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Introduction:

Anemia in pregnancy is a major public health burden with a higher incidence in low- and middle-income countries (LMICs) such as Nigeria (1). It is most commonly caused by iron deficiency, which accounts for 50–75% (2). Postnatal anemia may result from untreated antenatal anemia or as a result of blood loss that occurs during birth. (3), and its prevalence in LMIC has been estimated to range from 50 to 80% (4). A study in Eastern Nigeria found anemia at 48 hours and six weeks postpartum to be 73% and 48% respectively, in a cohort of 202 women followed from late pregnancy until six weeks postpartum (5).

Anemia and iron deficiency anemia in pregnancy lead to increased morbidity and mortality for the mother and affects the neonates adversely (6). Specifically, postnatal anemia increases the risk of infection, leads to poor wound healing, and causes fatigue and depression in the mother (7). It also adversely affects breastfeeding, due to insufficient milk productioncan reduce bonding between women and their newborn as a result of weakness and fatigue (3, 4, 8).

Oral iron is used routinely for the treatment of mild to moderate anemia in the postnatal period, while blood transfusion is offered for severe anemia or symptomatic women with moderate anemia (3). Oral iron, though cheap, causes significant gastrointestinal adverse effects such as vomiting, constipation, diarrhea, and abdominal pain (9), limiting adherence to this vital intervention which may pose a challenge in achieving optimum correction of anemia by the end of the postnatal period. Adherence to oral iron is reportedly low, with only 16% of women fully compliant with their treatment in a study among pregnant women in Cameroon, one of Nigeria’s neighboring countries (10).

Intravenous iron can be given as a single dose and is suitable for patients who respond poorly to oral iron and moderately anemic women that require more rapid iron replacement for symptom control (3). Intravenous iron corrects anemia faster and in fewer doses than oral iron, requiring less patient-provider interaction, a situation that is ideal in LMICs where loss to follow up is common for various reasons especially in the postpartum period. Froessler et al. reported on 214 women with iron deficiency anemia, 107 of whom were recruited postpartum, and found a more rapid increase in serum ferritin with administration of intravenous iron sucrose compared with oral ferrous sulphate in the treatment of postpartum anemia (11). A randomized controlled trial by Vanobberghen et al. conducted in Tanzania (230 women) found intravenous ferric carboxymaltose to be more effective than oral iron for treating postpartum anemia and iron deficiency anemia with an almost five times greater odds of normalized hemoglobin level and a significantly higher ferritin level (12).

Although clinicians are aware of intravenous iron, its use is not widespread in most obstetric units in Nigeria. An equivalence randomized controlled trial studied 284 postpartum women in southeastern Nigeria and found total dose infusion of high molecular weight iron dextran to be as effective as oral iron (III) hydroxide polymaltose tablets in correcting anemia by six weeks postpartum, when administered to postpartum women 48 hours or later after delivery (13). In most health facilities in Nigeria, women are often discharged home after delivery on oral iron (5) without strict monitoring of compliance to the medication. The uptake of postnatal care in Nigerian women is approximately 40% (14, 15), with one survey showing 37% of women receiving postnatal care within 2 days of delivery, 3% between 3 days and 6 weeks postpartum, while 60% did not receive any postpartum care (15). Most of the women discharged on oral iron will therefore not have the chance to have their hemoglobin levels or clinical states re-examined to determine whether their anemia has resolved.

As postpartum anemia is highly prevalent in Nigeria and has a significant detrimental impact on the physical and mental health of women and their newborns, this study will examine the clinical effectiveness of intravenous ferric carboxymaltose versus oral ferrous sulphate in postpartum Nigerian women. Also recognizing the potential difficulty of introducing such a treatment in Nigeria, the implementation research will help understand the implementation climate and assess key implementation outcomes of intravenous ferric carboxymaltose uptake in treating postpartum anemia in Nigeria.

Aims & Objectives

Our aim is to determine the clinical effectiveness, tolerability, and safety of intravenous ferric carboxymaltose (intervention) versus oral ferrous sulphate (control) for treating moderate to severe iron deficiency anemia in postpartum women (population). To evaluate the acceptability and feasibility of intravenous ferric carboxymaltose in treating postpartum anemia in Nigeria.

Study Outcomes

Outcome 1:

Primary clinical outcome

Proportion of participants who are non-anemic at six weeks postpartum. Non-anemic state is defined as hemoglobin level ≥ 11.0g/dl.

Secondary clinical outcomes

  • Proportion of women with probable postpartum depression after treatment, using the Edinburgh Postnatal Depression Scale at six weeks and six months postpartum
  • Change in mean postpartum hemoglobin levels at two weeks and six weeks post-initiation of treatment.
  • Achievement of a non-anemic state at six months postpartum.
  • Prevalence of moderate/severe anemia at six weeks and six months postpartum. Moderate anaemia is defined as hemoglobin level 7.0-9.9 g/dl and severe anemia as hemoglobin level <7.0g/dl.
  • Change in mean serum ferritin, serum transferrin, serum transferrin, serum iron and total iron binding capacity levels at two and six weeks postpartum.
  • Need for blood transfusion after treatment during the first 6 weeks postpartum
  • Prevalence of fatigue at six weeks and six months postpartum, using the Fatigue Severity Scale (revised FSS-5R version), which is a brief, specific, reliable, and valid measure of postpartum fatigue (22)
  • Proportion of women with secondary postpartum haemorrhage after treatment. This will be defined as excessive bleeding requiring surgical intervention or blood transfusion from 24 hours after delivery till 12 weeks postpartum (23)
  • Proportion of infants being breastfed (exclusive and any) at six weeks and six months postpartum.
  • Prevalence of impaired maternal-infant bonding at six weeks and six months postpartum measured using the Mother-to-Infant Bonding Scale (MIBS) (20).
  • Incidence of infections including urinary tract, perineal and surgical site infections, and puerperal sepsis till six weeks postpartum. Confirmed or suspected maternal infection within 6 weeks of birth, as defined by a new prescription of antibiotics for presumed perineal wound-related infection, endometritis or uterine infection, urinary tract infection or other systemic infection (clinical sepsis).
  • Incidence of hypophosphatemia at two weeks and six weeks postpartum. We will measure vitamin D, alkaline phosphatase, P1NP, FGF23, Ca, PO4, which are biomarkers of phosphorus homeostasis and bone turnover. Hypophosphatemia is defined as serum phosphate level <2.5mg/dL (0.81mmol/L). Mild hypophosphatemia as 2-2.5 mg/dL (0.65-0.81 mmol/L), moderate as 1-2 mg/dL (0.32-0.65 mmol/L), and severe as < 1 mg/dL (0.32 mmol/L).
  • Incidence of early neonatal death, defined as death of newborn from enrolment to before 28 completed days.
  • Incidence of infant death, defined as death before the age of six months.
  • Incidence of postnatal maternal death from enrolment up to 6 weeks and at 6 months postpartum.
  • Incidence of other adverse drug events.
  • Quality of life using the WHOQOL BREF at enrollment, 6 weeks and 6 months post-partum.

Outcome 2: Implementation Outcomes

To measure implementation outcomes considered most relevant and amenable to assessment in the study timeline. This will be divided into two parts:

Acceptability of the intervention to women and health care professionals

Feasibility/ organizational readiness for implementing the intervention

Methodology
  • Multi-center parallel, open label, superiority randomized controlled clinical trial, with women allocated on a 1:1 ratio.
  • The study will be conducted in four states in Nigeria, two states in the North – Kano and Kwara states, and two in the South – Lagos and Rivers states.
  • One tertiary, three secondary and one primary healthcare facility will be selected from each state, making 20 targeted facilities in total.

 

Study Population

Postpartum women with moderate to severe iron deficiency anemia.

 
Ethical Considerations
  • Ethical approval obtained from the National Health Research and Ethics Committee of Nigeria, Health Research and Ethics Committees of the Lagos University Teaching Hospital, and Aminu Kano Teaching Hospital, Kano State, and the State Health Service Commissions of Lagos, Rivers, Kano, and Kwara States.
  • The trial is duly registered at the Pan African Clinical Trials Registry (PACTR), International Clinical Trials Registry (ICTR) and Nigeria Clinical Trials Registry.
Principal Investigators & Co-Investigators
  1. Principal Investigator – Prof Bosede Afolabi
  2. Co-Investigator – Dr. Mobolanle Balogun
  3. Co-Investigator – Dr Titilope Adeyemo
  4. Co-Investigator – Dr Aduragbemi Banke-Thomas
  5. Co-Investigator – Dr Ochuwa Babah
  6. Co-Investigator – Dr Yewande Oshodi
  7. Co-Investigator – Dr Ejemai Eboreime
  8. Co-Investigator – Dr Eleanor Mitchell
  9. Co-Investigator – Dr Kate Walker
  10. Co-Investigator – Dr Ibraheem Abioye
  11. Co-Investigator – Professor Folasade Ogunsola
Study Sites

The study sites include:

  1. Lagos State
    • Lagos University Teaching Hospital (LUTH), Idi-Araba, Lagos
    • Mother and Child Centre, Amuwo-Odofin
    • Mother and Child Centre, Gbaja (maternity unit of Randle General Hospital, Surulere), Lagos
    • General Hospital, Ifako Ijaiye
    • Ipaja Primary Health Centre, Alimosho L.G.A., Lagos
  1. Rivers State
    • University of Port Harcourt Teaching Hospital (UPTH), PortHarcourt
    • Okrika General Hospital, Okrika
    • Bori General Hospital, Bori
    • Ahoada General Hospital, Ahoada
    • Model Primary Health Care Centre, Orogbum
  1. Kano State
    • Aminu Kano Teaching Hospital (AKTH), Kano
    • Waziri Gidado GH
    • Nuhu Bammali GH
    • Sheik Jeddah GH
    • Kabuga PHC
  1. Kwara State
    • University of Ilorin Teaching Hospital (UITH), Ilorin, Kwara
    • General hospital Ilorin
    • Adewole Cottage Hospital, Ilorin
    • Civil Service Hospital, Ilorin
    • Okelele Health Centre