¹Division of Human Nutrition and Epidemiology, Wageningen University, Wageningen. The Netherlands

²SEAMEO-TROPMED Regional Centre for Community Nutrition, University of Indonesia, Jakarta, Indonesia

³UNICEF, New York, USA

⁴Department of Gastroenterology, University Medical Centre, Nijmegen, The Netherlands

Correspondence to: C E West, Division of Human Nutrition and Epidemiology, Wageningen University, PO Box 8129, 6700 EV Wageningen, The Netherlands. E-mail: Clive.West@staff.nutepi.wau.nl

Guarantor: CE West.

Contributors: All authors were involved in the conception and planning of the study and writing of the paper; MKS and SM carried out the field work and analysed the data.

Objective: To investigate whether supplementation with vitamin A together with iron of Indonesian pregnant women decreases morbidity and improves growth of their infants during the first year of life.

Design: Women from a rural area in West Java, Indonesia, were randomly assigned on an individual basis to double-blind supplementation once weekly from ~18 weeks of pregnancy until delivery. Supplementation comprised 120 mg iron and 500 µg folic acid with or without 4800 RE vitamin A. Their newborn infants were followed up during the first year of life: weight, length, morbidity and food intake were assessed monthly.

Results: Infants whose mothers had taken vitamin A supplements during pregnancy had similar weight, length, weight gain and growth as their counterparts during the follow-up period. The proportions of infants with reported symptoms of morbidity were similar in the vitamin A plus iron group and the iron group. In addition immunisation coverage and feeding mode did not differ between the groups. All infants were breast-fed, but exclusive breast-feeding rapidly declined at 4 months of age. Infants with serum retinol concentrations >0.70 µmol/l increased their weight and length more during the first 6 months of life and had higher weight-for-age Z-scores during the first year of life than infants with serum retinol concentrations £0.70 µmol/l. Serum retinol concentrations were not associated with morbidity.

Conclusion: In this study, vitamin A supplementation in conjunction with iron supplementation of pregnant women did not improve growth or reduce morbidity of their infants during the first year of life.

Sponsorship: Netherlands Organization for Scientific Research-Netherlands Foundation for the Advancement of Tropical Research (NWO-WOTRO) (WV 93-280), the Neys-van Hoogstraten Foundation (IN 114), The Netherlands and the German Agency for Technical Cooperation (GTZ)/South East Asian Ministers of Education Organization, Tropical Medicine (SEAMEO-TROPMED), Indonesia.

European Journal of Clinical Nutrition (2002) 56, 338-346. DOI: 10.1038/sj/ejcn/1601318

infant; vitamin A and iron supplementation; gestation; growth; morbidity

Introduction

Vitamin A is one of the essential nutrients for health and development of infants (Underwood, 1994), which is shown by the reduction in mortality and morbidity by vitamin A supplementation of infants aged 6 months and older in populations with vitamin A deficiency (Beaton et al, 1993; Glasziou & Mackerras, 1993). However the impact of vitamin A supplementation on mortality and morbidity of infants younger than 6 months is less conclusive (Humphrey & Rice, 2000; WHO/CHD Immunisation-Linked Vitamin A Supplementation Study Group, 1998; West et al, 1995). Vitamin A supplementation during lactation has been shown to improve vitamin A status and reduce morbidity of infants through its effect on breast milk (Rice et al, 1999; Roy et al, 1997; Stoltzfus et al, 1993).

As reviewed before (Allen, 1994) the effect of vitamin A supplementation on growth is inconsistent. However vitamin A supplementation has been shown to improve growth of children in populations with vitamin A deficiency or xerophthalmia (Donnen et al, 1998; Muhilal et al, 1988; Mwanri et al, 2000; West et al, 1997), suggesting that vitamin A supplementation may be beneficial for growth in population in which vitamin A is a limiting factor.

In Indonesia, a large proportion of infants have micronutrient deficiencies and are underweight or stunted (World Health Organization, 2000; ACC/SCN, 2000). Inadequate maternal nutrition during pregnancy is thought to be one of the contributors to this (Frongillo, 1999; Waterlow & Schürch, 1994; Kusin et al, 1992). Vitamin A supplementation of women before and during pregnancy has been shown to reduce maternal nightblindness and mortality (West et al, 1999; Christian et al, 1998) and improve serum retinol levels in infants (Katz et al, 2000; Schmidt et al, 2001). However it did not reduce foetal loss or early infant mortality (Katz et al, 2000) and other outcomes of infants have not been reported so far.

Indonesia is one of the many countries that use iron supplementation for controlling maternal anaemia during pregnancy (Yip, 2000). Supervised weekly iron supplementation has been shown to perform similar to the ongoing governmental iron supplementation program in preventing iron deficiency anaemia (Muslimatun et al, 2001). In this study, we investigated whether vitamin A supplementation in concurrence of iron supplementation to Indonesian pregnant women decreases morbidity and improves growth of their infants during the first year of life.

Subjects and methods

Study design

The study was carried out in infants from five rural villages in Leuwiliang subdistrict, Bogor district, West Java, Indonesia. At ~18 weeks of pregnancy, their mothers had been randomly assigned on an individual basis to a double-blind, supervised supplementation once weekly from enrolment until delivery. Supplementation comprised 120 mg iron as ferrous sulphate and 500 µg folic acid or the same amounts of iron and folic acid plus 4800 RE vitamin A. Details of the study design and the effect of supplementation on maternal biochemical status near term and infant biochemical status at ~4 months of age have been published elsewhere (Muslimatun et al, 2001; Schmidt et al, 2001). After birth, infants were followed up during the first year of life. Growth, morbidity and nutrition were assessed monthly, while biochemical status was assessed at ~4 months of age. The study had been explained to the women at enrolment and only women who gave written informed consent were enrolled. The research was approved by the Ministry of Health Indonesia and the Ethical Committees of the Medical Faculty at the University of Indonesia and Wageningen University.

Monthly assessment

Weight and length of infants were measured and mothers interviewed for morbidity and food intake of their infants during their monthly visit to their neighbourhood health post (posyandu). In principal visits for each health post were planned on the same date of each month. However, in practice visits were made within a week before or after the planned date. It was attempted to reach individual mothers who were not able to attend through a visit at their home.

Anthropometry

Two pairs of trained field assistants measured weight and length of infants. Weight was measured to the nearest 50 g by using a baby weighing scale (Misaki, Japan) which was tared each time before use. Calibration with a standard weight (5 kg) at regular intervals showed that all scales were stable and precise. Recumbent length was measured to the nearest 0.1 cm by using a wooden length board (SEAMEO-TROPMED). Infants were measured with light clothing. Neonatal weight and length of infants had been measured by two of the authors (MKS and SM) during a postnatal home visit (Schmidt et al, 2001). All field assistants had received training and were supervised every month by the two authors mentioned above. At each supervision the supervisors also independently measured length and weight in a random sub-sample of ~5% of the infants (total n=163). The mean technical error, expressed as a standard deviation (s.d=Öåd²/2n, d=difference between paired measurements, n=number of infants) was 44 g and 0.70 cm. In addition the s.d. of pooled duplicate measurements in a random sample by the field assistants (recorded n=25) was 35 g and 0.46 cm. The reliability coefficients of the anthropometric measurements were high, 0.967 and 0.997 for length and weight respectively (Marks et al, 1989).

Morbidity

At the time of the anthropometric assessment the same field assistants interviewed the caretaker; in all but two cases the mother, of the infant about symptoms of morbidity in the 14 days preceding the visit. More specifically, mothers were asked to recall: diarrhoea, defined as more than three stools that were more liquid than usual in one day; fever, mother's evaluation of infant's body temperature above normal (hot to the touch; panas); running nose (pilek), nasal discharge; cough, persistent coughing; difficulty breathing, breathing with severe noise or wheezing or difficulty inhaling; ear discharge, fluid or plus draining from at least one ear; or vomiting. Questions were asked in Bahasa Indonesia or in the local language (Sundanese) if the mother did not understand the term. First the interviewer asked the mother for any symptoms and then asked her specifically for each category and for how many days the infant suffered from that specific symptom. Episodes were defined as a period of sickness separated by at least 3 days. Morbidity incidence rates were determined as total number of episodes divided by the number of days at risk. Days at risk were defined as the number of days on which morbidity was assessed (number of interviews ´ 14 days) minus the number of days not at risk, ie the total of days on which a symptom was reported plus 3 days for each separate episode.

In addition mothers were asked whether the infant had received immunisation since the last interview. Data on immunisation were crosschecked against the posyandu record of growth and immunisation. If inconsistencies were found data from the record were used. Mortality of infants was recorded at a home visit after death had been reported.

Breast-feeding and food intake

Together with the morbidity interview the mother was asked whether the infant was still breast-fed and whether the infant received any other liquid or food in the 14 days preceding the visit. Data on breast-feeding and food intake had also been collected at the postnatal home visit. The type of liquid or food was recorded using a pre-coded questionnaire. Infants were categorised as exclusively breast-fed, predominantly breast-fed (ie receiving breast milk plus water, tea, coffee or fruit juices, but no artificial milk), complementary fed, or non breast-fed (Labbok & Krasovec, 1990).

Biochemical measures

At ~4 months of age, non-fasting venous blood samples (~2 ml) were taken from infants and collected in a tube without anticoagulant between 09:00 and 12:00 h. It was not possible to obtain blood from all subjects due to maternal refusal and in some cases the amount of blood obtained was insufficient for all analyses. Haemoglobin was determined using the cyanmethemoglobin method (Test 3317; Merck, Darmstadt, Germany) at the Nutrition Research and Development Center Laboratory, Bogor. For serum ferritin, soluble transferrin receptor and retinol analyses, blood was allowed to clot before it was placed in a cool box with cooling elements for transport to the laboratory in Bogor. Blood samples were centrifuged at 3000 g for 10 min at room temperature and serum was distributed among three vials. Serum was kept at -20°C for 1 month and subsequently at -79°C. All analyses were carried out within 1 y of blood collection and have been described earlier (Schmidt et al, 2001).

Data analysis

Infants whose mothers had been supplemented during pregnancy with vitamin A plus iron (n=107) or iron alone (n=105) and who attended at least once the assessment at the health post were included for analysis (Figure 1). Infants' weights and lengths were converted into Z-scores using the NCHS/WHO reference data incorporated in the Epi-Info software (Epi-Info2000 version 1.0.5; CDC, Atlanta). NCHS/WHO reference data were also used to construct a reference curve weighed for the number of boys and girls in the study population. For analysis, follow up data of infants were grouped into monthly age groups of 0 (0-0.99 months)-12 (12-12.99 months). For additional analysis and presentation, morbidity and breast-feeding data were pooled into four age categories reflecting the different periods of mode of feeding and vulnerability to morbidity: 0-3, 4-6, 7-9 and 10-12 months. Differences in age, anthropometric and biochemical variables between groups were evaluated by independent t-test. Differences in proportion were evaluated by ² test. Data of morbidity were not normally distributed, therefore differences between groups were evaluated using non-parametric tests. For the analysis of growth and morbidity in relationship with serum retinol concentrations data of all infants were pooled and evaluated by t-test, ANOVA and multiple regression analysis as appropriate. The SPSS software package (Windows version 7.5.2; SPSS Inc., Chicago, IL) was used for all statistical analyses and a P-value of <0.05 was considered as significant.

Results

Infants were followed up at least until 1 y of age from May 1998 until November 1999. During this period 11 infants in the vitamin A plus iron group and 8 infants in the iron group were lost to follow up as a result of emigration from the research area or death (Figure 1). Infants were measured monthly but, because visits were not always on the same date, and due to temporary absence, refusal of the mother or sickness of the infant, some of the infants were not measured. In total 2330 anthropometric assessments, including 219 measurements at the postnatal visit, and 2188 morbidity interviews were made during the first year of follow-up.

The coverage of anthropometric measurements of infants at each monthly visit was >80%. Coverage or gender of infants did not differ between the vitamin A plus iron group and iron group at any monthly visit. We obtained 11-14 anthropometry measurements from 81.6% of the infants, 8-10 from 11.8% and 2-7 from 6.6%. The mean (s.e.m.) number of measurements of 11.5 (0.3) and period of follow-up of 11.3 (0.3) months in the vitamin A plus iron group were similar to those in the iron group, 11.9 (0.2) and 11.6 (0.2) months respectively.

Length and weight of infants who were supplemented with vitamin A during gestation did not differ from their counterparts at any age during the first year of life (Figure 2). During the 1 y follow-up the mean increase in length and weight gain of infants in the vitamin A plus iron group, 20.8 (0.5) cm (s.d.) and 4.78 (0.12) kg, respectively, were similar to those in the iron group, 21.3 (0.4) cm and 4.83 (0.11) kg, respectively. Selection of infants who had been followed up for 10 months or excluding infants who dropped out because of death or migration did not alter these results. Weight and length of all infants started to deviate below the NSCH/WHO reference population at 5 months of age (Figure 2). At 12 months of age 23 and 33% of the infants had Z-scores <-2 for height-for-age and weight-for-age, respectively.

The proportion of infants with reported health complaints were similar in both groups (Table 1), except that there were small inconsistent differences in reporting of cough between groups at 0-6 months of age (Table 1). The results were consistent if expressed and analysed as number of days, number of episodes or number of days per episode or incidence ratio (Table 2). Symptoms of morbidity were not related to gender of the infant.

Immunisation coverage was similar in both groups, 90.5% of the infants had at least received once vaccination of BCG (bacille Calmette-Guérin), oral polio and DTP (diphtheria, pertussis and tetanus) during the first year of life. Only 6.7% of the infants had already fully complied with the immunisation schedule, ie one BCG, three DTP, four polio, one measles and three hepatitis, at 1 y of age. During the study, 9 infants in the vitamin A plus iron group and 9 infants in the iron group received a vitamin A supplement from the midwives. This occurred at a mean age of 10.4 (3.9) months.

At the time of the postnatal visit, 208 of the 219 mothers were already breast-feeding their infants but 26 of these discarded some of the colostrum. A large proportion (84%) of mothers also gave some form of prelacteal feeding to their infants: formula milk, 7%; water, 14%; honey, 71%; banana, 14%; or other food or drinks, 34%. All but one infant were breast-fed at least until 6 months of age. The proportion of infants that were exclusively breast-fed, predominantly breast-fed, complementary fed or non breast-fed did not differ between the groups (Table 3). If we consider an infant no longer to be breast-fed exclusively because of having received prelacteal feeding, the proportion of infants that were exclusively breast-fed was small in both groups (Table 3). In both groups exclusive breast-feeding, whether or not taking into account prelacteal feeding, declined rapidly from 4 months of age while complementary feeding increased (Table 3).

Boys increased their length more and gained more weight than girls during the first year of life (Table 4). During the first 6 months of life, infants with serum retinol concentrations >0.70 µmol/l increased their weight and length more than those with serum retinol concentrations £0.70 µmol/l (Table 4). These differences remained significant if correcting for neonatal weight or length, serum ferritin and haemoglobin concentrations, supplementation group and gender. In addition infants with serum retinol concentrations 0.70 µmol/l had higher Z-scores for weight-for-age during the first year of life (Figure 3); similar trends were seen for height-for-age and weight-for-height Z-scores. Infants with serum retinol concentrations >0.70 µmol/l had similar prevalences of morbidity and did not differ with respect to type of feeding compared to infants with serum retinol concentrations £0.70 µmol/l (data not shown).

Discussion

In this study we demonstrated that weekly supplementation of pregnant women in Indonesia with vitamin A did not improve growth or reduce morbidity in their infants during the first year of life. This is in line with the findings of Katz et al, (2000), who found that foetal loss and early infant mortality were not reduced when Nepalese women were supplemented weekly with vitamin A during pregnancy. However vitamin A supplementation was beneficial in terms of reducing mortality in pregnant women (West et al, 1999). In addition vitamin A supplementation has been shown to reduce morbidity and mortality in children under 5 y old (Beaton et al, 1993; Glasziou & Mackerras, 1993). However it should be noted that this reduction in morbidity and mortality is only seen in children above the age of 6 months. Earlier we reported a significant but small difference in serum retinol concentrations of infants of the vitamin A plus iron group and iron group (Schmidt et al, 2001). However the amount of vitamin A given may have been too small to provoke an additional impact on infant growth or morbidity. On the other hand even infants given a large dose of vitamin A only had a small increase in serum retinol concentration and similar morbidity compared to infants given a placebo (Rahman et al, 1995). In addition a large trial in which infants were supplemented four times with 25 000 IU vitamin A and their mothers once with 200 000 IU did not show any effect on anthropometric status or morbidity of infants, although vitamin A status at 6 months of age improved (WHO/CHD Immunisation-Linked Vitamin A Supplementation Study Group, 1998).

In our study, we supplemented pregnant women with 4800 RE vitamin A each week. This amount is in line with WHO guidelines (World Health Organization, 1998), which allow a maximum weekly dose of 7500 RE, and does not exceed the Indonesian RDA of 700 RE per day (LIPI, 1994). Although the amount of vitamin A given may have been too small to have an impact on infant growth or morbidity, intake during pregnancy cannot be increased because of the teratogenic effects of vitamin A (World Health Organization, 1998).

Iron supplementation of both groups could partly explain the lack of effect of vitamin A supplementation on growth and morbidity (Angeles et al, 1993). In a study in Tanzanian school children, vitamin A plus iron supplementation also did not have an impact an growth compared to iron supplementation (Mwanri et al, 2000). Increase in iron stores of the infant through maternal iron supplementation during pregnancy may also have improved growth of our infants (Allen, 2000; Preziosi et al, 1997).

The relationship of xerophthalmia, which is indicative of severe vitamin A deficiency, with stunting, wasting and smaller increases in length and weight than non-xeropthalmic counterparts has been established (Sommer & West, 1996; Tarwotjo et al, 1992). We have shown that infants with serum retinol concentrations >0.70 µmol/l increased their weight and length more and had higher weight-for-age Z-scores until 1 y of age as compared to their counterparts. More of these infants were in the vitamin A plus iron group (26%) than in the iron group (16%); however, this difference was not significant (P=0.241). Infants started growth faltering and becoming underweight at 4-6 months of age as is typically seen in Southeast Asian and populations of other developing countries, and has been associated with factors such as nutrition, morbidity, prenatal nutrition, birth weight and parental height (Adair & Guilkey, 1997; Dewey, 1998; Hop et al, 2000; Kusin et al, 1994). The use of the NCHS/WHO reference has been criticized because it is not based on breastfed infants, but if we compared our infants to the WHO 12 month-breastfed pooled data the same trends were visible, although the deterioration was smaller (data not shown; WHO Working Group on Infant Growth, 1994).

The use of parental report as a method to establish morbidity has been suggested to be one of the reasons for the inconsistencies found in the effect of vitamin A supplementation on morbidity in community-based studies (Semba, 1994). However mothers have been found to report sickness of their children quite well (Kalter et al, 1991) and as education levels and other characteristics of mothers in both groups were comparable (data not shown), we do not expect that over- or under-reporting would be different between the groups. Morbidity prevalence could have been underestimated because we interviewed mothers only once a month about the past 14 days (Ruel et al, 1997). However, incidence of cough was comparable to that reported for infants from developing countries (WHO/CHD Immunisation-Linked Vitamin A Supplementation Study Group, 1998). Also other studies in which infants were supplemented with vitamin A did not show an effect on diarrhoea or respiratory diseases (Coutsoudis et al, 2000; Rahmathullah et al, 1991), or only an effect on duration of acute respiratory infections (Rahman et al, 1996).

The type of feeding during the first year of life and immunisation coverage were comparable between the groups, thus these could not have accounted for the lack of difference in growth and morbidity of infants. We conducted 2 week recalls using a pre-coded questionnaire, because a trial of 24 h recalls in mothers showed that this would be a more reliable measure of intake of foods other than breast milk. Although our method had the disadvantage of relying more on the mothers memory, obtaining dietary information for the 24 h before each visit may overestimate exclusive breastfeeding because some infants may receive fluids or foods on less than daily basis (Victoria et al, 1998).

Until 5 months of age infants in this population grew well, but thereafter growth faltering occurred, therefore further research is necessary regarding improvement of growth of infants after 4-6 months of age. The association between serum retinol concentrations and growth indicates that vitamin A plays a role in growth (Sommer & West, 1996). However our study showed that, in populations that are marginal vitamin A deficient (Muslimatun et al, 2001), vitamin A supplementation in conjunction with iron supplementation during pregnancy on community level has no impact on growth or morbidity of infants.

Acknowledgements

We are grateful to all mothers and infants who participated in this study for their willingness to attend our monthly measurements. We thank the field workers, voluntary health workers and midwives of Leuwiliang for their contribution to this project.

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Figure 1 Study profile.

Figure 2 Mean (s.e.m.) length and weight of infants from 0 to 12 months in the vitamin A plus iron group, iron group and reference values based on the NCHS standards.

Figure 3 Mean (s.e.m.) weight-for-age Z-scores at 0 to 12 months of age of infants with serum retinol concentrations >0.70 µmol/l and 0.70 µmol/l; differences evaluated by t-test, at 4 months, P=0.066; at 6 months P=0.045; at 7 months P=0.052.

Table 1 Proportion of infants in the vitamin A plus iron group and iron group suffering from selected symptoms of morbidity by age category

Table 2 Morbidity incidence (episodes per 100 infant days) of infants in the vitamin A plus iron group and iron group during the follow-up period

Table 3 Proportion of different feeding modes of infants in the vitamin A plus iron group and iron group by age category

Table 4 Weight gain and length increase by gender and serum retinol concentrations of infants during the first year of life^a