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Year : 2019  |  Volume : 22  |  Issue : 8  |  Page : 1132-1139

Daily versus twice daily dose of ferrous sulphate supplementation in pregnant women: A randomized clinical trial

1 Department of Obstetrics and Gynaecology, University of Abuja Teaching Hospital, Abuja, Nigeria
2 Department of Haematology, University of Abuja Teaching Hospital, Abuja, Nigeria

Date of Acceptance17-Apr-2019
Date of Web Publication14-Aug-2019

Correspondence Address:
Dr. H I Abdullahi
Department of Obstetrics and Gynaecology, University of Abuja Teaching Hospital, Abuja
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/njcp.njcp_211_18

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Background: The International Nutritional Anaemia Consultative Group has recommended a twice daily dose of 65 mg elemental iron supplementation in pregnant women living in areas where anaemia is prevalent contrary to the World Health Organization (WHO) universal recommendation of a daily dose of 60 mg. Whether twice or daily dose schedules proffer a better outcome is a subject of on-going research. Objective: To compare the effectiveness of the once versus twice daily doses of ferrous sulphate in the prevention of iron deficiency anaemia in pregnancy. Methods: There are about one hundred and eighty two (182) pregnant women at gestational ages of 14-24 weeks with haemoglobin (Hb) levels ≥10 g/dl but ≤14.5 g/dl were recruited during the antenatal booking clinic. They were randomized into receiving either once daily dose (65 mg of elemental iron) or twice daily dose (130 mg of elemental iron) of ferrous sulphate. Pre and post- supplementation haemoglobin, serum iron and ferritin levels were assessed at recruitment and at 37 weeks gestation respectively. Results: Eighty-four (84) and 80 women respectively in the once and twice daily dose groups were analysed. The serum haemoglobin was significantly lower (P = 0.002) among those on once daily than those on twice daily supplementation. The side effects were however, significantly higher in the twice daily group (P = 0.005, P = 0.043 and P = 0.004 respectively). There were no differences between the serum ferritin levels pre and post supplementation in both groups just as they were no reported significant differences in both birth weight of neonates (P = 0.936) and average gestational age at delivery (P = 0.469) between the two groups. Conclusion: Once daily (65 mg elemental iron) ferrous sulphate is as effective as twice daily (130 mg elemental iron) dose regimen in prevention of Anaemia in pregnancy in a developing economy like Nigeria. Once daily dose possesses fewer side effects and guarantees better compliance in this study.

Keywords: Anaemia in pregnancy, developing country, ferrous sulphate dose

How to cite this article:
Adaji J A, Isah A Y, Agida E T, Otu T, Abdullahi H I. Daily versus twice daily dose of ferrous sulphate supplementation in pregnant women: A randomized clinical trial. Niger J Clin Pract 2019;22:1132-9

How to cite this URL:
Adaji J A, Isah A Y, Agida E T, Otu T, Abdullahi H I. Daily versus twice daily dose of ferrous sulphate supplementation in pregnant women: A randomized clinical trial. Niger J Clin Pract [serial online] 2019 [cited 2023 Feb 1];22:1132-9. Available from:

   Introduction Top

Anaemia in pregnancy is an important complication of pregnancy globally and particularly in developing countries.[1],[2] An estimated 58.27 million women worldwide are anaemic during pregnancy with 95.7% living in developing countries.[3] The prevalence of anaemia in pregnancy in Africa has been estimated to be 35-75%.[3],[4] Maternal anaemia is considered a risk factor for poor pregnancy outcome and threat to the life of the mother and fetus.[3],[5] Anaemia is an important risk factor in pregnancy and it is associated with an increased incidence of both maternal and foetal morbidity and mortality.[6] Maternal anaemia contributes to an increase in perinatal mortality, low birth weight, still birth and foetal wastage.[6] The advent of Human immunodeficiency virus infection has compounded the challenge of anaemia in pregnancy.[7] Iron deficiency is the most common cause of anaemia during pregnancy.[1],[3],[5],[6],[7],[8] Pregnant women are especially susceptible to anaemia because requirements of iron during pregnancy are high, and it is difficult to meet the requirements through diet alone which is usually poor.[8] WHO data indicate that iron deficiency anaemia is a significant problem throughout the world ranging from 1% (average of 14%) in the industrialized countries to an average of 56% in developing countries including Nigeria.[1] According to the National Food Consumption and Nutrition Survey in 2003, 43.7% of pregnant women in Nigeria are iron deficient.[9] Anaemia in pregnancy has been estimated to contribute to 11.0% of maternal deaths with infants at the risk of developing iron deficiency anaemia which if uncorrected, may be associated with adverse behavioural and cognitive development.[4],[10] To prevent such adverse events, the World Health Organization (WHO) recommends universal oral iron supplementation for pregnant women (30-60 mg of elemental iron and 400 μg of folic acid daily) for 6 months in countries with prevalence of anaemia of less than 40% and for an additional 3 months postpartum in countries where the prevalence is more than 40%.[11],[12] The WHO however did not recommend multiple micronutrient supplementation for pregnant women, as there is currently no evidence that its routine use compared to iron and folic acid improves maternal and perinatal outcomes.[13] The International Nutritional Anaemia Consultative Group further recommended an increased daily dose to 120 mg of iron if the duration of supplementation in pregnant non-anaemic women is shorter or where the prevalence of iron deficiency in women is high such as reported in Nigeria, or in settings where pregnant women are generally anaemic.[9],[14] Iron supplementation in pregnancy has become a standard and routine practice as a prophylaxis against iron deficiency anaemia in pregnancy in Nigeria.[15] There is evidence that this intervention can prevent anaemia and bring benefits to the mother and especially to the fetus, such as a lower incidence of prematurity and intrauterine growth restriction with attendant improved neuro-psychomotor development.[16]

There is still neither consensus on the best dose, nor schedule of iron supplementation to prevent its deficiency during pregnancy without provoking haemo-concentration to the best of the researchers' knowledge in most developed countries such as Nigeria.[17],[18],[19] Several studies have compared the effect of different doses of iron supplementation on prevention of anaemia in pregnancy.[20] These trials included those comparing daily supplementation with 60 mg and 120 mg of elemental iron.[21],[22] In these trials, following iron supplementation, statistically significant increase in iron stores were observed in 120 mg group as compared to the 60 mg group.[21],[22] The side effects however increased with the higher daily dose.[21],[22] Though these reviews included developing countries like India and Myanmar, there was limited participation from Africa. The studies also limited their evaluation to only the effects of iron supplementation on haematological parameters with no mention of the effect on pregnancy outcome. There is therefore, paucity of data comparing once daily 200 mg of ferrous sulphate with twice daily 200 mg of ferrous sulphate for the prevention of iron deficiency anaemia in pregnancy in the West African Sub-region where anaemia in pregnancy is endemic including Nigeria.[4] It is hoped that a clinical trial comparing the once daily and twice daily supplementation protocol in the West African sub-region and Nigeria in particular, may objectively settle the debate on the most appropriate dose regimen (once or twice daily doses) suitable for west African region. The objective of this study therefore was to compare the effectiveness and efficacy of the once daily versus the twice daily dose of ferrous sulphate supplementation in pregnant women receiving antenatal care in our facility. Its effectiveness in preventing iron deficiency with increase in iron stores among others was sought and evaluated.

   Materials and Methods Top

The study was conducted at the department of Obstetrics and Gynaecology and the department of Haematology of University of Abuja Teaching Hospital, Abuja, from March 2015 to December 2015 involving 164 women. The study population comprised of pregnant women who presented at the booking clinic during the study period. The study population was a mixture of rural and urban dwellers.

This was a randomised clinical trial to compare the effectiveness and safety of once daily versus twice daily ferrous sulphate supplementation in the prevention of anaemia in pregnancy. Each ferrous sulphate tablet (200 mg) contains 65 mg of elemental iron. Pregnant Women were recruited at booking at gestational age between 14 and 24 weeks. Their haemoglobin (Hb) level must be ≥10 g/dl and ≤14.5 g/dl. An informed consent was obtained from the participants. Those recruited were given either 200 mg of ferrous sulphate daily or twice daily (FESULF manufactured by Therapeutic laboratories Nigeria NAFDAC REGISTRATION No 04 04 76). Both arms also received 5 mg of folic acid daily. Randomisation to the study arms was done by balloting. Allocation concealment was achieved by keeping 20 allocation slips with pre-assigned study allocations (10 per arm) in opaque containers. Sequential participants were asked to draw an allocation slip from the container without possibility of replacement. Laboratory staff reading the blood investigations was kept unaware of the treatment allocation during the trial. Before commencement of supplementation, samples were collected for serum haemoglobin, iron and ferritin. All women were instructed to take the iron tablets 30 min before meals and not to take them with tea, coffee or milk. Patients were educated about the usual side-effects of iron preparations and told to report nausea, vomiting, bowel disturbances or any other complications. They were also told to report if severe intolerance caused them to stop taking the supplements. The patients were advised to bring back their blister packets of ferrous sulphate at each antenatal visit. Compliance was checked both verbally and by checking the used blister packets. Those with compliance rates of up to 65% and above were classified as compliant. At 37 weeks gestation, samples were collected again for post supplementation serum haemoglobin (Hb), serum iron and serum ferritin. For women delivering before 37 weeks, post supplementation samples were collected in labour. The participant who developed anaemia during follow-up visit was treated based on the existing protocol in the hospital. The study was self-sponsored. The inclusion criteria were consecutive pregnant women who presented for antenatal booking during the study period at gestational age of 14-24 weeks and gave informed consent. The exclusion criteria were pregnant women who decline consent, those with history of intolerance to oral iron, chronic illnesses, menorrhagia, bleeding disorders, chronic peptic ulcer, bleeding haemorrhoids, or sickle cell disease as well as other haemoglobinopathies. Those women with prior blood transfusion, multiple pregnancies and history of obstetric haemorrhage in present or past pregnancies were also excluded just as those with conditions related to polycythaemia such as asthma and hypertensive disorders in pregnancy.

The sample size for each group was determined using the statistical formula for sample size calculation for 2 groups of equal sizes for a continuous variable outcome measure, stated below.[23]


n = minimum sample size per group

Zα = 1.96 Confidence level of 0.05

Zβ = 0.84 Acceptable power of 80% or 0.80

σ = Population variance of mean of serum ferritin (Standard deviation) which is 20 and was obtained in a previous study in Orlu, Nigeria.[24]

μ1 = Population mean of serum ferritin in 3rd trimester following 65 mg elemental iron which is 37.3 ng/ml (Group 1)

μ2= Population mean of serum ferritin in 3rd trimester following 130 mg elemental iron (Group 2). A minimum acceptable difference (effect size) of 25% was agreed as acceptable for this study and was set relative to μ1.

Thus μ2= 46.6 ng/ml

Substituting these values in the formula yielded:

n = 72.6 which was approximated to 73 participants per study arm.

Adjusting for 25% attrition rate this gave a sample size of 91 participants per study arm.

The primary outcome measure was post-supplementation maternal ferritin levels. The secondary outcome measures were post supplementation maternal serum haemoglobin, maternal serum Iron, birth weight and preterm delivery.

Mythic 22 Haematology autoanalyzer was the standard method that was available for haemoglobin estimation in the hospital and was used to estimate the haemoglobin. Haemoglobin concentration is given as g/dl. Serum ferritin was done using the ELISA machine, Stat Fax 2600 (Awareness Tech Inc., Palm city, FL, USA) with the Calbiotech, Inc. (CBI) Ferritin ELISA Kit.

Data were analysed using Statistical Package for Social Science (SPSS version 21).

The categorical variables were analysed with the Chi square test (X 2 – test) while continuous variables were analysed using t-test. A P value of ≤ 0.05 was accepted to indicate statistical significance. Per protocol analysis was used in analysis of the results.

   Results Top

Ninty-one (91) women were recruited in each arm of the study. Eighty-four (84) in once daily dose group and 80 in the twice daily group were eventually analysed. Ten (57%) of the participants were lost to follow up while 3 (16.7%) had mid trimester miscarriages. four had a combination of early side effects severe enough to allow for discontinuation and one participant had severe anaemia with blood transfusion. [Figure 1].
Figure 1: Trial profile

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About seventy per cent (70%) of women recruited in each arm of the study had at least secondary education. There were no statistically significant differences in the demographic characteristics of the two groups [Table 1].
Table 1: Socio-demographic variables of participants

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In general, all the reported side effects notably, nausea, vomiting and epigastric pain were higher in the twice daily ferrous sulphate group (P = 0.005, 0.043 and 0.004 respectively). [Table 2] describes the compliance with drug regimen between the two groups. There are about forty five per cent of those receiving twice daily dose failed to comply with administration request when compared with just 25% rate observed among those on once daily dose. A statistical significant non-compliance rate was also observed among the twice daily group (P = 0.009) [Table 2].
Table 2: Side effects and compliance level

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[Table 3] summarises the haematological end point measures of the study. The highest recorded haemoglobin level among the once daily group was significantly higher than the highest recorded among the twice daily group at the end of drug administration (P = 0.002). The serum Iron level after the trial demonstrated narrower range in the twice daily group (62.1 – 111.9 μg/dl) when compared with once daily group (48.2 – 147.4 μg/dl). The difference is statistically significant in favour of the once daily group (P = 0.040). There was no statistically significant difference in the iron reserve (ferritin) between the two groups before and after the drug administration (P = 0.451, 0.955 respectively).
Table 3: Serum haemoglobin, iron, and ferritin levels before and after the two supplementation regimens

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The fetal outcome measures were comparable between the two groups. Both the prevalence of low birth weight babies and average gestational age at delivery were similar with no significant difference between the two groups (P = 0.928 and 0.467 respectively). [Table 4]
Table 4: Fetal outcomes

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A woman in the once daily group and 2 in the twice daily group had out of hospital delivery.

   Discussion Top

The study comparing the effect of once daily versus twice daily ferrous sulphate supplementation on maternal haemoglobin and iron stores, the side effects and the effect of the two regimens on birth weight and prematurity have been conducted.

All the reported side effects were notably higher in the twice daily group than the once daily group with nausea, vomiting and epigastric pain being statistically significant. The metallic taste popularly associated with Iron supplements may have been responsible for the reported nausea and vomiting and the acid reflux oesophagitis responsible for epigastric pain in this study.[25] Perhaps, these complications may be dose dependent since they appear more pronounced among those taking the twice daily dose. This trend is consistent with the findings of Souza et al. who compared daily, twice weekly and weekly doses and reported higher side effects in those with higher doses of supplementation.[26] Sloan et al., Shatrugna et al. and Beard have all corroborated the fact that increasing the dose of elemental iron also increases the chances of side-effects.[27],[28],[29] It is also likely that persistence of nausea and vomiting beyond 16th week of pregnancy in up to 20% of women may have been responsible or a contributory factor to the recorded side effects.[30]

Consequently, compliance to ferrous sulphate was better among the once daily group compared to the twice daily group. Seventy-five per cent (75%) of the once daily group were compliant which compared with 55% compliance recorded among the twice daily group was statistically significant (OR = 0.41, CI = 0.210-0.790, P = 0.009). Almost all studies comparing compliance rate have consistently shown a statistically significant declining compliance trend with increasing frequency of doses prescribed.[26],[29] Researchers have shown that perhaps, the non-superiority of higher doses when compared with once daily dose regimen might be attributable to low adherence with the higher dose regimens [16] as demonstrated in this study where compliance among the twice daily dose was as low as 55%. This has been attributed to the side effects of higher supplementation regimens.[31] The same may have also been the reason why statistically significant increases in serum ferritin and haemoglobin levels were not seen in the twice daily group in this study.

There was a marginal reduction in the serum levels of ferritin in both groups. The mean levels however, still remained within the normal range of serum ferritin.[32] This is in keeping with existing literature that suggests that serum ferritin levels may fall regardless of supplementation regimen as pregnancy progresses.[24],[33],[34] It is notable that during pregnancy there is a significant increase in the amount of iron required to increase the red cell mass and transfer of increasing amounts of iron to both the growing fetus and placenta [3],[9] The common finding in these trials where the ferritin levels dropped slightly is that the supplementation was done in non- anaemic women [24],[33],[34] similar to the protocol in this study. The findings from our study however, were not in keeping with previous studies by Reddaiah et al., Than-Toe et al. and Abioye et al. who demonstrated that iron supplementation was associated with increase in serum ferritin level.[21],[22],[35] The common finding in these later trials of elevated serum ferritin levels seen after supplementation may be attributed to the fact that most of the women included were anaemic even before supplementation.[19],[21],[22],[35] The greater magnitude of response to iron supplementation in women with sub-optimal baseline hematologic status has been suggested to be due to increases in erythropoietin secretion in them.[36] Also linked to this may be the effect of hepcidin, the main hormone that regulates ferritin balance.[37] These may have been the reasons for the lack of increase in ferritin level in this study since majority of the women had normal ferritin levels at onset of supplementation. In pregnancy, serum ferritin concentration is maximal at 12–16 weeks gestation, then falls with advancing gestation to reach a nadir at the third trimester and therefore supplementation should maintain serum ferritin at a higher concentration.[37] This was however not the case in our study. The serum haemoglobin levels also decreased significantly after supplementation in both groups of women (once daily: 10.2 ± 0.8 g/dl vs twice daily 10.5 ± 0.3 gldl, P = 0.002). This finding corroborates with what was seen in the study by Bouzari et al., where daily supplementation with ferrous sulphate was compared with thrice weekly and once weekly ferrous sulphate, and they found a decrease in serum haemoglobin after supplementation in the daily and weekly groups and an increase in the thrice weekly group.[33] Our work was in agreement with that of Okwara et al. in which women took once daily dose also and showed a decline in haemoglobin from 11.2 g/dl in the first trimester to 10.4 g/dl in the third trimester similar to what was found in our study.[24] The common denominator in the two trials concerning ferritin is that the trials were conducted in non-anaemic women and as such the prevailing factors in ferritin are also of importance here. It may be postulated therefore that exogenous administration of iron in non- anaemic women has tendency to suppress the endogenous release of erythropoietin that may facilitate rise in heamoglogin level contrary to what is expected when women are anaemic. Whether this is an assumption or fact is a subject of another research. On the other hand, trials by Than-Toe et al. and Reddaiah et al. which compared daily versus twice daily iron showed a non-significant increase in the haemoglobin level post supplementation but with higher increase among the twice daily groups.[21],[22] Mumtaz et al. also showed that there was increase in haemoglobin level after supplementation.[38] These trials were in anaemic women where a significant increase is expected and probably, corroborating the above unproven assertion. In our study, even though there was a decrease in haemoglobin in both groups after supplementation, the decrease was more in the once daily group and this was statistically significant (once daily 10.2 ± 0.8 g/dl Vs twice daily 10.5 ± 0.3 g/dl P = 0.002). It therefore seems that twice daily dose may appreciably prevent significant decrease in haemoglobin concentration after supplementation without significant increase in ferritin especially when the values at booking are barely optimal by WHO standard as seen in this study. Even though ferritin and haemoglobin levels investigated in this study showed a decreasing trend, there was a statistically significant rise in the level of serum iron both in the once daily and the twice daily group similar to what was found by Okwara et al. and Than-Toe et al.[23],[24] These results may be explained by the fact that the usual pharmacokinetic measurement of serum iron levels may be unreliable when evaluating the bioavailability and efficacy of iron preparations.[39] This has been attributed to its ubiquity, compartmentalized sites of action and complex metabolism.[39] The use of micronized dispersible ferric pyrophosphate combined with alpha-lactalbumin among anaemic pregnant women was associated with significant increase in haemoglobin, ferritin and serum iron with no significant side effects.[40] However this form of iron is not readily available in this part of the world. The fetal outcomes in this study were similar in both groups as it relates to normal birth weight (P = 0.936), low birth weight (P = 0.928) and gestational age at delivery (P = 0.467). This finding was similar to the findings by Yekta et al. in which birth outcome was compared in non- anaemic women on supplementation with once daily, twice weekly and weekly iron. In that study, infants born to women who were assigned to the different treatment groups showed no significant difference in average birth weight (P = 0.521).[41] The difference in gestational age at delivery was not significant across the randomization groups (P = 0.13), as well the incidence of preterm delivery, and low birth weight (P = 0.31, 0.25, and 0.33, respectively). Even though fetal iron supply is provided by deflection of a significant proportion of maternal iron to the developing fetus, it had no significant adverse bearing on the fetal outcome in this study probably because the haematological parameters remained within normal limits.[41] Some notable limitations in this study have been included but not limited to the fact that the reported side effects were unspecific and difficult to ascertain if they were drug or pregnancy related. It was also difficult to ensure actual compliance as participants could be taking other haematinics and still bring empty packs for evaluation. It is also known that ferritin is an acute phase reactant and values obtained may not have been a true representation of iron supplementation in patients who had infection or inflammation.[8] Perhaps, if C-reactive proteins were evaluated in those women, a causal relationship may be established.

The findings of this study, together with the recommendation by WHO provide support for a policy of offering routine iron supplementation to all women during pregnancy. From this study therefore, it appears that the once daily ferrous sulphate supplementation is not only as effective as twice daily dose in non-anaemic pregnant women but also associated with fewer side effects and guarantees better compliance. Routine once daily dose of 65 mg of ferrous sulphate may be advocated for prevention of anaemia in pregnancy in developing countries provided the woman has normal heamoglobin level for that environment at booking. The implications for future research in view of one of the limitations of this study may be that there is need for more studies to determine if serum ferritin level or serum transferrin level is a better indicator of iron stores in pregnancy.

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Conflicts of interest

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  [Figure 1]

  [Table 1], [Table 2], [Table 3], [Table 4]


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