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Year : 2018  |  Volume : 55  |  Issue : 3  |  Page : 197-202

Comparison of the effectiveness of two-dose versus three-dose sulphadoxine-pyrimethamine in preventing adverse pregnancy outcomes in Nigeria

Department of Clinical Pharmacy and Pharmacy Management, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, Nigeria

Date of Submission29-Jul-2017
Date of Acceptance18-Jun-2018
Date of Web Publication4-Jan-2019

Correspondence Address:
Nneka U Igboeli
Department of Clinical Pharmacy and Pharmacy Management, University of Nigeria, Nsukka, Enugu State
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0972-9062.249128

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Background & objectives: Three doses of intermittent preventive treatment with sulphadoxine-pyrimethamine (IPTp-SP) has been adopted as the new recommendation for prevention of malaria in pregnancy. This study evaluated the effectiveness of two-dose versus three-dose of SP for IPTp-SP in the prevention of low birth weight (LBW) and malaria parasitaemia.
Methods: An open, randomized, controlled, longitudinal trial was conducted in a secondary level hospital in Nsukka region of Enugu State, Nigeria. A sample of 210 pregnant women within gestational ages of 16–24 wk were recruited at antenatal clinics and equally randomized to either a two-dose SP or three-dose SP group. The primary endpoints were LBWs, peripheral, and placental parasitaemia, while the secondary endpoints were maternal anaemia, pre-term birth, clinical malaria and adverse effects of SP.
Results: Among 207 cases followed till delivery, the prevalence of parasitaemia was lower in three-dose group than in two-dose group for both peripheral (9.3% versus 27.8%) and placental (10.6% versus 25.6%) parasitaemia. The adjusted odds ratios (aOR) were 0.15 [95% confidence interval (CI), 0.05 – 0.45] and 0.17 (95% CI, 0.06–0.51), respectively. The prevalence of LBW was also lower in three-dose (3.5%) than in two-dose (12.2%) group (aOR, 0.15; 95% CI, 0.04–0.63); however, the prevalence of maternal anaemia, pre-term births, clinical malaria and SP adverse effects were similar between the two arms of treatment.
Interpretation & conclusion: Addition of a third SP dose to the standard two-dose SP for IPTp led to improved reductions in the risk of some adverse pregnancy outcomes.

Keywords: IPTp-SP; low birth weight; malaria parasitaemia; sulphadoxine-pyrimethamine; three-dose SP; two-dose SP

How to cite this article:
Igboeli NU, Adibe MO, Ukwe CV, Aguwa CN. Comparison of the effectiveness of two-dose versus three-dose sulphadoxine-pyrimethamine in preventing adverse pregnancy outcomes in Nigeria. J Vector Borne Dis 2018;55:197-202

How to cite this URL:
Igboeli NU, Adibe MO, Ukwe CV, Aguwa CN. Comparison of the effectiveness of two-dose versus three-dose sulphadoxine-pyrimethamine in preventing adverse pregnancy outcomes in Nigeria. J Vector Borne Dis [serial online] 2018 [cited 2022 Jan 29];55:197-202. Available from: https://www.jvbd.org/text.asp?2018/55/3/197/249128

  Introduction Top

Intermittent preventive treatment with sulphadoxinepyrimethamine (IPTp-SP) has been recorded to be beneficial in multiple studies for decreasing the prevalence of maternal anaemia, placental malaria, and reducing the risks of low birth weight (LBW) of newborns in pregnant women[1]. The World Health Organization initially recommended at least two doses of SP before delivery in human immunodeficiency virus (HIV) negative pregnant women[2]. However, this recommendation was later reviewed for two major reasons. The first reason, was the evidence of reduced effectiveness of SP for IPTp in patients[3]. The second reason, was the growing concerns over the decreasing effectiveness of the two-dose regimen of SP for IPTp in countries with high levels of resistance to SP, especially in Eastern and Southern African regions that also carry the highest incidence of HIV in the world[4]. Hence, the latest updated WHO policy recommendation has changed from at least two-dose SP before delivery to monthly SP dosing up to the time of delivery for all pregnant women in areas of stable (moderate-to-high) malaria transmission. This entails that all pregnant women should receive an SP dose every month at each scheduled antenatal care visit after quickening and that the last dose can be administered up to the time of delivery, without safety concerns[5].

Nigeria has adopted the monthly IPTp-SP dosing as its main malaria control intervention in pregnancy. Other studies elsewhere have reported the superiority of the three-dose IPTp-SP over the two-dose IPTp-SP for prevention of adverse pregnancy outcomes in both HIV-negative and positive women[6]. Thus, there is need to document the added benefits or otherwise, of not strictly restricting IPTp-SP to only two doses in HIV negative pregnant women in Nigeria.

  Material & Methods Top

Study design and sample collection

It was an open, randomized, controlled, prospective and longitudinal study spanning over a period of six months. It was also a superiority trial evaluating the supposed superiority of three-dose SP over two-dose SP in a Mission hospital in Nsukka, Enugu State of Nigeria.

The pooled prevalence estimate of placental parasitaemia for the year 2000–11 for West and Central Africa was reported to be 38.2%[7]. This prevalence rate was used as an estimate for placental parasitaemia prevalence in Nigeria. This is because Nigeria is a West African country and the report[7] covered a period (2000–11) when most of the African countries were still adopting the initial policy of at least two-dose SP for IPTp. Using a target 50% reduction in placental parasitaemia in the intervention group as a significant superior reduction, a sample size calculation was done for the superiority trial. In total, 170 patients were calculated to have an 80% chance of significantly detecting (at p < 0.05) a decrease in the primary outcome measure from 38% in the control group to 19% in the experimental group.

Sample size calculation was done using the power calculator available from: www.sealedenvelope.com[8]. The power calculator for binary outcome trial used the following formula for sample size calculation:

n = f (α, β) × [p1 × 100 –p1) + p2 × (100 – p2])/(p2 – p1)[2]

Where, p1 and p2 are the percent success in the control and experimental groups, respectively. However, to allow for 5% non-compliance or ‘drop outs’, in both the control and experimental groups, 210 patients were included.

Pregnant women attending antenatal care (ANC) between 16–24 wk of gestation, and who were HIV-negative, and gave their informed consent were recruited. Random sequence generator from: www.random.org[9] was used to generate a randomization of 210 allocations into two columns signifying the two arms. Then, these numbers were printed and written in allocation slips. Allocation concealment was achieved by keeping 10 allocation slips with pre-assigned study allocations (5 per arm) in opaque containers. Sequential participants were asked to draw one allocation slip from the container without possibility of replacement.

Socio-demographic characteristics, use of preventive measures, maternal height and weight, obstetric and clinical histories were collected by means of questionnaires, measurements and patients' ANC folders. Baseline haemoglobin levels assessment was routinely done by the hospital for every first ANC visit and baseline investigations for presence of parasitaemia and parasitaemia count were also done by thin and thick smears, respectively. Routine antenatal care was given to all women. Women in the three-dose group received the first dose between 16–24 wk of gestation, the second dose between 20–32 wk, and the third dose not later than 36 wk. Women in the two-dose group also received the first dose between 16–24 wk of gestation and the second dose between 25–36 wk. All the women received ferrous sulphate (200 mg containing 60 mg of elemental iron) and folic acid (5 mg) daily. Women were asked to withhold folic acid for one wk following each SP dose in accordance with the National Antimalarial Treatment Guidelines. The women were asked to continue monthly scheduled follow-up visits to the clinic or to come in between the scheduled visits, if they fall ill. During each visit, the women were asked for signs and symptoms of malaria and also if they experienced any side-effect following SP administration. They were also examined for skin rashes and any reported side effect noted in the data records against the study number of patient. Those with clinical signs of malaria and who tested positive to rapid diagnostic test (RDT) kit were treated according to the national treatment guidelines with artemisinin-combination therapy (ACT)—Artemether-Lumefantrine. Blood samples were collected from the study participants at >36 wk and analysed for haemoglobin level and peripheral parasitaemia.

At the time of delivery, the newborns were weighed and birth weights were recorded. The placental parasitaemia was assessed from a blood sample that was collected from the maternal side of the placenta into an EDTA bottle. Thick and thin blood films were prepared from the blood sample. They were Giemsa-stained and examined by light microscopy under an oil-immersion objective, of 1000 × magnification. Parasitaemia (asexual or sexual) in thick films were estimated by counting asexual or sexual parasites relative to 1000 leukocytes. From this figure, the parasite density was calculated assuming a leukocyte count of 8000 μl−1 of blood.

The primary endpoints were LBWs, peripheral and placental parasitaemia while the secondary endpoints were maternal anaemia, pre-term birth, clinical malaria and adverse effects of SP.

Ethical statement

The study was carried out following an ethical clearance with letter number UNTH/CSA/329/VoL5 from the University of Nigeria Teaching Hospital, Enugu State and approval from the hospital's administration.

Statistical analyses

Statistical analyses were performed using the SPSS package v. 16 (SPSS Inc., Chicago, IL, USA). A modified intention-to-treat (ITT) approach used in those women who at least had one primary outcome measured, were included. Simple descriptive analyses (frequency and mean) were used to represent demographic and clinical variables by the study groups. Two-sample comparisons were made using Student's t-test for normally distributed variables, while comparisons of proportions were carried out using Chi-square. Logistic regression models were used to determine effect of either two-dose or three-dose group on prevalence of both primary and secondary outcomes. Adjusted odds ratio was also calculated for these binary outcomes by adjusting for possible literature-reported confounding variables like gravidity, maternal body mass index (BMI), maternal age group, newborn's gender, baseline parasitaemia, baseline anaemia, secondary smoking and adherence to ITN (ADITN). The criterion for statistical significance was considered at p-value ≤ 0.05.

  Results Top


No significant differences were found between the socio-demographics of the two treatment arms for the considered variables—Age group, educational level, occupation, alcohol consumption, secondary smoking status, number of people living in the households (p > 0.05), [Table 1].
Table 1: Socio-demographic characteristics of pregnant women in two treatment arms

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Other preventative measures

The use of other malaria preventives, apart from IPTp-SP was similar between the two treatment groups except for the use of insecticide spray (p = 0.007). Majority of the women use insecticide-treated bednets (ITNs) (86.4%) and they started using it by the middle of their pregnancy (62.3%) [Table 2].
Table 2: Preventive measures used by pregnant women

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Baseline obstetric characteristics

The two treatment groups had similar obstetric characteristics at baseline except for maternal weight (p = 0.006) and height (p = 0.004). However, their BMI was similar between the two groups (p = 0.051), [Table 3].
Table 3: Baseline obstetric data of two treatment arms

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Comparison of outcomes of three-dose and two-dose SP

Primary outcomes: There was significant risk reduction observed in the following adverse outcomes in the three-dose SP group compared to the two-dose SP group: LBW deliveries [OR = 0.26, 95% CI = 0.07 – 0.96]; peripheral parasitaemia [OR = 0.27, 95% CI = 0.11–0.63] and placental parasitaemia [OR = 0.35, 95% CI = 0.15–0.80]. These risks were further reduced for LBW deliveries, peripheral and placental parasitaemia after adjusting for confounding variables [Table 4]. The risk of having moderate anaemia [OR = 0.76, 95% CI = 0.41–1.41] or severe anaemia [OR=0.51, 95% CI = 0.09–2.87] amongst the women showed a non-significant trend towards reduction for women in the three-dose SP group.
Table 4: Primary and secondary outcomes by treatment arm

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Sub-group analyses by gravidity revealed that in the three-dose treatment group, only primigravidae maintained a significantly reduced risk of having LBW deliveries, peripheral parasitaemia and placental parasitaemia (all at p < 0.05). On further adjustment for confounding variables, the risks were further reduced for LBW deliveries, peripheral and placental parasitaemia.

Secondary outcomes: The risk of maternal anaemia, pre-term delivery and clinical malaria were non-significantly reduced (all at p < 0.05) in the three-dose group while the risk of experiencing adverse effect following SP administration was non-significantly increased (p > 0.05) in the three-dose group. Further, sub-group analysis of pre-term delivery and clinical malaria by gravidity resulted still in non-significant changes in odds ratio for either sub-groups, even after adjustment for confounders.

  Discussion Top

This study demonstrated a significantly higher effectiveness of three-dose SP over two-dose SP in reducing some adverse maternal and fetal outcomes. The incidence of mild adverse effects from SP administration was moderate among the women and similar between the two trial groups.

The reduction in both peripheral and placental parasitaemia was expected considering that three-dose group received their last dose, on average, one month closer to term. This may have led to the clearance of infections and reduction in the susceptibility to new infections at term by providing an extra period of post-treatment prophylaxis of approximately 4–6 wk.

Positive effect of three dose SP on birth weight have also been consistently reported in many trials regardless of variations in study design, malaria endemicity and degree of SP resistance[6]. There was clinically relevant reduction in the risk of LBW by 85%. In two similar trials in West Africa, the one in Burkina Faso[10] reported a nonsignificant trend towards reduced risk of LBW deliveries only after a per protocol analysis was carried out while the Mali study[11] demonstrated the superiority of threedose SP over standard two-dose SP in reducing the risk of LBW deliveries. Low uptake of the third dose of SP and an unexpected lower intensity of malaria transmission (< 20% baseline parasitaemia) recorded at the Burkina Faso study were given as possible confounders of the effectiveness of the three-dose regimen. A closely related study in Lagos, Nigeria where two-dose SP was albeit compared to a monthly IPTp-SP, concluded that there was no significant difference in effectiveness between the two arms of treatment in reducing LBW or parasitaemia. However, the Lagos study based its findings on the analysis of only a subset of 149 women out of the 259 originally randomized to each arm of the study without any description of the spread of this subset between the two arms. Thus, the possibility of reduced power in the results following in-equivalent distribution into the two arms of treatment cannot be ruled out. Another important factor to consider is that the Lagos study was carried out in an urban area with a possibly lower malaria burden as was reflected in a baseline parasitaemia level of less than 3%[12]. On the other hand, the present study site mostly serves referrals of women from the surrounding rural communities and the baseline parasitaemia prevalence was 23%.

The positive effect of three-dose SP on prevalence of LBW noted in this study could also reflect an association with fetal growth rather than pre-term delivery as the three-dose SP did not lead to significant reduction in the risk of pre-term delivery. It may suggest a more complete protection in the last two trimesters, including the last 6–10 wk of pregnancy which have been noted to be a pivotal time for fetal growth. Observations in healthy pregnancies have shown that, of the total fetal weight gain, 28 and 55% occurs during the last 6 and 10 wk of pregnancy, respectively[12].

The impact of three-dose SP on prevalence rates of primary outcomes were more pronounced among primigravidae. Earlier studies have shown IPTp-SP to be more effective in first pregnancies as observed in this study[1],[13],[14]. Despite the large recorded impact of threedose SP on both the parasitaemia and birth weight, its impact on prevalence of moderate anaemia was modest and non-significant. Similar results have been reported elsewhere[11].

The risk of other adverse secondary outcomes including pre-term delivery, clinical malaria and adverse effects were not affected by the addition of a third SP dose. Preterm births and clinical malaria generally indicated a trend towards reduction of risk while the risk for adverse effects of SP was higher in three-dose SP, although these risks did not reach a statistically significant difference between the two arms of treatment. A similar non-significant trend towards pre-term delivery risk reduction was reported for three-dose treatment groups in a systematic review[6]. The prevalence of adverse effect was similar between both treatment arms. This signifies that the added SP dose in the three-dose group was as tolerable as using only the recommended two-dose SP.

Monthly IPTp-SP dosing as is currently being advocated by the WHO[5], means that the women receive at least three or more doses of SP before delivery. Using three or more doses of SP have been reported to be more effective than the standard two-dose SP in reducing adverse pregnancy outcomes[6]. Thus, monthly IPTp-SP dosing could be comparable to three-dose SP. However, with monthly dosing there is the issue of ease of implementation. The programmatic challenges of implementation of IPTp and achieving high coverage have been faced in 2007, when only an estimated 25% of pregnant women received at least one dose of IPTp-SP[15]. Thus, it may be preferable to recommend monthly SP as against recommending ‘least three doses of SP’ for IPTp because it virtually eliminates the risk of inadvertently under-dosing pregnant women. This was confirmed when Gill et al[16] in 2007 re-analyzed their previous work in order to evaluate the dose response relationship with IPTp-SP. They found that ~15% of mothers assigned to receive the standard once-per trimester two dose regimen received only a single dose of SP compared with <1% of mothers assigned to receive intensive monthly IPTp (I-IPTp)[16]. The increased effectiveness of three or more doses of SP can be applied programmatically bearing in mind that the WHO recommends at least four ANC visits with the last three visits coming after quickening, thus leaving at least three opportunities at monthly interval for the administration of IPTp-SP.

  Conclusion Top

The study has demonstrated that an added dose of SP to the standard two-dose SP-IPTp significantly reduces the risk of most malaria-associated adverse pregnancy outcomes. This result provides evidence that the current WHO recommendation of more than two doses of SP for IPTp results in better pregnancy outcomes than the initial two-dose IPTp-SP for HIV-negative pregnant women in Nigeria.

Conflict of interest

The authors declare no conflict of interest.

  References Top

ter Kuile FO, van Eijk AM, Filler SJ. Effect of sulfadoxine-pyrimethamine resistance on the efficacy of intermittent preventive therapy for malaria control during pregnancy: A systematic review. JAMA 2007; 297(23): 2603–16.  Back to cited text no. 1
A strategic framework for malaria prevention and control during pregnancy in the Africa region 2004. Geneva: World Health Organization Regional Office for Africa. Available from: http:// www.who.int/malaria/publications/atoz/afr_mal_04_01/en/ (Accessed on February 18, 2013).  Back to cited text no. 2
Feng G, Simpson JA, Chaluluka E, Molyneux ME, Rogerson SJ. Decreasing burden of malaria in pregnancy in Malawian women and its relationship to use of intermittent preventive therapy or bednets. PLoS One 2010; 5(8): e12012.  Back to cited text no. 3
Global report: UNAIDS report on the global AIDS epidemic 2010. “UNAIDS/10.11E|JC1958E”. Joint United Nations Programme on HIV/AIDS (UNAIDS). Geneva: WHO Library Cataloguing-in-Publication Data 2010; p. 364. Available from: http:// files. unaids. org/en/media/unaids/contentassets/documents/unaidspublication/2010/20101123_globalreport_en%5b1%5d.pdf (Accessed on February 23, 2013).  Back to cited text no. 4
WHO/GMP, Updated WHO policy recommendation (October 2012): Intermittent preventive treatment of malaria in pregnancy using sulfadoxine-pyrimethamine (IPTp-SP). Geneva: World Health Organization/Global Malaria Programme 2012. Available from: http://www.who.int/malaria/publications/atoz/who_iptp_sp_policy_recommendation/en/ (Accessed on April 21, 2013).  Back to cited text no. 5
Kayentao K, Garner P, van Eijk AM, Naidoo I, Roper C, Mulokozi A, et al. Intermittent preventive therapy for malaria during pregnancy using 2 vs 3 or more doses of sulfadoxine-pyrimethamine and risk of low birth weight in Africa: Systematic review and meta-analysis. JAMA 2013; 309(6): 594–604.  Back to cited text no. 6
Chico M, Mayaud P, Ariti C, Maybe D, Ronsmans C, Chandramohan D. Prevalence of malaria and sexually transmitted and reproductive tract infections in pregnancy in sub-Saharan Africa: A systematic review. JAMA 2012; 307(19): 2079–86.  Back to cited text no. 7
Sealed Envelope Ltd 2012. Power calculator for binary outcome superiority trial. Available: https:// www.sealedenvelope.com/ power/binary-superiority/. (Accessed on January 4, 2013.)  Back to cited text no. 8
Random.org 1998–2013. Random string generator. Available from: https://www.random.org/strings/ (Accessed on January 7, 2013).  Back to cited text no. 9
Vale I, Tinto H, Drabo MK, Huybregts L, Henry M, Roberfroid D, et al. Intermittent preventive treatment of malaria with sulfadoxine-pyrimethamine during pregnancy in Burkina Faso. Malar J 2010; 9: 324.  Back to cited text no. 10
Diarise OS, Kayentao K, Traoré BT, Djimde A, Traoré B, Diablo M, et al. Superiority of 3 over 2 doses of intermittent preventive treatment with sulfadoxine-pyrimethamine for the prevention of malaria during pregnancy in Mali: A randomized controlled trial. Clin Infect Dis 2011; 53(3): 215–23.  Back to cited text no. 11
Agomo CO, Oyibo WA, Odukoya-Maije F. Parasitologic assessment of two-dose and monthly intermittent preventive treatment of malaria during pregnancy with sulphadoxine-pyrimethamine (IPTp-SP) in Lagos, Nigeria. Malar Res Treat 2011; 2011:6. doi: 10.4061/2011/932895.  Back to cited text no. 12
Gamble C, Ekwaru PJ, Garner P, ter Kuile FO. Insecticide-treated nets for the prevention of malaria in pregnancy: A systematic review of randomised controlled trials. PLoS Med 2007; 4(3): e107.  Back to cited text no. 13
Mbaye A, Richardson K, Balajo B, Dunyo S, Shulman C, Milligan P, et al. A randomized, placebo-controlled trial of intermittent preventive treatment with sulphadoxine-pyrimethamine in Gambian multigravidae. Trop Med Int Health 2006; 11(7): 992–1002.  Back to cited text no. 14
van Eijk AM, Hill J, Allegan VA, Kirui V, Getting P, ter Kuile FO, et al. Coverage of malaria protection in pregnant women in sub-Saharan Africa: A synthesis and analysis of national survey data. Lancet Infect Dis 2011; 11(3): 190–207.  Back to cited text no. 15
Gill CJ, MacLeod WB, Mwanakasale V, Chalwe V, Mwananyanda L, Campo D, et al. Inferiority of single-dose sulfadoxinepyrimethamine intermittent preventive therapy for malaria during pregnancy among HIV-positive Zambian women. J Infect Dis 2007; 196(11): 1577–84.  Back to cited text no. 16


  [Table 1], [Table 2], [Table 3], [Table 4]

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