Clinical trial NCT04594070
Conditions: Pregnancy Related Iron Deficiency Anemia of Pregnancy
Keywords: Pregnancy Iron deficiency Anemia Iron supplementation
Sponsor: The University of Texas Medical Branch, Galveston
Start date: 2020-10-27; Completion date: 2024-01-12
Enrollment: 14 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The target population for our study is pregnant women in the first or second trimester with a diagnosis of iron deficiency anemia. If a subject is eligible, written consent will be obtained by person to person contact. Eligible participants will be randomized to receive either daily oral iron supplementation or every other day oral iron supplementation.

Detailed description:
Eligible pregnant women in the first or second trimester who carry a diagnosis of iron deficiency anemia as defined by the American College of Obstetrics and Gynecology will be approached, consented, and randomized to receive either daily oral ferrous sulfate (325mg) supplementation or every other day oral ferrous sulfate (650mg). Participants will undergo a phone survey 2-4 weeks after starting the study to assess for side effects. Participants will continue routine care and surveillance of iron deficiency in pregnancy until the end of pregnancy.

Arms: arm 1: Oral ferrous sulfate, 325 mg, take once daily arm 2: Oral ferrous sulfated, 650mg, taken once daily every other day
Interventions: intervention 1: Ferrous sulfate
Intervention descriptions: intervention 1: Iron supplementation

Protocol documents:
Prot_SAP_000.pdf: 
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The University of Texas Medical Branch at Galveston 
Research Protocol # 20-0068 
 
Title: A Randomized Trial of Intermittent Oral Iron Supplementation vs. Daily Oral Iron Supplementation for 
the Treatment of Anemia in Pregnancy 
 
Principle Investigators: Melody Safarzadeh, MD, MS 
 
Faculty Sponsor: Gayle Olson, MD 
 
Funding Sponsor: Departmental 
 
 
1. Introduction and Purpose: 
Anemia in pregnancy affects 18-21% of pregnant women in the United States and is associated with low birth 
weight, preterm delivery, and perinatal mortality as well as a possible association with postpartum depression 
and poor mental and psychomotor performance testing of offspring. Current treatment of iron deficiency anemia 
in pregnancy consists of daily iron supplementation with the intent of raising hemoglobin back to normal ranges. 
A recent review examining misconceptions in the management of iron deficiency described the misconception 
of high dose daily iron supplementation noting, “low daily doses (e.g. 50 mg) or moderate doses (e.g. 100 mg) 
every other day may increase both tolerance and efficacy of oral iron supplementation” (1). Further 
commentaries call for continuing research into every other day dosing (2). Given the prevalence and 
complications of iron deficiency anemia in pregnancy, we propose to study if alternate day dosing of oral iron 
supplementation is statistically superior or at least not inferior to daily dosing in raising third trimester 
hemoglobin. 
 
Brief Study Design and Rationale 
Two randomly assigned groups will be compared during the antepartum period: 
1. Control Group: standard of care, daily oral iron supplementation of ferrous sulfate 325 mg (65 mg 
elemental iron) taken by mouth once daily. 
2. Intervention Group: alternate day dosing oral iron supplementation of ferrous sulfate 650 mg (130 mg 
elemental iron) taken by mouth every other day. 
 
Historically twice or thrice daily oral iron supplementation has been the recommended as the first line treatment 
of iron deficiency anemia. This standard of care for oral iron therapy is starting to change (1, 2) with some 
current textbooks and guidelines recommending either daily or every other day dosing regimens (3, 4). The 
standard of care at UTMB for the detection and treatment of iron deficiency anemia is as follows. All pregnant 
patients undergo blood draws at their first appointment for anemia screening. Those patients who are identified 
as anemic then undergo further studies to determine the type of anemia. Those patients determined to have iron 
deficiency anemia receive oral iron supplementation. There are many different iron supplements that are used at 
UTMB to treat iron deficiency in pregnancy. These supplements vary in elemental iron content, enteral coatings, 
and supplements combined with vitamins and minerals. The choice of which iron supplement that patients 
receive is left to the discretion of the provider caring for the patient. Among these choices, ferrous sulfate 
(325mg, with 65mg elemental iron) is very commonly prescribed to UTMB patients and thus is the oral iron 
therapy that will be used for this study. Standard UTMB treatment surveillance includes blood draws at least 
every trimester or more frequently based on symptomatology of patient and provider discretion. This study will 
follow the UTMB standard treatment surveillance protocol and thus study participants will have no study 
specific blood collections. As part of this standard surveillance if hemoglobin levels remain low patients may be 
considered for more aggressive treatments such as IV iron infusion or transfusion. The decision to escalate 
treatment takes into account risk of cesarean delivery and risk of obstetric hemorrhage among other 
considerations and will be left to the discretion of the provider. 
 
 


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Primary outcomes: 
• 
Change in hemoglobin and hematocrit in the 3rd trimester 
 
Secondary outcomes: 
• 
Assessment of GI adverse effects determined by survey 
• 
Analysis of CBC indices including reticulocyte count, MCV, etc. 
• 
Iron studies at time of diagnosis 
• 
Need for parental iron supplementation 
• 
Need for transfusion in the peripartum period 
• 
Postpartum hemoglobin and hematocrit 
• 
Neonatal weight 
• 
Presence of antepartum fetal growth restriction 
• 
Neonatal outcomes such as NICU admission, hyperbilirubinemia, and APGAR scores 
• 
Relationship of obesity to effectiveness of supplementation in both study arms 
 
Study Risks and Benefits: 
The known risks of oral iron therapy are gastrointestinal upset such as nausea and vomiting, constipation, and 
abdominal pain. Oral iron supplementation for the treatment of iron deficiency anemia in pregnancy is the 
standard of care and as such has been demonstrated to be a safe and effective treatment. Studies have 
demonstrated that intermittent dosing of oral iron can result in increased iron absorption, however this has not 
been studied in a pregnant population (5, 6).  
 
2. Background: 
The prevalence of iron deficiency anemia (IDA) in reproductive aged women aged 20-49 years is estimated to 
be 9.2% (7). In pregnancy, rates of anemia affect between 18-21% of pregnant women in the United States with 
non-Hispanic blacks and teenage mothers affected at even higher rates (8, 9). Outside of pregnancy anemia has 
been estimated to account for 8.8% of global disability (10). However, during pregnancy IDA has been 
associated with increased risk of low birth weight, preterm delivery, and perinatal mortality as well as a possible 
association with postpartum depression and poor mental and psychomotor performance testing of offspring (8). 
Gabbe et al. notes that “In developing nations, severe anemia is alarmingly common and is a major cause of 
maternal morbidity and mortality” (11). Pregnant patients with anemia are at further risk for blood transfusion in 
the event of postpartum hemorrhage. 
 
In pregnancy, hematology physiology changes drastically. Total blood volume increases by approximately 50% 
and red blood cell mass increases by 25% (8). The relative increase of blood volume compared to red blood cell 
mass causes a physiologic anemia of pregnancy and therefore the hemoglobin and hematocrit threshold for 
diagnosing anemia in pregnancy are different than that of a non-pregnant adult (8). This increase in red blood 
cell mass, combined with the needs of the fetus, placenta, and normal anticipated blood loss from vaginal 
delivery represent a total additional need of 1,000 mg iron for a pregnancy. It is therefore, unsurprising that the 
most common etiology of anemia in pregnancy is iron deficiency, representing 75% of all anemia in pregnancy 
(11). 
 
The World Health Organization (WHO) recommends that pregnant women take 60 mg elemental iron daily 
while noting that 30 mg might be sufficient (12, 13). The American College of Obstetrics and Gynecology 
(ACOG) however notes that, “It is unclear whether iron supplementation in well-nourished pregnant women 
who are not anemic affects perinatal outcomes” (8). Most pregnant women receive some level of iron 
supplementation through the administration of prenatal vitamins. 
 
The definitive diagnosis of iron deficiency should be made with measurement of serum iron, ferritin, and 
transferrin saturation; however, recent iron therapy and extended periods of anemia can complicate the 
interpretation of these results (11). The diagnosis of iron deficiency is often presumed in pregnant patients with 


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a hemoglobin below 11 g/dl in the first trimester and/or 10.5 g/dl in the second trimester and iron therapy is 
often empirically started without first obtaining iron studies (8).  
 
For iron deficient anemic individuals, the current recommendation for treatment by the CDC is oral 
supplementation of 60-120 mg of elemental iron daily (14). However this regimen is being questioned with 
some sources recommending every other day dosing (3, 4, 15). Ideally response to supplementation should be 
seen in about 3 weeks in a non-pregnant patient (16). In pregnancy response of an anemic patient to oral iron 
therapy should be seen with reticulocytosis after 3-10 days and hemoglobin should begin to increase within one 
week (11, 17). Iron stores however may take 1 month or longer to replenish (11, 18). Of note, obese patients 
have been found to have decreased iron stores thought to be secondary to an inflammatory response from 
obesity and increased levels of Hepcidin (19). 
 
While generally considered safe, oral iron supplementation can be commonly associated with adverse 
gastrointestinal complaints including metallic taste, nausea, vomiting, heartburn, epigastric pain, diarrhea, and 
constipation (20).  
 
Early studies have begun to question the effectiveness of daily iron supplementation in IDA. Internationally, 
studies conducted in Malawi (2000) and China (1996) for anemic and non-anemic pregnancy women 
demonstrated no difference between outcomes (21, 22). A 2015 Cochrane review examined intermittent iron 
supplementation in anemic concluded that there was no benefit to intermittent supplementation, however this 
review was limited by a small number of poor quality studies included in the meta-analysis (23). Faced with the 
obvious limitations of these studies, a more systematic investigation into the physiology and biochemistry of 
oral iron supplementation was then described. The absorption of iron is a tightly regulated process with 
hepcidin, the principal iron regulatory hormone, functioning to inhibit iron absorption in the gut (20, 24). In 
pregnancy, hepcidin levels have been demonstrated to be lower (25). In response to elevated iron stores, 
hepcidin levels increase thereby inhibiting further systemic iron absorption (26). Recent data has described that 
oral iron supplementation can increase hepcidin levels as well. In 2015, a study demonstrated that after oral iron 
supplementation of 60 mg elemental iron or greater, hepcidin levels increased for the next 24 hours which in 
turn decreased the fractional iron absorption (27). A follow-up study in non-anemic, iron deficient women 
demonstrated that the inhibitory effect of hepcidin on daily iron dosing could be overcome with single day 
dosing on alternate days with increased cumulative iron absorption in the alternate day dosing group (6). This 
study was further strengthened with a similar trial, this time in iron-deficient, anemic women which 
demonstrated that alternate day of 100-200 mg elemental iron resulted in higher fractional iron absorption with 
lower GI side effects when comparted to daily dosing (5). Based on studies such as these, some experts have 
suggested the current treatment of iron therapy may be incorrect, and that alternate day dosing might be 
beneficial, though further studies are needed (1, 2, 4, 16, 20, 28). Several similar studies are currently in process 
at this time, links listed in the references section (29-32). 
 
3. Concise Summary of Project: 
This trial will be a comparative pragmatic open label randomized controlled trial of daily versus alternate day 
dosing of oral iron in anemic pregnant patients.  
 
Two randomly assigned groups will be compared during the antepartum period: 
1. Control Group: standard of care, daily oral iron supplementation (325 mg PO daily ferrous sulfate) 
2. Intervention Group: alternate day dosing oral iron supplementation (650 mg PO every other day ferrous 
sulfate) 
325mg Ferrous sulfate is a standard oral iron supplement providing 65 mg of elemental iron per dose. Standard 
dosing recommendations for the treatment of iron deficiency anemia is between 65 to 200 mg elemental iron 
daily. 
 
Each group will receive a phone survey 2-4 weeks after initiation of therapy to assess side effects of each group 
as well as compliance. Call is anticipated to last approximately 10-15 minutes. This survey has previously been 
validated in assessing gastrointestinal symptoms for those taking oral iron supplementation (33). 


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The number of subjects studied will be 86 subjects at UTMB, we plan to approach and consent up to 96 patients 
to allow for screening failures, early withdrawals, and patients lost to follow-up, and patients who must 
withdraw due to failure of therapy. Failure of therapy for the purposes of this study will be patients who require 
parental iron supplementation or transfusion. Study to last an anticipated length of 3 years. If our sample size is 
not achieved, we will submit to the IRB an addendum to increase the number of consented subjects to achieve 
the desired sample size. 
 
 
4. Study Procedures: 
Patient Population 
The patient population will be selected from obstetric patients receiving prenatal care in the UTMB health 
system. This population can broadly be divided into patients cared for by one of the UTMB faculty obstetric 
providers and those who receive care through the Regional Maternal and Child Health Program (RMCHP). We 
anticipate that the majority of the patients in this study will be recruited from the RMCHP patients. 
 
Locations 
All RMCHP clinics locations will be possible recruitment sites, however we anticipate that the bulk of the 
recruitment will occurs at the Galveston, Pasadena, and Angleton clinics were the PI and perinatal research 
division staff are frequently located. Research staff will travel to each clinic and consenting and enrolling will 
only occur when research staff are present. 
 
Research Team 
The research team (or research staff) will consist of the PI, faculty sponsor, trained research coordinator, and 
additional staff to be trained and added to the research protocol. All members of the research team will be able 
to screen and consent subjects. Physician research team members will be responsible for providing the 
prescriptions to patients who agree to take part in this study. The PI and faculty sponsor will work together to 
ensure that the team is of sufficient size to carry out the project. Consenting and enrollment of subjects will only 
occur when a research team member is physically present at a study location. 
 
Screening 
All pregnant patients undergo a laboratory screen for anemia at the first prenatal appointment as part of the 
UTMB standard of care. Eligible patients (1st or 2nd trimester patients with a hemoglobin below 11 g/dl or 10.5 
g/dl respectively) will be screened and approached at their next prenatal appointment for consent (detailed under 
section 9). We request a waiver to screen these patients. 
 
The anticipated procedures flow is as follows 
1. Research staff will travel to location 
2. Research staff will confirm with provider that possible subjects are appropriate candidates for treatment 
with ferrous sulfate 
3. Research staff will approach screened patients to obtain consent from possible subjects 
4. Subjects will be randomized using a randomization log with group assignment, subject name, and 
medical record number 
a. Daily dosing group will take ferrous sulfate 325 mg (65 mg elemental iron) by mouth daily 
b. Alternate day dosing group will take ferrous sulfate 650 mg (130 mg elemental iron) by mouth 
every other day 
5. Prescriptions for the appropriate regimen will be provided by the research staff 
a. If the research staff is a physician, the appropriate prescription will be sent at time of encounter 
b. If the research staff is a non-physician, a physician research staff member will be alerted and the 
appropriate prescription will be sent on the same day 
6. After patient is consented and enrolled, the provider will be notified and a note will be placed in the 
electronic chart indicating that the patient is enrolled in the study. 


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7. Subjects will continue to receive standard, routine prenatal care and surveillance of iron deficiency 
anemia in pregnancy 
a. Research staff and PI will monitor surveillance data by chart review 
8. 2-4 weeks after initiation of respective iron regimen research staff will contact subjects by phone to 
administer a 5-10 min survey to assess GI side effects and compliance with regimen. 
9. Research staff will conduct chart review to obtain the datapoints for the primary and secondary 
outcomes (described in section 1) 
 
Survey Details 
2-4 weeks after randomization, the patient will receive a phone call from a member of research staff to conduct a 
brief  5-10 min survey to assess gastrointestinal side effects of iron supplementation and compliance. Patients 
will be made aware of this survey in the consenting process. Study subjects will then resume standard prenatal 
care visits. 
 
Additional details 
The routine prenatal visits for pregnant patients with anemia include at least monthly venipunctures to monitor 
the treatment of anemia and intervene if necessary. Our primary outcome of 3rd trimester hemoglobin as well as 
laboratory secondary outcomes are convenient data points collected in the standard treatment and surveillance of 
anemia in pregnancy. As such patients will not need any study specific venipuncture or visits. Prenatal visits are 
frequent with monthly visits in the 1st trimester, bi-monthly visits in the 2nd trimester, and weekly visits in the 3rd 
trimester with 24 hour after hours care phone services available. The frequency and ready availability of 
appointments ensures that any symptomatic patient will quickly be seen and evaluated. 
 
Any subject that requires escalation of treatment beyond oral supplementation (IV iron infusion or blood 
transfusion) will be referred to receive appropriate intervention. These subjects will still be included in the 
intent-to-treat analysis. The routine surveillance of anemic pregnant patients described above ensures that any 
treatment failure will be quickly identified and addressed. 
 
Outcomes 
Our primary outcome will be change in hemoglobin and hematocrit in the 3rd trimester. Based on the available 
evidence with hypothesize that alternate day dosing of oral iron supplementation will be superior or at least not 
inferior to daily oral iron supplementation. Additionally we aim to assess the secondary outcomes as listed in the 
introduction obtained by chart review. Data to be collected includes population characteristics including 
demographics and data points described in the outcomes listed under the introduction obtained by chart review. 
A detailed explanation of the analysis of the primary outcome is described in a later section. 
 
5. Sub-Study Procedures: 
Not applicable 
 
6. Criteria for Inclusion of Subjects: 
• 
Maternal age ≥ 18 years and <50 years 
• 
Prenatal care provided at UTMB  
• 
Hemoglobin below 11 g/dl in the first trimester and/or 10.5 g/dl in the second trimester 
• 
Microcytic anemia 
• 
Singleton gestation 
 
 
7. Criteria for Exclusion of Subjects: 
• 
Enrolled in another trial that may affect outcome at the discretion of the PI 
• 
Diagnosis of malabsorptive disorder or history of gastric bypass procedure 
• 
Known diagnosis of anemia other than iron deficiency (thalassemia, macrocytic anemia, sickle cell, etc.) 
• 
History of cardiopulmonary disease 


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• 
Severe anemia of requiring transfusion or parental iron at time of randomization 
 
8. Sources of Research Material: 
The primary and secondary outcomes for this trial will be obtained from chart review for enrolled patients. 
 
9. Recruitment Methods and Consenting Process: 
Patients receiving prenatal care at the UTMB/RMCHP clinics will be screened to identify patients with a 
hemoglobin below 11 g/dl in the first trimester and/or 10.5 g/dl in the second trimester who also satisfy 
inclusion and exclusion criteria. RMCHP clinical providers will be educated about the trial prior to enrollment. 
We plan to identify these patients by screening the charts of patients scheduled in clinic to identify potential 
subjects. Information to be reviewed as part of the screening process will be hemoglobin laboratory data and 
relevant exclusion and inclusion history. Research staff will function as the screeners and will alert providers 
that their patient is a potential subject. The provider caring for that patient will then be informed of the patient’s 
eligibility. Research staff will work with the provider to ensure that the study intervention is appropriate therapy 
for the patient. If the provider agrees that the study intervention is appropriate, the provider will then approach 
the patient to ascertain interest in participation. If the patient has interest, the provider will introduce the 
research staff to the patient who will then explain the study the patient as part of the consenting process. A 
screening log will be used to track all subjects approached for the study. At the time of consent and 
randomization, the patient will be educated as to the dosing regimen as well as the routine treatment surveillance 
that will occur. This will be done by the research staff consenting the patient. 
 
Spanish speakers: 
Spanish speaking patients will be screened by use of a Spanish interpreter and all patient study materials and 
surveys will be translated into Spanish. 
 
Consenting process: 
Written consent will be obtained at the follow up visit by direct person-to-person conversation. The PI or a 
collaborator will be responsible for the informed consent. Subjects will be given time needed in order to fully 
understand and read the consent forms. All efforts will be made by the research staff to answer all questions the 
subject has and to ascertain that subjects have the right to refuse to participate in the study. The consent form 
and process will describe that patients will be randomly assigned to either the study or control group. Each 
patient will be informed that participation is completely voluntary and in no way will affect the prenatal care 
they receive. 
 
10. Potential Risks: 
Randomization Risk: 
Since treatment will be randomized, it is possible that one or more of the other treatment groups will have 
more benefit or lower side effects than the other group. 
 
Loss of Confidentiality: 
Any time information is collected, there is a potential risk for loss of confidentiality. Every effort will be 
made to keep the subject’s information confidential; however, this cannot be guaranteed.  
 
Persistence of anemia 
The every other day dosing group receives iron less frequently than the daily iron dosing group. This 
could cause an increased risk of persistence of anemia as the every other day dosing may not work as 
well as every day dosing. 
 
11. Subject Safety and Data Monitoring: 
The PI and research coordinator will be responsible for monitoring the safety of this study. Details of monitoring 
submitted separately. 
 
12. Procedures to Maintain Confidentiality: 


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Data collection will be identified with a participant ID number. Data will be collected and stored with the 
participant ID code only. The master enrollment log linking subject identifiers with study ID numbers will be 
kept in a password-protected database. Relevant data variables (specified under outcomes) will be collected by 
chart review and placed into an Excel or Access file. These files will not contain identifiable information and 
will be stored in password protected, secured UTMB servers. The research coordinator and PI will be available 
to monitor the data and correct any discrepancies based on source documents if needed. 
 
13. Potential Benefits: 
The potential benefits of the study to the intervention group (alternate day dosing) include: 
1. Improved fractional absorption of iron with corresponding improvement of anemia compared to 
standard oral iron replacement therapy 
2. Decreased GI side effects with alternate day dosing 
 
14. Biostatistics: 
We hypothesize that the intervention group will have a higher hemoglobin level in the third trimester than the 
standard group. The primary analysis will be conducted on an intention-to- treat basis. Between-group 
differences in continuous variables, will be assessed using Student t test or Man-Whitney rank sum test and 
results will be given as mean, standard deviation or median range as appropriate. Categorical variables will be 
assessed using the Pearson chi-square test or Fisher exact test as appropriate.  For dichotomous endpoints, 
relative risk (RR) and 95% CI values will be calculated.  P <0.05 will be considered significant. The analysis 
will be performed after study completion. 
Based on our historical data at our center of 56 anemic women with iron deficient anemia that received standard 
daily iron supplementation: third trimester hemoglobin mean of 10.27 ± 1 g/dL. We will first do a noninferiority 
approach. If noninferiority is not met, we will do a superiority analysis. For the noninferiority: If there is truly 
no difference between the standard and experimental treatment, then 68 subjects will be required to be 90% sure 
that the lower limit of a one-sided 95% confidence interval (or equivalently a 90% two-sided confidence 
interval) will be above the non-inferiority limit of -1. For the superiority: We estimate that a minimum sample of 
39 per group, total N= 78 women will be needed to provide a power of 90% with a two-sided alpha level of 0.05 
and a 1 g/dL difference in hemoglobin between control and intervention. We plan to enroll 86 patients in order 
to account for up to 10% missing data or loss to follow up. If no differences are noted among groups (non 
inferiority hypothesis failed) we will be performing a superiority approach. Stata 16 will be used for the 
statistical analysis. 
 
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