

In conclusion, our findings indicate that anemia during pregnancy is adversely associated with neonatal growth and weekly hematinic supplementations is an equally effective mode of treatment of anemia among pregnant women. The strategy of weekly supplementation has the potential of increasing the compliance and make the distribution of tablets simpler by using the existing MCH services.

Contributors: SG coordinated the study, analyzed and interpreted the data and drafted the manuscript; he will act as the guarantor for the paper. KNA conceived the idea and helped in drafting the paper. CM collected data and helped in analysis. NA helped in counseling and data collection.

Funding: None.

Competing interests: None declared.

1. Indian Council of Medical Research. Evaluation of the National Nutritional Anemia Prophylaxis Program. New Delhi. Indian Council of Medical Research, 1989.

2. Indian Council of Medical Research. Supplementation trial in pregnant women with 60 mg, 120 mg, and 180 mg iron with 500 µg of folic acid. New Delhi. Indian Council of Medical Research, 1992; pp 641.

3. Ridwan E, Schulink 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: 884-890.

4. Gross R, Schultink W, Juliawati. Treatment of anemia with weekly iron supplementation. Lancet 1994; 344: 821.

5. Beard JL. Weekly iron intervention: The case for intermittent iron supplementation. Am J Clin Nutr 1998; 68: 209-212.

6. Halberg L, Combating iron deficiency: Daily administration of iron is far superior to weekly administration. Am J Clin Nutr 1998; 68: 213-217.

7. Cook ID, Reddy MB. Efficacy of weekly compared with daily iron supplementation. Am J Clin Nutr 1995; 62: 117-120.

8. Singla PN, Tyagi M, Kumar A, Dash D, Shankar R. Fetal growth in maternal anemia. J Trop Pediatr 1997; 43: 89-92.

9. Dacie JV, Lewis SM. Basic haematological techniques. In: Practical hematology, 6th edn. Edinburgh. Churchill Livingston, 1984; pp22-49.

10. Nicholson J F, Pesce MA. Reference ranges for laboratory tests and procedures. In: Nelson Text Book of Pediatrics. 16th edn. Eds. Behrman RE. Kleigman RM. Jenson HB. Philadelphia, W.B. Saunders, 2000; p 2185.

11. Gomber S, Satish K, Rusia U, Gupta P, Agarwal KN, Sharma S. Prevalence and etiology of nutritional anemias in early childhood in an urban slum. Indian J Med Res 1998; 107: 269-273.

12. Agarwal DK, Agarwal K N. Physical growth in Indian affluent children (Birth-6 years). Indian Pediatr 1994; 31: 380-412.

13. Dubowitz LMS, Dubowitz V, Goldberg C. Clinical assessment of gestational age in the newborn infant. J Pediatr 1970; 77: 1-10.

14. Report of the Meeting on Prevention and Control of Nutritional Anemia. Ministry of Health and Family Welfare, Government of India and UNICEF, New Delhi, 1989.

15. Viteri FE, Liu X, Tolomei K, Martin A. True absorption and retention of supplemental iron is more efficient when iron is administered every three days rather than daily to iron-normal and iron deficient rats. J Nutr 1995; 125: 82-91.

16. Sharma A, Prasad K, Rao Visweswara K. Identification of an appropriate strategy to control anemia in adolescent girls of poor communities. Indian Pediatr 2000; 37: 261-267.

17. Fenton V, Cavill I, Fisher J. Iron stores in pregnancy. Br J Hematol 1977; 37: 145-149.

18. Kelly A M, MacDonald DJ, Mc Nay MB. Ferritin as an assessment of iron stores in normal pregnancy. Br J Obstet Gynecol 1977; 84: 434-438.

19. Murphy L S, Agarwal K N, Khanna S. Placental morphometric and morphological alterations in maternal undernutrition. Am J Obstet Gynecol 1976; 124: 641-644.

20. Rusia U, Bhatia A, Kapoor S, Madan N, Nair V, Sood S K. Placental morphology and histochemistry in iron deficiency anemia. Indian J Med Res 1988; 87: 468-474.