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The effects of prophylactic iron during pregnancy on maternal and child health in developing settings with endemic malaria and high prevalence of HIV remain unclear. This paper describes the rationale, implementation and success of a pragmatic randomised controlled trial comparing routine iron supplementation vs. screening and treatment for anaemia during pregnancy. The setting was two health centres in Maputo, Mozambique. Pregnant women (≥12-week gestation; ≥18 years old; and not with a high-risk pregnancy, n=4326) were recruited. The main outcomes are preterm delivery and low birthweight. The women were randomly assigned to one of two iron administration policies: a routine iron group (n=2184) received 60mg of ferrous sulphate plus 400μg of folic acid daily while a selective iron group (n=2142) had screening and treatment for anaemia and a daily intake of 1mg of folic acid. The recruitment, follow-up, and collection of follow-up data were successful; both groups were similar to each other in all the trial stages. Collection of delivery data was challenging and data on about 40% of births is missing. These are currently being traced through different hospitals and health centres. The compliance of the study personnel and the women with regard to regular measurement of haemoglobin and intake of the iron and folic acid tablets was high and similar in both trial arms. Taking into account the various constraints encountered, the stages of the present trial prior to delivery were carried out well.
The specific objectives of the trial were: (1) to evaluate whether routine iron prophylaxis from the first prenatal visit until delivery (called ‘routine iron’ subsequently) is better than screening and treatment for anaemia (called ‘selective iron’) in regard to maternal and child health, such as preterm delivery, low birthweight and perinatal mortality; (2) to assess whether there is a difference in the effects of iron between high and low seasons of malaria; and (3) to assess whether screening and iron treatment for anaemia is more feasible than routine iron prophylaxis in terms of the use of health care providers and overall compliance in Maputo, Mozambique. Originally, we had had malaria activation as one of the primary outcomes, but the pilot showed it to be unfeasible because the needed equipments were not available in the nurses’ office; thus, we collected information on symptoms suggestive of malaria (fever, headache, cold, vomiting/nausea, and body aches during pregnancy). In line with these objectives, we formulated four working hypotheses: (1) preterm delivery, low birthweight and perinatal mortality are more common among women who receive routine iron prophylaxis; (2) (modified after the pilot) routine iron prophylaxis during pregnancy increases symptoms suggestive of malaria; (3) the health problems in hypotheses 1 and 2 are more prominent in the season of high malaria; and (4) screening and treatment for anaemia is equally feasible than routine iron prophylaxis in terms of use of health care providers and overall compliance. The study was carried out in the health centre (clinic settings) of 1° de Maio in Maputo City (the capital) (March 2007–December 2008) and in the health centre of Machava 2 in Maputo Province (June 2007–March 2008), Mozambique; Machava is adjacent to Maputo City. The study centres are urban health centres and were chosen on the basis of the following criteria: they did prenatal care and had maternity ward for child delivery; the two main general hospitals were referral hospitals; the number of births was sufficient to complete the study in the planned time; they had a good accessibility to facilitate the supervision of the study; the centres had an ongoing prevention of vertical transmission of the HIV programme; care providers were interested in the programme; and data collection was feasible. The health profile of Mozambique is typical of sub‐Saharan African countries, with nearly 55% of its 23 million people living below the poverty line (The World Bank 2011). The main causes of morbidity and mortality are infectious and parasitic diseases, with malaria accounting for 30–40% mortality. At the time of the trial, the prevalence of HIV/AIDS was estimated to be around 16% nationally, and around 20% in Maputo City (Measure Demographic and Health Surveys 2009). Health care is administered by the state through district, provincial and national systems (Lindlöw et al. 2004). Prenatal consultations are recommended from the third month of pregnancy and are usually carried out, along with delivery, by mother‐and‐child health (MCH) nurses. Women who come for their first prenatal consultation with a pregnancy of less than 3 months are not seen and are asked to return when the pregnancy becomes visible. Women with problems prior to the third month are referred to a hospital. Seventy‐five per cent of women in Maputo City have four or more prenatal consultations, with 50% starting their first prenatal visits by the fourth or fifth month (Lindlöw et al. 2004). Like in all public health centres in Mozambique, prenatal care and delivery were free of charge. Care recommendations at the time of the study included: daily prophylactic iron‐folate supplementation (60 mg + 400 μg) throughout pregnancy, one dose of mebendazol 500 mg (for intestinal parasite), malaria prophylaxis with sulfadoxine pyrimethamine, as well as haemoglobin measurement and syphilis screening at the first prenatal visit. Three doses of tetanus vaccine were recommended: at the fifth and seventh months and at delivery. Malaria was diagnosed during prenatal consultations through a laboratory test and by clinical signs. Voluntary HIV testing was offered in many health centres, including our study centres (Mozambiqan Ministry of Health 2002). Usually, women arrived at the health centre around 6 am–7 am, with the prenatal consultation ending around 1 pm. At the prenatal sessions, women collectively received information and counselling regarding HIV, vaccinations, and advice on diet. After the collective information session, women were individually attended to by MCH nurses, during which time they had a (voluntary) HIV test and tetanus vaccination. After the individual consultation, the women were sent to the heath centre laboratory to have blood tests for syphilis, haemoglobin, and (primiparous women) blood group determination. Haemoglobin was routinely measured only during the first prenatal consultation, but if a woman presented clinical signs of anaemia, she could have further laboratory tests. Mothers were given a prenatal card on their first visit and were requested to bring it on subsequent visits. The card was to be completed at each prenatal visit and to be given to the birthplace (called hospitals subsequently). After delivery, in some health centres/hospitals the prenatal card was given back to the woman, while for some it was retained in the hospital archives. The prenatal card also had a section covering births, but not all hospitals completed it. Health centres had no individual records for pregnant women; they had a book of first visits including woman’s names, age and date of visit. In addition, only the numbers of subsequent visits were recorded, and these were not linked to individual women. Data on births were collected using separate forms, which were kept by the hospitals. Furthermore, hospitals had other records (admission books, birth books, books for complications, etc) that varied from one hospital to another. Hospital archiving was variable and unreliable. Often, documents were put into a box and retained in a room containing other things too. Post‐natal visits were not customary, and no form was used in those visits. The main reason for attending the health centre after delivery was for contraception. In the two study health centres, general information about the study was given to all women attending their first prenatal visit during the routine early morning health‐education sessions. Recruitment occurred during the individual consultations. The physical locations of the two study centres were slightly different: in the 1° de Maio health centre, a room separate from the prenatal visit room was used, while in the Machava centre, it was the same room. In both centres, the women first went for the voluntary HIV testing; the nurses estimated that about 99% of the women had the HIV test. In the 1° de Maio health centre, the women first had their routine prenatal care consultation with the MCH nurse, followed by the visit to the study nurse. The study nurse checked for eligibility, and those who met the inclusion criteria were asked if they wanted to join the study. In Machava, it was the MCH nurse who asked if the woman wanted to join the trial. If she agreed, the study nurse sat jointly with the MCH nurse when the information on the woman’s history was collected and completed the data collection form simultaneously while the routine nurse completed the routine prenatal form. After the consultation, women in the selective iron group had their haemoglobin measured using HemoCue® (Hemocue AB, Ängelholm, Sweden). Women were then supposed to be guided to the laboratory to have the routine tests. Study nurses were given a study recruitment book into which they entered the following information on the recruited women: name, age, and number of previous pregnancies and births. The study nurses were retired nurses employed by the project. They were given training and a study manual, which they used to carry out the different steps of the study. In the Machava health centre, the MCH nurses collected the data on subsequent visits. The MCH nurses were paid a little incentive ($10.00 to $25.00 per month, depending on the number of women present at each visit) by the project for accommodating the study and for guiding the study nurses. Recruitment and randomisation into the study took place from November 21, 2006 to March 31, 2008. All pregnant women having their first prenatal visit were the target group. Women excluded from the study were those who missed attending to the study nurses; those too early in pregnancy (<12 weeks), women with high obstetric risk and those less than 18 years of age. Women in the Routine iron group (i.e. routine iron prophylaxis from the first to the last prenatal visit) received 30 tablets (supply of one month) of 60 mg of ferrous sulphate plus 400 μg of folic acid per day. Women in the Selective iron group (i.e. regular screening for haemoglobin level and treatment for anaemia) were given 30 tablets of 1 mg of folic acid per day. At each visit the nurses measured the haemoglobin using a rapid haemoglobin measure (HemoCue Hb 201+). If their haemoglobin was below the cut‐off of <9 g/dL Hb, they received a double dose of iron (60 + 60 mg for treatment of anaemia). The iron plus folic acid tablets were round and red in colour, while the folic acid only tablets were round and yellow in colour. The tablets were given in a plastic bag that had the drug's name and dose on it. The main outcomes were preterm delivery (delivery <37 weeks of gestation, estimated from last menstrual period) and low birthweight (<2500 g). Originally, malaria activation was one of the primary outcomes, but as the pilot showed it to be unfeasible, we dropped it. Instead, we collected information on symptoms suggestive of malaria (fever, headache, cold, vomiting/nausea and body aches during pregnancy as secondary outcomes) and self‐reported malaria during pregnancy (the woman was asked by the study nurse whether she has had diagnosed malaria since her last visit). Secondary outcomes were perinatal mortality (as available from the local registers; unlikely to cover early stillbirths or neonatal births occurring at home), complications during pregnancy and labour, and symptoms suggestive of malaria. As there was no prior reliable information on baseline rates or what impact iron might have, we calculated the sample size with various assumptions of the baseline rates, power (85 and 90%), significance level of 5%, and the size of the difference to be detected (20 and 30%) for preterm delivery, low birth rate, (clinical malaria) and perinatal mortality. Based on these calculations and the expected feasibility, the target size chosen was 2000 women for each group. The STATA 7 (StataCorp LP, College Station, TX, USA) was used to estimate the sample size. Women who agreed to participate and met the inclusion criteria were randomised into either Routine iron group or Selective iron group. The STATA statistical software was used to generate sequential random numbers separately for the two centres, and the women were assigned to either of the groups with a probability of 50%. The codes for the groups were put into sealed and sequentially numbered opaque envelopes; the woman's study number was repeated on all the documents in the envelope. The envelope contained a study identification card (pink for the Selective group and yellow for the Routine iron group, 10 × 20 cm) and an informed consent form. The envelopes were put into a box and the study nurses were advised to pick them in order. Before the nurse opened the envelope, she wrote the woman's name on it. After opening, the coloured study identification card was stapled to the maternity card. Informed consent was requested in two stages: first orally, and again after opening the envelope, this time with written confirmation. An envelope was opened for each woman who had orally agreed to join the trial. Women were asked to sign or thumb‐print the informed consent form. Nurses read and explained the text of the form to those who could not read Portuguese. Women were informed about the study on an individual basis. Detailed information was given about the group the woman was assigned to, while it was also explained that the woman had the right not to follow the recommendations. The information included data collection procedures, such as longer first visit and meeting the study nurse at each visit. Those who refused to participate were assured that their decision would not influence their routine care. Data were collected through three methods: (1) abstracting data from mothers' maternity cards and birth records around the time of the visit/hospital stay; (2) asking women questions at prenatal visits; and (3) for birth data only, collecting data from hospital records, death registers, as well as calling women to complete missing data. The first two methods were used mainly for data collection during pregnancy, while the last method (involving mixed methods) was used for collection of delivery data. The first two mentioned methods are described here. In the 1° de Maio health centre and at the first visit at the Machava health centre, data from prenatal visits were collected by the trained study nurses using data collection forms. In subsequent visits to the Machava health centre, data were collected by the MCH nurses who were giving routine care. Study women were identified by the colour study identification card stapled to the maternity card. Clinical data were abstracted from the maternity cards. Additional questions were asked, for example, on whether the woman had had malaria since the previous visit, whether any malaria prophylaxis was taken, and whether the iron and folic acid tablets were taken by the women. Researchers regularly collected these forms from the health centres; coding and data entry were done by research assistants at the Eduardo Mondlane University using Microsoft Access. The data were later transferred to STATA for data analysis. The study nurses were given diaries to record any incidents at the health centres, any lack of iron tablets, lack of HIV tests (reagents) or any information they felt was valuable. The information from these diaries was regularly checked by the study coordinators. At delivery, the study women were identified by the colour identification card stapled to their maternity card. Nurses taking care of deliveries at the study health centres were informed of the study and were requested to tear the study identification card from the maternity card, staple it to the (routine) delivery card, and put the delivery card into a separate study box. The study nurses abstracted data from the delivery cards onto the data collection forms daily. At the two second‐level referral hospitals (Mavalane and Jose Macamo), the MCH nurses were informed of the study and asked likewise to put the delivery cards aside. The study coordinators collected the data from these referral hospitals every 1–2 weeks. We could not organise the birth data collection at the central hospital (third‐level hospital) or other potential birthplaces. The women were instructed and encouraged at each visit to take the tablets they were given. Women allocated to the Routine iron group could refuse to take the iron tables, in which case they were classified as non‐compliant with the intervention. Women who belonged to the Selective iron group and wanted iron (even if their haemoglobin level was not below the cut‐off level) were given iron and were classified as non‐compliant with the intervention. To assess whether nurses had given the tablets and that women had taken the tablets, a few questions were asked on each subsequent visit, including ‘Was haemoglobin measured?’; ‘Was iron/folic acid given to the woman?’; ‘Number of iron/folic acids given?’; and ‘Did the woman take the tablets during the past week?’ Ethical approval for the study was obtained from the Mozambique Ministry of Health Ethics Committee [CNBS (Ref. 84/CNBS/06) ]. A positive statement was obtained from the National Institute for Health and Welfare, Helsinki, Finland (Dno 2571/501/2007). The study was monitored for reliable data collection and the safety of the intervention. Decreased haemoglobin levels in the screening group were reported to the local ethics committee. The study nurses kept diaries on ‘any events’, the stock of iron tablets in the health centre, any lack of HIV tests and reagents. They kept a register on the women's attendance to subsequent visits and kept a separate stock of iron tablets purchased for the study; the stock was to be used in the event that the health centre ran out of iron tablets; they reported to the local coordinators. Local coordinators and international coordinators visited the study sites regularly and verified that the study procedures were followed in regard to informing the women, randomisation, recruitment, the technique for measuring haemoglobin using HemoCue, handing out of iron/folic acid tablets and the data collection. Study nurses reported to the local coordinators and local coordinators reported to the international coordinators. A pilot study to study the feasibility of recruitment and follow‐up during pregnancy was carried out between November 2006 and March 2007 in the 1° de Maio health centre to test the feasibility of recruitment (Parkkali et al. 2008). A total of 781 women were enrolled into the pilot study, 134 of whom were followed until delivery; the pilot did not test the completeness of birth data collection. The setting up of the pilot study was time consuming and administrative issues and authorisations took longer than expected. However, after practical obstacles had been solved, the study design turned out to be feasible. The mean number of women recruited per week was 43. The women came from various nearby areas. Anaemia prevalence (Hb < 9 g/dL) in the selective iron group at recruitment was 36% (n = 140) according to HemoCue. By the standard measurement (Lovibond®; The Tintometer Limited, UK) it was 0.5%. Of the 134 deliveries, 78% (n = 104) took place in the health centre, 17% (n = 23) in the referral hospital (Mavalane) and 5% (n = 7) at home. Home deliveries were recorded in the maternity delivery register at the health centre when the women came with their newborn to have vaccinations and to receive the baby card. The changes made to the trial protocol included a slight modification to the data collection forms and dropping the aim of collecting data on malaria activation, which had proved unfeasible. The main procedures were not modified. The data were analysed by basically computing descriptive results (means and proportions) of the differences between the iron groups.
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