Compliance of daily iron supplementation during pregnancy affecting the hemoglobin level in second trimester and at term

Objectives: To determine the compliance rate of iron supplementation during pregnancy and the hemoglobin concentration in second trimester and at term. Methods: The study conducted among term pregnant women admission to the hospital for delivery who had nonanemic status at the initial visit for antenatal care, received daily iron supplementation before 20 weeks of gestation. They were interviewed to obtain the personal data, daily taking the supplemented tablet and side-effects. The compliance rate categorized as >80%, >50-80%, 25-50%, and < 25% according to the women’s response that they took daily tablet of 6-7, 3-5, 2, and 0-1 days/week, respectively. The type of supplementation and laboratory results of hemoglobin level were retrieved from their medical records. Results: Almost 90% of 350 participants had the compliance rate of >80%. The common side-effects were nausea and constipation. The side-effect rates were 10.5%, 12.1%, 66.7% in >80%, >50-80%, <25% compliance groups, respectively. In second trimester and term pregnancy revealed some anemic women. While hemoglobin concentrations above 13 gm/dl, which dened as high concentrated hemoglobin, revealed 12% during second trimester, and up to 30% at term in high compliance group. Conclusions: There was high compliance rate of iron supplementation with the high hemoglobin level markedly found in high compliance group.

Results: Almost 90% of 350 participants had the compliance rate of >80%. The common side-effects were nausea and constipation. The side-effect rates were 10.5%, 12.1%, 66.7% in >80%, >50-80%, <25% compliance groups, respectively. In second trimester and term pregnancy revealed some anemic women. While hemoglobin concentrations above 13 gm/dl, which de ned as high concentrated hemoglobin, revealed 12% during second trimester, and up to 30% at term in high compliance group.
Conclusions: There was high compliance rate of iron supplementation with the high hemoglobin level markedly found in high compliance group.

Background
Worldwide prevalence of anemia among pregnant women was 41.8% and iron de ciency anemia is the most common cause of this problem (1)(2)(3). Iron de ciency during pregnancy is thought to be caused by multifactorial such as lowiron diet intake, malabsorption in gastrointestinal tract, parasitic diseases or short inter-pregnancy interval (4). Iron de ciency anemia was associated with adverse pregnancy outcomes such as preterm delivery, low birth weight, and peri-partum blood transfusion (5)(6)(7).
Iron requirement of pregnant women are greater than in the non-pregnant state. Approximately 1000 mg of elemental iron is needed in normal pregnancy in addition to 500 mg of them is consumed for maternal red blood cell production (8)(9). Insu cient iron storage in pregnant women are generally observed, subsequently ordinary iron supplementation during pregnancy is bene cial (10)(11). However, in previous studies' ndings the compliance rate of iron supplement in pregnant women were merely 41.4-65.9% (13)(14)(15). There are many factors association with non-regularly taking the iron tablet, such as gastrointestinal side effects, low educational status, late antenatal care (> 16 weeks of gestation), and no receiving health education about the bene t of iron supplementation. Ugwu et al. (2014) reported the leading obstacle to comply to daily iron intake was gastrointestinal side effects about 41.7%. Several gastrointestinal side-effects of oral iron supplementation included heartburn, nausea, stomach cramping, constipation, diarrhea, and vomiting (16).
World Health Organization (WHO) recommended daily iron and folic acid supplementation with 30-60 mg of elemental iron and 0.4 mg folic acid for pregnant women to prevent maternal anemia, puerperal sepsis, low birth weight, and preterm birth. If daily iron is not acceptable due to side-effects, and in populations with an anemic prevalence among pregnant women of less than 20%, then the intermittent oral iron and folic acid supplementation with 120 mg of elemental iron and 2.8 mg folic acid once weekly is recommended (12). Prevalence of anemia among pregnant women aged 15-49 years in 2011 of the global survey, Thailand was categorized in the prevalence group of greater than 20% (1). Therefore, daily iron supplementation is a routine practice for antenatal care in our setting.
Though during antenatal care we do a routine blood test to assess general health status including anemia, thalassemia, hepatitis, syphilis and HIV infection. The women without anemia and some with high hemoglobin concentration from blood test at initial visit, second trimester, and at term, they still received iron supplementation. So, we plan to evaluate the compliance rate and the hemoglobin concentration in second trimester through at term pregnancy among groups of different rate of compliance.

Methods
This study was a questionnaire-based prospective cross-sectional study conducted at Srinagarind Hospital, a tertiary hospital in Khon Kaen, Thailand. Study protocol was approved by the Khon Kaen University Ethics Committee in Human Research (HE611623). All participants provided written informed consent before data collection. Regarding a compliance rate of 65.9% from a previous study (15), with 95% con dence level and an error margin of 5%, the estimated sample size was at least 349.
Inclusion criteria counted in 18-year-old or older, term pregnancy, non-anemic status at initial blood test on antenatal care and received daily iron supplementations before 20 weeks of gestation. Non-anemic status was de ned as hemoglobin level 11.0, 10.5, 11.0 gm/dl or more in rst, second, and third trimester, respectively. Hemoglobin concentrations above 13 gm/dl was de ned as high concentrated hemoglobin. Women with thalassemia disease or any contraindication for iron supplementation were excluded. The data gathered from participants after admission to the hospital for delivery. They were interviewed to obtain the personal data, regularity of daily taking the supplemented tablet and happening of side-effects (e.g. nausea, vomiting, abdominal cramping, bloating, constipation, and diarrhea). The compliance rate categorized as > 80%, > 50-80%, 25-50%, and < 25% according to the women's response that they took daily tablet of 6-7, 3-5, 2, and 0-1 days/week, respectively. Their medical records were reviewed to retrieve the type of supplementation and laboratory results of hemoglobin level during second trimester, and at term pregnancy. The protocol was conducted in the respect for the individual, the right to self-determination and the right to make informed decision regarding participation in the project, both initially and during the course of the research which in accordance with the principles of the Declaration of Helsinki.
Descriptive statistics were used to describe the demographic baseline characteristics. Numerical data were expressed as mean, standard deviation, percentages and 95% con dence interval (CI) to demonstrate the precision of the data.
Categorical variables were expressed as percentages. A p-value < 0.05 was considered statistically signi cant.

Results
A total of 350 pregnant women were recruited between August 9, 2019 and June 15, 2020. From 350 questionnaires were implemented, 324 (92.6%) were completely lled out. Most of the incomplete data resulted of lacking to record hemoglobin level at term pregnancy. The participants' characteristics were shown in Table 1 as their mean aged of 29.3 years, majority of them in the aged range of 20-35 years. Almost 60% were the second pregnancy, while almost all (98%) had stable marital status. More than half had graduate education and none smoking exposure. Most of them received Triferdine (59.4%) and ObiminAZ (38.0%) as the tablet for iron supplementation. Triferdine is produced and supplied by the Government Pharmaceutical Organization, contained of iron 60.81 mg, potassium iodide 0.15 mg; folic acid 0.4 mg. ObiminAZ is the product of the commercial pharmaceutical company, contained ferrous fumarate 200 mg, iodine 0.2 mg, folic acid 1 mg, and vitamin A, B1, B2, B6, B12, C, D, E, nicotinamide, zinc, and calcium lactate. The compliance as in Table 2 demonstrated that almost 90% of participants had compliance rate of greater than 80%. There was none in the compliance rate of 25-50% and a few of women in compliance rate < 25%.  In Table 3 showed the frequency and rate of side-effects occurrence among different compliance groups of iron supplementation. Mostly of reported side-effects were nausea and constipation. The less compliance rate found in the more proportion of side-effects occurrence as the results revealed that the total proportion of side-effects occurrence were 10.5%, 12.1%, 66.7% in > 80%, > 50-80%, < 25% compliance groups, respectively. In this study, the hemoglobin level in second trimester of pregnancy were evaluated vary between 28 and 36 weeks of gestation. According to the hospital protocol to take blood test for complete blood count, VDRL and anti-HIV in gestation of 28-32 weeks, however some of them were tested out of the hospital protocol range. Hemoglobin level at term was available in 324 from 350 women. The results in Tables 4 and 5, there was no difference rate of anemia during second trimester between all groups of compliance (p-value > 0.05). While at term pregnancy, rate of anemia was 50% (N = 1/2, 95%CI: 1.25-98.74) in < 25% compliance group. The lowest hemoglobin concentration was 9.7 gm/dl in second trimester and was 9.9 gm/dl at term of gestation, all of them were in > 80% and > 50-80% compliance groups. None of them had severe anemia.

Discussion
Iron supplementation during pregnancy had been practiced for decades in developing country. According to WHO recommendation to implement daily iron supplementation during pregnancy to prevent pregnancy complications when the prevalence of anemia greater than 20% (12). The last WHO global survey in 2011publicized the prevalence of anemia in Thailand greater than 20% (1). In view of that, routine iron supplementation in non-anemic pregnant women is also be practiced for antenatal care in this study setting. However, the study revealed that almost 90% of pregnant women had such a high compliance rate of > 80%, the side effects rate was around 10%, they still had anemia in second trimester and at term 1-2%. Other than that they challenged with high hemoglobin concentration rate of 12% and 32% in second trimester and at term, respectively.
The iron supplementation is a recommended practice for antenatal care to improve pregnancy outcomes. Sometimes it can cause undesired side effects which is unable to tolerate in some women. In this study ndings found such a high compliance rate of 89.7% when compared to other studies with high compliance rates of 80-85% (18). While there were low compliance rates in many studies of 20-60% (17)(18)(19). Other than the side effects of iron supplementation might affect the compliance, in previous studies found that it may associate with marital status, maternal age, and educational level (13-14, 19, 21). In addition, the study's results showed that the more side-effects occurrence found in the less compliance rate as the results revealed that the total proportion of side-effects occurrence were 10.5%, 12.1%, 66.7% in > 80%, 50-80%, < 25% compliance groups, respectively. The result was consistent with those reported from previous studies that iron supplementation signi cantly increased risk of gastrointestinal sideeffects, 19.7-63.3% of non-compliance women (13,(16)(17)19).
In our study, though there was no signi cant difference of anemia developed during second trimester and at term pregnancy between all compliance groups. However, there was anemia in second trimester and at term 1-2% in > 80% compliance group and found one of two woman developed anemia in < 25% compliance group at term pregnancy. This was contrast to previous studies that anemia was signi cant associated with non-compliance of iron supplementation (14,(22)(23).This inconsistent data may due to including nearly 30% of anemic women at initial of their studies. Other than that, in our setting is a prevalence area of thalassemia that iron supplementation could not prevent anemia. So that we still found anemia in high compliance group.
Regarding to the study's ndings that high hemoglobin concentration occurred with a substantial portion (12% − 32%) in high compliance groups. Although, there was lack of evidence indicating that iron supplementation can result in abnormally high hemoglobin concentration (21). However, without iron supplementation during pregnancy would not be anemia in women with hemoglobin level greater than 13.2 gm/dl (22). Hemoglobin level greater than 13.0 gm/dl was associated with SGA, stillbirth, preeclampsia, gestational diabetes, low birth weight and preterm delivery (24)(25).
Thus, health-care providers should take more precaution to offer iron supplementation for non-anemic pregnant women to avoid maternal high hemoglobin concentration status and diminish undesirable side-effects. Otherwise, intermittent iron supplementation should be encouraged to apply in non-anemic pregnant women (11)(12).
The strengthening results of this study may account to that all information to evaluate the compliance of taking daily iron supplementation was obtained directly from participants who provided well co-operative response on concerning of the effect on their pregnancy outcomes if they could not take enough tablet. Nonetheless, it had too small number of participants in less compliance groups to assess the factors that may affect the compliance other than the side effects. In addition, further study to assess if it is necessary to implement iron supplementation in non-anemic women in the setting with routine blood testing for anemia during antenatal care at the initial visit and in second trimester.

Conclusions
We found high compliance rate of iron supplementation in non-anemic pregnant women, with the more occurrence of side-effects had the less compliance. While anemia still appeared in high compliance women, where anemia due to other cause should be concerned. Other than that high hemoglobin concentration substantially be found in high compliance group. Therefore, health-care providers should keep more thoughtfulness in the women who have hemoglobin level greater than 13 gm/dl on initial visit of antenatal care before implementing routine iron supplementation to avoid maternal high hemoglobin concentration status and diminish undesirable side-effects. Ethics approval and consent to participate Study protocol was approved by the Khon Kaen University Ethics Committee in Human Research (HE611623) before starting data collection. All participants provided written informed consent before data collection.

Consent to publish
Not applicable

Availability of data
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.