Rationale and objectives

An initial prospective randomised controlled trial was conducted between March 2007 and January 2009 at the Launceston General Hospital (LGH), a tertiary referral centre for Northern Tasmania, Australia. The initial study assessed Hb and serum ferritin levels after intravenous followed by oral iron therapy versus oral iron therapy only. The current study constitutes a follow-up on the earlier one and took place between January 2010 and January 2011 and focused on HRQoL, breastfeeding duration and child health. Informed consent was obtained from all participants in accordance with the Declaration of Helsinki. The original and the follow-up studies were approved by the Tasmanian Human Research Ethics Committee and registered in the Australian New Zealand Clinical Trials Registry (http://www.ANZCTR.org.au/ACTRN12609000177257.aspx) and the WHO Clinical Trials Registry (http://www.who.int/trialsearch/trial.aspx?trialid=ACTRN12609000596202).

In the original study, we prospectively assessed HRQoL at baseline prior to treatment in the second trimester, 4 weeks after the initiation of treatment, in the third trimester before delivery, and at 6–8 weeks postdelivery. In the follow-up study, an HRQoL questionnaire was completed that incorporated the original questionnaire plus additional parameters such as the length of the breastfeeding period and occurrence of postnatal depression as well as child growth data. This was performed at a median of 32 months postintervention in order to assess the long-term effects of both treatment types on mothers’ HRQoL in relation to data from the earlier study. This questionnaire, although completed prospectively, had a retrospective component that asked the participating mothers the same questions again that they had previously answered prospectively. These data were compared with the mothers’ original prospective QoL data for validation purposes.

Participants

Pregnant women aged 18 years or above who presented to the LGH with IDA between 2007 and 2009 were invited to participate. In the original study (figure 1), 196 Caucasian pregnant women aged 18 years or above were identified who had moderate IDA, defined as Hb ≤115 g/l (reference range (RR) 120–160 g/l), and low iron stores, based on serum ferritin levels <30 µg/l (RR 30–440 µg/l).

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Figure 1

Patients flow chart. *Fourteen patients were admitted late in labour, and no blood samples were taken before delivery. ^†The primary hypothesis examined the change in haemoglobin levels between the time of booking and immediately prior to delivery; an ‘intention-to-treat’ analysis was performed according to original randomisation group on those patients who had blood samples taken before delivery, whether or not the treatment was completed as per the protocol. ^‡Twenty-one patients withdrew from the trial treatments, and all but one of these patients agreed to continued collection of haematological and other trial data; eight patients gave no reason for withdrawal. ^§Five patients did not complete the intended treatments, but did not choose to withdraw themselves; three patients in the oral iron group were treated with intravenous iron when their haemoglobin was judged not to have responded adequately to oral iron, while one patient was unable to attend for intravenous iron treatment.

Of the original evaluable 183 pregnant Caucasian women randomised to receive oral iron or a single intravenous iron polymaltose infusion, 126 women completed the QoL follow-up study (table 1). The median age was 29 years at enrolment (range, 21–43); and the median follow-up period was 32 months (range, 26–42) with an average follow-up period of 36 months postdelivery.

Randomisation and interventions

Informed consent was obtained from all patients. Treatment arms were allocated in blocks of 10 by computer-generated random assignment, and allocation was done by concealed envelopes. This was done by the LGH pharmacy department in order to avoid possible bias. The oral-only treatment arm comprised iron sulphate 250 mg tablets once daily, (elemental iron 80 mg, Abbott, Australasia Pty Ltd) to be taken daily within 2 days after booking until delivery. The intravenous arm required a single intravenous infusion of iron polymaltose (Ferrosig, Sigma Pharmaceuticals, Sydney, NSW,Australia) within 1 week after first antenatal visit followed by oral iron identical to the other arm. Pre-enrolment, there were no significant differences in the dietary iron intake or supplement intake between the two groups based on a specially designed questionnaire addressing these issues.14 Patients assigned to intravenous iron polymaltose received a 100 mg test dose dissolved in 50–100 ml normal saline infused over 30 min. Clinical observation and vital signs were assessed initially and every 15 min from the start of the infusion. After the test-dose was tolerated, the remainder of the iron polymaltose dose was infused. The total dose of intravenous iron polymaltose was calculated according to the patients’ body weight at their first antenatal visit and entry Hb level according to the product guidelines; iron dose in mg (50 mg/1 ml)=body weight (maximum 90) in kg×[target Hb (120 g/l)−actual Hb (in g/l)×constant factor (0.24)+iron depot (500)].14

Outcome measurement

Two HRQoL questionnaires were administered during the initial and follow-up studies. First, a clinical questionnaire was completed prospectively by trained midwives at 4 weeks after initiation of treatment, at 28 and 34 weeks gestation, and then 6–8 weeks postdelivery. This questionnaire assessed four aspects: energy levels, activity, tolerance and side effects of the treatment. This was used to guide individual patient clinical decision-making as well as to provide a safety audit of the trial treatments.14 Second, a prospective/retrospective survey was conducted between June and October 2010 by trained research personnel via phone interview using a modified version of the SF-36 HRQoL questionnaire, similar to a version published previously.16 ,17 Additional modifications for this study included: (1) use of eleven of the 36 questions (table 2) and (2) the women were asked to recall their response to each of the questions at four timepoints; pretrial prior to commencement of iron therapy during the pregnancy, 4 weeks after the start of iron therapy, 1 week after delivery and the last 4 weeks prior to the telephone questionnaire contact (table 2). This was compared in a retrospective manner to the same questions answered earlier prospectively by the participants at these different timepoints. In order to validate the retrospective use of the modified SF-36 questionnaire to assess the women's HRQoL during and after pregnancy, we estimated the associations of the physical activity component of the prospective monitoring questionnaire following entry into the trial with the Physical Component Scale values of the modified SF-36 at each of the timepoints. We hypothesised that the association would be greatest at 4 weeks after enrolment compared to trial entry, time of delivery or at the time of questionnaire completion. In addition, data concerning breastfeeding and the health of the child were collected from the baby's growth booklet. This included breastfeeding duration, baby gender, age, weight and previous hospitalisation, if any, in addition to the baby's sleep quality since birth and specific growth data for the children as set by the APEG. Hb and ferritin levels for participants at delivery were available for all participants; however, no further testing was performed during the follow-up. The principal investigators, including the statistician, evaluated the questionnaire results data.

Statistical methods

The HRQoL scores that form the raw data for this analysis are rank-order in nature. Means and SDs of the scores were estimated using generalised estimating equations for illustrative purposes only. Physical and mental composite scores were calculated in the modified SF-36 according to the SF-12 scoring guidelines.16 ,17 Group comparison and covariate effect size calculation, OR (with 95% CIs and p values) were estimated using repeated measures of ordinal logistic regression, with covariates selected for inclusion by backward stepwise regression (p-value for exclusion 0.22) from maternal age, Hb, ferritin, Socio-Economic Indexes for Areas ( based on the Collector District of residence of mothers), quality of sleep, use and duration of breastfeeding, hospitalisation of the baby, baby gender and mode of delivery. This included randomisation group covariate interactions in the starting model with exclusion of those interactions using the above criteria. When iron status was selected for inclusion in the model, the association between iron status (ferritin) and HRQoL was reported independently of the trial treatment group. p Values were corrected for multiple comparisons where necessary by the Holm method. The effect of intravenous iron versus oral iron on time of cessation of breastfeeding was compared by estimation of the HR with 95% CIs and p values by Cox proportional hazards regression adjusted for covariates selected for inclusion by backward stepwise regression (p-value for exclusion 0.22). The time to cessation of breast-feeding was taken from the subject's baby growth booklet for all participants. Neonatal growth in the treatment groups was compared by multivariate third-order polynomial regression as an approximation to APEG growth assessment. The iron status variables used in the multivariate regression models were selected by stepwise regression. All HRQoL statistical analyses were performed using Stata SE for Windows V.11.1 (StataCorp, College Station, Texas, USA).