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Keywords:

  • intermittent preventive treatment in pregnancy;
  • malaria;
  • anaemia;
  • birthweight;
  • multigravidae;
  • The Gambia
  • traitement préventif intermittent dans la grossesse;
  • malaria;
  • anémie;
  • poids de naissance;
  • multipare;
  • Gambie
  • tratamiento preventivo intermitente durante el embarazo;
  • malaria;
  • anemia;
  • peso al nacer;
  • multigrávidas;
  • Gambia

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

We investigated the ability of intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine/pyrimethamine to prevent anaemia and low birthweight in Gambian multigravidae. Between July 2002 and February 2004, 2688 multigravidae living in a rural area of The Gambia received SP (1346 women) or placebo (1342 women) up to four times during pregnancy and were followed until 6-weeks post-partum. Shortly after delivery, 10.7% of women in the intervention group and 8.8% in the control group were severely anaemic [Hb < 7 g/dl, risk difference = 0.02 (95% CI −0.01, 0.04), P = 0.17]. The overall mean birthweight of infants born to women who had received SP (3103 g) was very similar to that observed in infants born to women in the control group [3075 g; difference = 28 g (95% CI −11 g, 67 g), P = 0.16]. However, among women who did not use a bednet (either insecticide treated or untreated), infants born to women who had received SP weighed more than infants born to women in the control group [3147 g vs. 3044 g; difference 143 g (95% CI 53 g, 232 g), interaction test P < 0.001]. This study did not show that IPTp with SP benefited Gambian multigravidae overall but that it may benefit a sub-group of women who do not use a bednet. In areas such as The Gambia, provision of insecticide-treated bednets to multigravidae may provide an adequate means of protection against malaria in pregnancy without the need for additional IPTp.

Nous avons investigué l'habilité du traitement préventif intermittent à base de sulfadoxine/pyrimethamine (SP) au cours de la grossesse, à prévenir contre l'anémie et le faible poids à la naissance chez des multipares gambiennes. Entre juillet 2002 et février 2004, 2688 multipares vivant en zone rurale en Gambie ont reçu soit du SP (1346 femmes) ou du placebo (1342 femmes) et ce, jusqu’à 4 fois durant la grossesse. Elles ont été suivies jusqu’à six semaines de post-partum. Très tôt après l'accouchement, 10,7% des femmes dans le groupe d'intervention étaient sévèrement anémiques (Hb < 7 g/dl) comparée à 8,8% dans le groupe contrôle (différence de risque = 0,02; IC95%: 0,01–0,04, p = 0,17). Le poids moyen total des enfants nés de mères ayant reçu du SP (3103 g) était fort similaire à celui des enfants nés de mères dans le groupe contrôle (3075 g) (différence de poids moyen = 28 g, IC 95%: 11–67, p = 0,16). Cependant, parmi les mères qui n'ont pas utilisé de moustiquaire (imprégnée d'insecticide ou non), les enfants nés de mères qui ont reçu du SP pesaient plus que les enfants nés de mères dans le groupe contrôle (3147 g versus 3044 g, différence = 143 g, IC95%: 53–232, test d'interaction: p < 0,001). Cette étude n'a pas démontré l'existence d'un bénéfice pour le traitement préventif intermittent à base de SP chez les multipares gambiennes en général, mais ce traitement pourrait bénéficier au sous groupe de femmes qui n'utilisent pas de moustiquaire. Dans des régions comme la Gambie, procurer des moustiquaires imprégnées d'insecticide aux multipares peut être un moyen de protection adéquat contre la malaria au cours de la grossesse sans le besoin additionnel d'un traitement préventif intermittent.

Hemos evaluado la habilidad del tratamiento preventivo intermitente durante el embarazo (IPTp) con sulfadoxina pirimetamina (SP) para prevenir la anemia y el bajo peso al nacer en mujeres multigrávidas en Gambia. Entre Julio 2002 y Febrero 2004, 2688 mujeres multigrávidas viviendo en un área rural de Gambia, recibieron hasta cuatro veces durante el embarazo, SP (1346 mujeres) o placebo (1342 mujeres) y fueron seguidas hasta seis semanas después del parto. Poco después de dar a luz, 10.7% de las mujeres en el grupo de intervención tenían una anemia severa (Hb < 7 g/dl), comparado con un 8.8% del grupo control (diferencia de riesgo = 0.02, [95% CI −0.01, 0.04]) (p = 0.17). El peso promedio al nacer de los niños nacidos de mujeres que habían recibido SP (3103 g) fue muy similar al observado en niños nacidos de mujeres en el grupo control (3075 g; diferencia = 28 g, [95% CI −11 g, 67 g] p = 0.16). Sin embargo, entre las mujeres que no utilizaron una red mosquitera (tanto impregnada como sin impregnar), los niños nacidos de mujeres que habían recibido SP pesaron más que los niños nacidos de mujeres del grupo control (3147 g versus 3044 g; diferencia 143 g, [95% CI 53 g, 232 g]) (test de interacción p < 0.001). Este estudio no demostró que en general, el IPTp con SP beneficiase a mujeres gambianas multigrávidas. Sin embargo, si podría beneficiar a un sub-grupo de mujeres que no utilizan mosquitera. En áreas como en Gambia, el suministro de redes mosquiteras impregnadas a mujeres multigrávidas podría proveer un medio de protección adecuado frente a la malaria durante el embarazo, sin necesidad de utilizar adicionalmente el IPTp.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Malaria in pregnancy is an important, preventable cause of maternal and perinatal morbidity and mortality (Brabin 1991; Menendez 1995; Diagne et al. 2000). In areas with a low level of transmission, malaria infection in pregnancy is usually symptomatic and may result in loss of the foetus and/or in maternal death (Luxemburger et al. 2001; Hammerich et al. 2002). In areas of high or medium endemicity, most malaria infections in pregnancy are asymptomatic and so infected women do not seek treatment. Thus, a preventive strategy is needed. Two approaches to the prevention of malaria in pregnancy are advocated – insecticide treated bednets (ITNs) and intermittent preventive treatment (IPT).

Although initial studies of the impact of ITNs on the outcome of pregnancy gave mixed results, a large trial in western Kenya has demonstrated convincingly that ITNs can reduce both maternal anaemia and the incidence of low birthweight, even in an area of high transmission (Ter Kuile et al. 2003).

Initial attempts to prevent malaria during pregnancy using antimalarials involved regular administration of drugs throughout pregnancy in order to sustain protective blood levels (chemoprophylaxis). However, compliance with chemoprophylaxis was generally poor, especially when chloroquine was used. The concept of IPTp, which involves the administration of a full therapeutic course of an antimalarial to pregnant women at risk at specified times regardless of whether or not they are infected, evolved as a means of overcoming the problem of poor compliance with chemoprophylaxis. Initial studies conducted in Malawi (Schultz et al. 1994) showed that a full course of sulphadoxine/pyrimethamine (SP) given twice during pregnancy reduced the prevalence of placental malaria. Subsequent studies in Malawi have shown that IPTp with SP protects against low birthweight in a dose related manner when given through the routine antenatal services (Verhoeff et al. 1998; Rogerson et al. 2000) and, in Kenya, IPT with SP given two or three times during pregnancy reduced the prevalence of severe anaemia in primigravidae (Shulman et al. 1999). Other studies conducted in Kenya have shown a beneficial effect of IPTp on low birthweight, although this may be muted in women who are HIV positive (Parise et al. 1998; van Eijk et al. 2004). On the basis of these findings, WHO now recommends IPT with SP for all pregnant women resident in areas of medium or high malaria endemicity (WHO 2000).

Intermittent preventive treatment would be expected to be most effective in primigravidae and secundigravidae who are most at risk from malaria and several trials have been limited to women in these groups. In other studies, women of all gravidities have been considered together and no separate analyses of outcome by gravidity have been presented. There is, therefore, little information on the value of IPTp or chemoprophylaxis in women of high gravidity who are HIV negative. In the first study of chemoprophylaxis in pregnancy, undertaken in Nigeria, no significant protection against low birthweight in women of gravidities two to four was detected (Morley et al. 1964). In The Gambia, the protective effects of chemoprophylaxis with Maloprim® (pyrimethamine +dapsone) against low birthweight and anaemia were largely restricted to primigravidae although the prevalence of parasitaemia was reduced in both primigravidae and multigravidae (Greenwood et al. 1989). In Malawi, IPTp with SP showed a prominent dose effect in primigravidae but no effect of dose was seen in multigravidae (Verhoeff et al. 1998; Rogerson et al. 2000). Thus, although IPTp with SP is recommended for women of all gravidities, there is little evidence to support its use in multigravidae in areas where the prevalence of HIV is low. We are unaware of any previous trial that has specifically addressed the effectiveness of IPTp with SP in multigravidae or whether IPTp should be given year round in areas where the transmission of malaria is seasonal. For these reasons, we conducted a study of IPTp with SP in multigravid women in The Gambia, where malaria transmission is very seasonal.

Materials and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Study area and study population

The study was undertaken between July 2002 and February 2004 in an area around the town of Farafenni, the third largest town in The Gambia, situated 170 km inland from the capital, Banjul. The area is one of typical sub-Sahelian savanna with a single rainy season, which lasts from July–November, followed by a long dry season. The average annual rainfall during the period 1999–2003 was 845 mm with a large variability between years. Malaria is seasonal with intense transmission occurring only during the latter part of the rainy season (Greenwood et al. 1987).

All women who attended one of 14 clinics situated on the north and south banks of the river Gambia near to Farafenni for antenatal care and who were identified as multigravidae were invited to join the study. At the time of the study, the recommended policy of the Ministry of Health for the prevention of malaria in pregnancy was chloroquine chemoprophylaxis for primigravidae and anaemic multigravidae (Hb < 10 g/dl) but this was not being implemented in the study area at the time of the trial.

Recruitment

An identification number was given to each potentially eligible woman who attended the antenatal clinic and a first questionnaire was completed to assess eligibility. Eligibility criteria were – a pregnancy of more than 15 weeks duration; an Hb concentration of more than 7 g/dl; absence of a history of allergy to sulphonamides; absence of severe or chronic diseases; willingness to be visited by a field worker during and after pregnancy; willingness to have two finger prick blood samples taken at delivery and 6 weeks later. For each eligible woman, written, informed consent was obtained and a recruitment form completed which provided information on age, village of residence, previous illness, previous obstetric history, treatment during the current pregnancy, education and socio-economic status including house construction. Information on the use of an untreated or treated bednet was obtained at a subsequent visit to the subject's compound. A finger prick blood sample was obtained for determination of Hb concentration and for preparation of two thick blood films. Screening for HIV was not undertaken routinely but the prevalence of HIV infection among antenatal clinic attenders in the study area at the time of the study was <1% (Schim van der Loeff et al. 2003).

Randomization

Women were individually randomized in blocks of 12; each field worker was assigned a number of blocks to ensure balanced numbers in each clinic.

Drug administration

Tablets (SP or identical placebo) were obtained from Cosmos Pharmaceuticals, Nairobi. Solubility and drug content (pyrimethamine 25 mg + sulphadoxine 500 mg) were confirmed by high-pressure liquid chromatography (HPLC). Tablets were pre-packed in envelopes, four envelopes were prepared for each woman – one for each potential IPT treatment, pre-labelled with the same packet number and placed in a wallet bearing the subject's number and packet number.

After enrolment, three tablets of SP or placebo were given under observation. Women were also given a supply of ‘Fefol’ tablets (500 μg of folic acid and 47 mg of ferrous sulphate) to be taken at home for a month. Women with an Hb concentration of 9–11 g/dl were asked to take two tablets a day and those with an Hb > 11 g/dl one tablet a day. At each subsequent monthly antenatal clinic visit, women were given three tablets of SP or placebo, under observation, up to a maximum of four treatments in one pregnancy. The timing of dosage was not constrained and depended upon when a woman attended an antenatal clinic. If she had not received a dose within the previous month, SP or placebo was given up to a maximum of four doses. Similar numbers of women in each group received one, two, three or four doses. The mean gap between the time of last drug administration was 29 days for the women who received SP and 28 days for those who received placebo.

Surveillance

Women were visited at home twice per week by a project field worker to assess the state of their pregnancy and to encourage them to attend monthly antenatal clinics. If a diagnosis of malaria was suspected on attendance at an antenatal clinic, a blood film was obtained. Parasitaemic women were treated with chloroquine (25 mg/kg) in accordance with Ministry of Health guidelines in place at the time of the study even though a study conducted in the west of the Gambia in 2002 showed a 28% day 14 failure rate in children treatment with chloroquine. First line treatment has subsequently been changed to chloroquine and SP. A follow-up visit was made by a field worker 72 h later and a further blood film obtained to confirm that treatment had been effective. If parasites were still present SP was given.

Women with a high risk of obstetric complications were encouraged to deliver in hospital or the health centre and 37% did so, 36% in the SP group and 38% in the placebo group. Deliveries at home were detected by field staff during their regular visits to study women. If during such a visit, a woman was found to have delivered, the field worker took a finger prick blood sample for measurement of Hb concentration and preparation of thick blood films and, if a live delivery had occurred, weighed the baby. Haemoglobin concentrations were obtained for 91% of women between 3 and 5 days after delivery.

Actual birthweights were obtained from only 5% of women; 87% of newborns were weighed between 3 and 5 days after birth. In the Gambia, an infant's weight falls on average by about 4% at day 4 after birth, returning to birthweight at day 7 and it is possible to use this information to calculate an estimated birthweight (Greenwood et al. 1989). However, as this was a large, individually randomized trial it was not considered necessary by the project's statistician to make these adjustments on this occasion and actual weights obtained have been used. Women were visited 6 weeks and 1 year after delivery to investigate the health of their child.

Laboratory methods

Haemoglobin was measured with a Hemocue (HemoCue AB, Ängelholm, Sweden). Thick blood films were stained with Giemsa stain. Slides were read by two microscopists who were blind to the treatment code. If results were discrepant, the slide was read by a third microscopist and the majority view used for analysis. One hundred high power fields were read before a slide was declared negative. In The Gambia, almost all malaria infections in pregnancy are caused by Plasmodium falciparum. The prevalences of parasitaemia posted in the results refer to the presence of asexual forms of this parasite.

Sample size

To detect with 80% power (using a 5% significance level) a 40% reduction in the prevalence of anaemia (Hb < 7 g/dl), assuming prevalence in the control group of 7%, 1128 women per group were required. For 80% power to detect a 20% reduction in the prevalence of an Hb < 9 g/dl, 892 were needed in each group. Allowing for loss to follow-up of 15%, we therefore projected that 1390 per group were needed. For birthweight endpoints, we assumed a mean of birthweight of 3000 g and a SD of 500 g. For 90% power to detect an increase in birthweight of 75 g and allowing for 20% loss to follow-up 1169 babies per group were needed but for similar power to detect a 30% reduction in the proportion low birthweight (<2.5 kg), we calculated that at least 1550 women per group would be needed. The study was, therefore, not powered for this endpoint. We anticipated that over a recruitment period of 18 months 2500–3000 women could be recruited.

Data management and statistical methods

After double data entry and verification had been completed, the database was locked and archived at the Medical Research Council Laboratories and a copy on CD sent to the chairman of the Data Safety and Management Board (DSMB). Statistical analysis was performed using S-Plus and STATA. Analysis was by intention to treat (ITT). Women with missing data were documented but omitted from analysis. Logistic regression was carried out on the anaemia and birthweight variables in order to allow for the impact of covariates likely to influence outcome (clinic, age, bednet usage and Hb concentration at enrolment). Linear regression models were used to analyse Hb concentration and birthweight distributions. As the primary outcomes were based on haemoglobin concentrations and birthweights at delivery, measurements taken more than 7 days after delivery were excluded.

Ethics

Ethical clearance for the study was obtained from the MRC/Gambian Government and London School of Hygiene and Tropical Medicine ethics committees. A DSMB was established before the start of the trial and followed the study's progress. An analytical plan was approved by the DSMB.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Trial profile

A total of 4148 multigravid women were screened; 2688 were recruited and randomized to receive SP (1346 women) or placebo (1342 women) (Figure 1). One hundred and sixty-seven women were ineligible because of their fundal height or Hb concentration and 570 non-Gambian women, who were mainly resident in Senegal, were not enrolled because of concerns as to whether they would attend for follow-up. Of the 1342 allocated to receive SP, 13% (223 women) were lost to follow-up compared with a 13% (236) loss in the placebo group. The main reason for loss to follow-up was delivery out of the study area.

image

Figure 1.  Trial profile.

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Characteristics of the study women

The characteristics of the women who received SP or placebo are shown in Table 1. The two groups were comparable in regard to age, gestational age, parity, initial Hb concentration, presence of parasitaemia on enrolment, bednet usage, month of delivery and number of treatments received. Seventy-eight per cent of women slept under a bednet, 93% of whom stated that they always slept under the bednet. Seventy-eight per cent of bednets had been treated with an insecticide and were in a good condition (<5 finger-sized holes). Bednet usage did not differ significantly between the SP and placebo groups. The mean number of treatments received did not differ significantly between women who received SP and those who received placebo.

Table 1.   Characteristics of intervention and control groups
 All womenSPPlacebo
n = 1346%n = 1342%
  1. SP, sulphadoxine/pyrimethamine.

Age (years)
 15–1916081517949
 20–2916998525084750
 30–397733784939551
 40–504628611839
Parity
 03117551445
 15662734829352
 25042535025150
 3–612996625163749
 >62881414914751
Initial Hb(g/dl)
 7–918899405094950
 >97994065139349
Initial parasitaemia
 Plasmodium falciparum4022071519515
Delivery month
 November–January5362825325447
 February–April4722345023850
 May–July5212574926451
 August–October8204115040950
Bednet usage
 Always17298835184649
 Sometimes13063496751
 Never5262544827252
Number of treatments
 One4142155219948
 Two5753005227548
 Three6823224736053
 Four6833425034150
Education
 No education2971515114649
 Madrassa and adult literacy2111105250105950
 Primary15475497951
 Secondary and technical11861525748
Ethnic
 Mandinka13116454966651
 Fula6863565233048
 Wolof5172504826752
 Other16689547746

Effect of intermittent preventive treatment with sulphadoxine/pyrimethamine on the prevalence of peripheral parasitaemia

The prevalence of peripheral parasitaemia with P. falciparum asexual stage parasites in the first week after delivery was significantly lower in women in the SP group than in women who received placebo [3% (34/1035) vs. 9% (91/1010); RR: 0.36 (95% CI 0.25, 0.53); P < 0.001; Table 2]. No relationship with the number of doses given was observed. At 6-weeks post-partum, the prevalence of parasitaemia was still lower in women in the SP group than in those who had received placebo [7% (66/922) vs. 13% (122/928); RR: 0.54 (95% CI 0.41, 0.72); P < 0.001].

Table 2.   The prevalence of Plasmodium falciparum asexual parasitaemia at the time of delivery by number of treatments
Number of treatmentsTotal number of womenSPPlacebo Risk ratio (95%CI)
  1. SP, sulphadoxine/pyrimethamine.

Any204534/1035 (3%)91/1010 (9%)0.36 (0.25, 0.54)
One3580/193 (0%)14/165 (9%)
Two4968/261 (3%)10/235 (4%)0.72 (0.29, 1.79)
Three58710/275 (4%)34/312 (11%)0.33 (0.17, 0.66)
Four59816/301 (5%)33/297 (11%)0.48 (0.27, 0.85)

Effect of intermittent preventive treatment with sulphadoxine/pyrimethamine on anaemia

There was no significant overall difference in the proportion of women with severe anaemia (Hb <7 g/dl) shortly after delivery between the SP group (10.7%) and the placebo group (8.8%) [risk difference = 0.02 (95% CI −0.01, 0.04)]. Observations made 6 weeks after delivery showed a similar picture (2.7% of women in the SP group were severely anaemic compared with 1.6% in the control group [risk difference = 0.03 (95% CI −0.004, 0.06)]. The distribution of haemoglobin concentrations shortly after delivery was very similar in the two groups (Figure 2). However there was a significant interaction between the effect of sleeping under a bednet and IPT in their effects on anaemia after delivery. The use of a bednet was associated with a reduced risk of anaemia in the group that received placebo, but not in the group that received SP. Among the women who used a bednet, there was a slightly increased risk of anaemia in those who received SP compared with those who received placebo (OR 1.4, 95% CI 0.99, 2.1), whereas among women who did not use a bednet, SP seemed to have no effect on the risk of anaemia. This interaction was significant (P = 0.049) but when effects on mean haemoglobin were considered, no significant interaction between treatment and bednet use was found.

image

Figure 2.  Distribution of the haemoglobin concentration after delivery by treatment group.

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Age, parity, education, marital status, gestational age, ethnic group and month of delivery were specified in the analysis plan as covariates to consider in an adjusted analysis. Age, parity, education and marital status were not associated with the risk of severe anaemia. Gestational age at enrolment and ethnic group were associated, women who enrolled at an earlier gestational age and therefore received the full number of doses were less likely to be anaemic at delivery in both treatment groups, but there was no interaction between treatment group and number of treatments in their effects on anaemia (Table 3).

Table 3.   Adjusted odds ratios for the risk of severe anaemia (Hb < 7 g/dl) at delivery
 Mean Hb g/dl (SD = 1.83)% Hb  < 7 g/dl Adjusted odds ratio (95%CI)†
  1. SP, sulphadoxine/pyrimethamine.

  2. *The test of interaction of the effect of intermittent preventive treatment with the effect of bednets was significant with P = 0.049 (Wald test).

  3. †Odds ratio from logistic regression with antenatal clinic included as a random effect, based on data for 1939 women whose records had non-missing data for all the covariates.

Use a bednet
 Placebo*9.46.9 (51/738)1
 SP9.310 (77/774)1.4 (0.99, 2.1)
Do not use a bednet
 Placebo9.016 (35/219)1
 SP8.913 (28/213)0.74 (0.43, 1.3)
Use a bednet
 No8.915 (63/432)1
 Yes9.48.5 (128/1511)0.51 (0.31, 0.86)
Gestational age
 16–209.76.0 (11/182)1
 21–259.58.6 (35/408)1.5 (0.75, 3.1)
 26–309.210 (91/870)1.8 (0.93, 3.5)
 31–359.112 (54/436)1.9 (0.95, 3.9)
 36–409.36.2 (12/194)0.99 (0.41, 2.4)
Ethnic group
 Mandinka9.56.8 (73/1068)1
 Fula9.013 (63/485)1.6 (1.1, 2.4)
 Wollof9.013 (53/403)1.4 (0.85, 2.3)
 Other9.611 (14/129)1.4 (0.73, 2.8)
Month of delivery
 January–March9.38.9 (41/463)1
 April–June9.57.6 (31/406)0.77 (0.46, 1.3)
 July–September9.210 (72/718)1.1 (0.72, 1.7)
 October– December9.212 (59/504)1.3 (0.83, 2.0)

Effect of intermittent preventive treatment with sulphadoxine/pyrimethamine on birthweight

Overall, there was no significant difference between the two groups in mean birthweight (Table 4), proportions of low birthweight babies (<2500 g) (5.4% for SP and 7.1% for placebo) or in the overall distribution of birthweights (Figure 3). However, there was a statistically significant interaction between bednet use (always, sometimes or never) and treatment (P < 0.001) for mean birthweight. For the women that ‘always’ or ‘sometimes’ slept under a bednet, mean birthweights were similar in the SP and placebo groups. For women who did not use a bednet, mean birthweight was greater in those who took SP than in those who took placebo, a difference of 143 g (after adjustment for covariates, 133 g, 95% CI: 47 g, 219 g; Table 4). Birthweight was associated with gestational age at first antenatal visit and independently associated with the number of IPT doses received. There was no association with ethnic group and there was no interaction between treatment effect and the number of doses received.

Table 4.   Mean birthweight and adjusted estimates of treatment effect
 Mean birthweightAdjusted difference in mean birthweight (95%CI)Low birthweight (%) (<2500 g)
  1. SP, sulphadoxine/pyrimethamine.

  2. *Test of interaction between the effect of nets and intermittent preventive treatment was significant with a P-value = 0.001.

Uses a bednet
 Placebo*30906.4 (46/716)
 SP30945.0 (−40, 50)5.4 (40/738)
Does not use a bednet
 Placebo30048.5 (17/201)
 SP3147133 (47, 219)5.7 (11/193)
Gravidity
 2304753 (−3.7, 102)5.7 (22/383)
 >230996.3 (92/1465)
Gestation at enrolment
 16–2030764.9 (9/185)
 21–253057−7.8 (−85, 69)7.7 (29/375)
 26–30307032 (−40, 105)6.7 (51/763)
 31–353137141 (57, 226)4.9 (19/387)
 35–403154183 (75, 291)4.4 (6/138)
Doses received
 130747.4 (22/299)
 2304516 (−51, 83)7.7 (34/443)
 33124139 (68, 209)4.6 (26/562)
 43094129 (54, 204)5.9 (32/544)
Month of delivery
 January–March30688.3 (36/432)
 April–June3042−39 (−100, 22)7.8 (29/372)
 July–September312237 (−18, 91)4.9 (29/587)
 October–December310219 (−39, 77)4.4 (20/457)
image

Figure 3.  Distribution of birthweights by treatment group.

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Because secundigravidae have a higher risk of malaria and its deleterious effects than women of higher gravidity, the effect of SP on low birthweight was determined separately for 384 secundigravidae. Overall there was no significant difference in mean birthweight between women who received SP and those who received placebo [−8.0 g (95% CI −110, 94 g)]. However, among secundigravidae who did not use a bednet a substantial increase in mean birthweight was seen in women who received SP compared with those who received placebo [196 g (95% CI 23, 368)], which was more marked than that observed in women of higher gravidity in whom the increase was 124 g (95% CI 24, 224). This interaction was, however, not statistically significant. Among women of higher gravidity there was no suggestion that parity influenced outcome.

Effect of season on the impact of intermittent preventive treatment in pregnancy

As expected, the proportions of women with severe anaemia at delivery increased with the number of months of pregnancy spent during the peak transmission season (June–November) (χ2 = 18.0, P < 0.001), as did the proportion of women who were parasitaemic (χ2 = 32.0, P < 0.001). However, paradoxically the prevalence of low birthweight decreased as the number of months of pregnancy during the peak transmission season increased (χ2 = 12.4, P = 0.01).

Tests for interaction between treatment and the number of months of pregnancy during the peak transmission season on severe anaemia at delivery, low birthweight and prevalence of parasitaemia were not statistically significant (P-values 0.79, 0.73 and 0.56, respectively).

Outcome of pregnancy

Information on the outcome of pregnancy and on the survival of babies born to study women is summarized in Table 5. Numbers of miscarriages and stillbirths were similar in women who had received SP or placebo. There were more deaths during the first 6 weeks of life in infants born to women who had previously received SP rather than placebo but the difference between groups is not statistically significant (χ2 = 2.7; P = 0.1).

Table 5.   Outcome of pregnancy in 2017 women who received sulphadoxine/pyrimethamine (SP) or placebo
 SP (n = 1022)Placebo (n = 995)Total (n = 2017)
Miscarriage5 (0.5%)2 (0.2%)7 (0.3%)
Still birth12 (1.2%)13 (1.3%)25 (1.2%)
Live birth1005 (98.3%)980 (98.5%)1985 (98.5%)
Death by 6 weeks39 (4.0%)26 (2.7%)65 (3.4%)

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

This study did not show any beneficial effect of IPTp with SP on anaemia or low birthweight in Gambian multigravidae overall although it did reduce the prevalence of peripheral blood parasitaemia. It is possible that some benefit ensued from this reduction in parasitaemia that was not mediated through an effect on birthweight or anaemia. It has been shown that placental parasitaemia at the time of delivery may increase subsequent susceptibility of infants to malaria (Le Hesran et al. 1997), although this has not been seen in all studies. Thus, the infants of women who received SP may have obtained some benefit although this was not apparent in their mothers.

We have considered a number of possible reasons why no beneficial effect on anaemia and birth-weight was seen in this study. We are confident that the lack of effect was not because of poor compliance as attendance at antenatal clinics was high and SP was given under direct observation on an average of three occasions. The drug content and solubility of the tablets used in the trial were confirmed by HPLC and the randomization process checked by testing a randomly chosen set of tablets. We are also confident that SP resistance was not the reason, as in a study undertaken in primigravidae in the Farafenni district at the same time as this trial, treatment with a single dose of SP was highly effective in clearing parasitaemia at day 14 after treatment (Mbaye A, Richardson K, Balajo B et al. American Journal of Tropical Medicine and Hygiene, in press), even among women who received a folic acid supplement. A similarly high cure rate following treatment with SP (97.3%) was seen in children with clinical malaria resident in the same area in 1999 (von Seidlein et al. 2001).

It is possible that in a study which extended over 2 years, an effect of IPTp during the relatively short period of high malaria transmission might have been masked. Analysis of the possible impact of season on the outcome of pregnancy is difficult because gestation frequently spans both high and low transmission seasons but an analysis which took into account the number of months of pregnancy spent during the period of high malaria transmission showed no protective effect for IPTp in women who may have been most at risk. The reason for the seeming decrease in the proportion of low birthweight babies during the high transmission season is not apparent and may have been a chance finding.

The lack of an effect of IPTp on the prevalence of anaemia or low birthweight in Gambian multigravidae is not surprising. In a study undertaken in the same area in 1984–1987 in which pregnant women were given chemoprophylaxis with Maloprim®, a marked reduction in the prevalence of anaemia and low birthweight was observed in primigravidae but no beneficial effect on packed cell volume or birthweight was seen in multigravidae, despite a reduction in parasitaemia in both groups of women, as seen in this study (Greenwood et al. 1989).

The policy implications of our findings are unclear. At present IPTp with SP is recommended for all pregnancies and it is administratively convenient to have a common policy for all pregnant women. In areas where the prevalence of HIV infection is high, there is evidence that women of all gravidities benefit from IPTp and, in such communities, a strong case can be made for giving IPTp to women of all gravidities. However, in areas of low HIV prevalence, such as The Gambia, the situation is more difficult. Although SP is relatively cheap, administration of IPTp with SP to all pregnant women regardless of gravidity may be a waste of scarce resources. Although SP is generally considered to be a safe drug when used for IPTp, it can rarely cause serious skin reactions and haematological side effects. No serious adverse events attributable to the administration of SP were seen in this study but among women who slept under a bednet and who were thus partially protected from malaria, anaemia was more prevalent in those who took SP than among those who took placebo. It is possible that this could have been because the sulphonamide component of SP can cause haemolysis in subjects who are glucose-6-phosphate-dehydrogenase deficient and this enzyme deficiency is present in the Farafenni area, although only at a modest level (Sirugo et al. 2004). Both cost and safety issues may become even more important if increasing resistance to SP forces the use of alternative drugs for IPTp, which are likely to be more expensive.

The logical conclusion from this study is that in The Gambia, and in areas with a similar pattern of malaria and low HIV prevalence, IPTp should be restricted to primigravidae. However, such a policy carries a risk of transferring the increased susceptibility to malaria seen in first pregnancies to second or subsequent pregnancies. We know of only one study that has addressed this issue specifically (Greenwood et al. 1994). A study in the Farafenni area showed no increased risk in second pregnancies among women who had received chemoprohylaxis with Maloprim during their first pregnancy. However, although the results of this study are reassuring, it was too small to give a definitive answer. In a more recent study undertaken in Kenya, a reduction in anti Pf EMP1 antibody concentrations was observed during the third trimester among primigravidae who had received IPTp with SP (Staalsoe et al. 2004). If, on the grounds of cost or safety, national malaria control programmes in The Gambia or elsewhere decide to restrict IPTp to first, or perhaps first and second pregnancies further study of the long-term consequences of this policy is essential.

An unexpected finding which may provide some help in addressing the difficult policy issues that our study raises was the finding of significant protection against low birthweight in women who received IPTp with SP if they never slept under a bednet. A trend in the same direction was seen for anaemia. Bednet coverage, including the use of ITNs (about 70%), was high among women in our study. This resulted in part from the high overall usage of bednets in The Gambia but also as a consequence of a distribution programme supported by UNICEF at the time of the study. Unfortunately, we obtained only limited information on bednet use during the trial. As this appears to be an important variable in determining the efficacy of IPT, future trials should obtain as much information on bednet usage as possible. There is little information on the value of combining IPTp and ITNs in the prevention of malaria in pregnancy. In an area on the coast of Kenya, protection against anaemia was only a little higher in women who received IPTp and who also used ITNs than it was in those who did not use nets (55%vs. 40%, a non significant difference) (Shulman et al. 1999). In another study undertaken in western Kenya, both ITNs and IPTp with SP were effective in preventing against maternal anaemia in primigravidae and secundigravidae, with IPTp being a little more effective than ITNs, especially in secundigravidae. Little additional benefit was obtained from a combination of the two (Njagi et al. 2003). More studies on the combined use of ITNs and IPTp are needed. It is possible that if an effective ITN is used regularly, IPTp may not be required. If this is the case, national malaria control programmes could focus on the distribution of ITNs, preferably long-lasting nets, at antenatal clinics (Guyatt & Ochola 2003) as their primary strategy for preventing malaria in pregnancy, reserving IPTp for primigravidae or women resident in areas of high HIV prevalence.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Firstly, we thank the women who agreed to participate in this study. We also thank Sana Jawara, Divisional Health Office, Lower River Division, the field supervisors Fabakaray Sanyang, Momodou Jobe and Faramba Ceesay and the many field assistants and laboratory staff who contributed to the trial. The support of Margaret Pinder in the supervision of the laboratory staff, and the support of the administrative staff of the MRC Laboratories, The Gambia is gratefully acknowledged. We thank members of the DSMB (Dr Aggrey Oloo, Professor Brabin, Dr Bojang and Dr Joanna Schellenberg) who oversaw the project. SP tablets and placebo were supplied by Cosmos Pharmaceuticals, Nairobi. We thank Harpakash Kaur for undertaking HPLC analysis. The trial was supported by the Medical Research Council and the Gates Malaria Partnership, which is funded by the Bill and Melinda Gates foundation.

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  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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