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 Table of Contents  
Year : 2016  |  Volume : 23  |  Issue : 2  |  Page : 57-61

A comparative study of azithromycin and sulphadoxine-pyrimethamine as prophylaxis against malaria in pregnancy

1 Department of Obstetrics and Gynaecology, Adeoyo Maternity Teaching Hospital, Ibadan, Oyo State, Nigeria
2 Department of Obstetrics and Gynaecology, College of Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria
3 Department of Pharmacology and Therapeutics, College of Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria

Date of Web Publication13-Jul-2016

Correspondence Address:
Folasade Adenike Bello
Department of Obstetrics and Gynaecology, College of Medicine, University of Ibadan, Ibadan, Oyo State
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1117-1936.186295

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Context: The benefit of malaria prophylaxis in pregnancy is threatened by emergence of Plasmodium falciparum resistance to antimalarial agents for chemoprophylaxis and treatment.
Aim: This study aimed to compare the effectiveness of azithromycin (AZ) with sulphadoxine-pyrimethamine (SP) for malaria prevention.
Settings and Design: A prospective comparative study of antenatal clinic attendees at the University College Hospital, Ibadan, Nigeria. Participants were randomised to receive SP or AZ.
Subjects and Methods: The subjects were antenatal attendees and Samples for malaria parasitaemia were collected and repeated at follow-up visits; maternal peripheral blood film, placental and cord blood samples were collected at delivery.
Statistical Analysis Used: Chi-square test and t-test in a per-protocol analysis.
Results: Of 200 participants (100 in each group), 166 (83.0%) completed the study: 86 (86.0%) of SP and 80 (80.0%) of AZ groups, respectively (P = 0.26). Four (4.7%) participants who had SP compared to five (6.2%) in AZ group developed malaria at mean gestational ages of 30.3 ± 1.56 and 33.0 ± 8.6, respectively (P = 0.56). Positive peripheral, placental and cord blood parasitaemia were found in ≤2% of the participants. Drug tolerability and foetal outcomes were comparable for both groups.
Conclusion: AZ was comparable to SP for prevention of malaria in pregnancy and may be used in patients who do not tolerate SP.

Keywords: Azithromycin, intermittent preventive treatment for malaria in pregnancy, sulphadoxine-pyrimethamine

How to cite this article:
Abdus-Salam RA, Bello FA, Fehintola FA, Arowojolu AO. A comparative study of azithromycin and sulphadoxine-pyrimethamine as prophylaxis against malaria in pregnancy. Niger Postgrad Med J 2016;23:57-61

How to cite this URL:
Abdus-Salam RA, Bello FA, Fehintola FA, Arowojolu AO. A comparative study of azithromycin and sulphadoxine-pyrimethamine as prophylaxis against malaria in pregnancy. Niger Postgrad Med J [serial online] 2016 [cited 2020 Jul 7];23:57-61. Available from: http://www.npmj.org/text.asp?2016/23/2/57/186295

  Introduction Top

Malaria is a protozoan infection caused by Plasmodium species; Plasmodium falciparum being the most common cause of malaria infection in Africa and causing most severe infections.[1],[2],[3] Other species that naturally infect humans include Plasmodium vivax, Plasmodium ovale, Plasmodium malariae and Plasmodium knowlesi.[3],[4],[5] There were about 3.3 billion people estimated to be at risk of malaria infection in 2013 with 1.2 billion being at high risk; 198 million cases of malaria and an estimated 584,000 malaria deaths occurred.[5] About 90% of the global malaria burden occurs in Sub-Saharan Africa,[1],[2] and the burden of malaria in Sub-Saharan Africa is mostly borne by under-five children and pregnant women.[1],[6] Malaria infection in pregnancy (MIP) remains a public health problem in the tropical and subtropical regions of the world.[2] Primigravidae are more affected than multigravidae in areas of high malaria transmission, whereas all parity groups are equally affected in low malaria transmission areas.[7],[8],[9] The complications of maternal malaria infection include anaemia of varying degrees, maternal death, spontaneous abortion, preterm delivery, low birth weight, intrauterine growth restriction, stillbirth, neonatal death and congenital malaria.[8],[10],[11] MIP is characterised by peripheral and placental parasitaemia. Peripheral parasitaemia is most common in the second trimester of pregnancy.[10]

The strategies to reduce the burden of malaria infections include the use of insecticide-treated nets (ITNs)/long-lasting insecticidal nets (LLINs), intermittent preventive treatment for malaria in pregnancy (IPTp) and prompt case management in addition to environmental control of its vector.[1],[2],[3],[6] The aims of IPTp are clearance of the peripheral and placental parasites, and provision of intermittent chemoprophylaxis against MIP.[12] Sulphadoxine-pyrimethamine (SP) is an antifolate antimalarial drug.[13] The World Health Organization recommends IPTp-SP to be given from the second trimester as three tablets of SP, administered at least 1 month apart, which can be given until delivery without adverse effect.[14] The occurrence of P. falciparum resistance to SP in Africa threatens its use in the IPTp. Several antimalarial agents such as mefloquine, SP, and chloroquine, and antibacterial agents such as azithromycin (AZ) and erythromycin with antimalarial properties have been used in clinical trials as single drugs or in combination, in an attempt to identify alternatives to SP for prevention of malaria in pregnancy.[12],[15],[16],[17] AZ, a macrolide antibiotic, is a derivative of erythromycin with antimalarial effect.[18],[19] It is effective in the treatment of sexually transmitted infections and has a wide spectrum of antimicrobial effects. It acts by inhibition of protein synthesis and has a prolonged duration of action.[19],[20] It has a high tissue penetration, tissue half-life of 2–4 days and elimination half-life of 3 days;[19] this permits a daily dose and short treatment duration. It is safe in pregnant and breastfeeding women.[21]

There is an emergence of resistance to SP in Sub-Saharan Africa,[22],[23] and it is important to identify alternatives for its use as IPTp. Some studies have compared SP with AZ either with the AZ in combination with another antimalarial or the SP in combination with another antimalarial [12],[24] in the treatment of malaria. However, these studies have not compared these drugs as monotherapy for IPTp. Others studied males or non-pregnant females [25] rather than pregnant women. This study aimed to compare AZ with SP for IPTp in terms of efficacy, adverse reaction and foetal outcomes, and as an effective alternate to SP in pregnant women.

  Subjects and Methods Top

This was a prospective comparative study conducted over a period of 9 months (from January 2012 to September 2012) following approval by the University of Ibadan (UI)/University College Hospital (UCH) Ethics Committee (approval reference number UI/EC/11/0160, dated 26/01/2012). The study hypothesis was that AZ is as effective as SP for malaria prophylaxis in the IPTp.

The study population included consenting pregnant women attending the antenatal clinic of the UCH, Ibadan, Nigeria. The participants were enrolled if they met the inclusion criterion: Booked pregnant women who were in the second trimester. The exclusion criteria included previous IPTp in index pregnancy (before recruitment), allergy to SP or allergy to macrolide antibiotics and chronic illness. The participants were randomised into either the SP or AZ groups following written informed consent. The enrolment was done during the antenatal clinic visit.

At enrolment, sociodemographic data, general medical and obstetric histories were obtained from the participants. The general physical and obstetric examinations were done; baseline packed cell volume, blood film for malaria parasites and other routine antenatal investigations were done. The participants subsequently received either of the intervention drugs – SP or AZ after foetal movement was perceived in the second trimester. The participants in the SP group received a first dose of three tablets SP each containing 500 mg of sulphadoxine and 25 mg of pyrimethamine (Vitadar, Strides Vital Nigeria Limited, Lagos, Nigeria). A repeat dose of SP was administered 4 weeks after the first dose of SP to participants in the SP group. The participants in the AZ group received AZ tablet (Azithrin, Strides Vital Nigeria Limited, Lagos, Nigeria) 500 mg daily for three consecutive days. All the participants had routine haematinics and were followed up by phone calls to encourage compliance. The participants were counselled on the benefits of ITN/LLINs and were encouraged to use them. The follow-up entailed a history of illness or any symptom, drug reaction or history of other drug use; blood film samples for malaria parasite were taken at antenatal visits, delivery and at postpartum visit. Maternal peripheral blood sample was obtained from a thumb prick and smeared on a slide. To minimise participants' discomfort, capillary blood was obtained at the antenatal clinic side laboratory, from the same thumb prick used for haematocrit estimation. The placental blood sample was obtained from the maternal surface of the placenta using the incision method [26],[27] and cord blood sample was obtained from the placental portion of the cord. The slides were air-dried and stained with Giemsa stain and examined for parasite and parasite pigments. The babies and the placentae were weighed (in grams) within 30 min of life. Low birth weight was defined as a birth weight of <2500 g. A slide is pronounced negative if no malaria parasite was found in 200 oil immersion fields or after counting 500 white blood cells.

The sample size was calculated based on a malaria parasite prevalence of 10.5%,[28] power of 80% and a 5% level of significance to determine a 10% difference in malaria parasitaemia between the AZ and SP groups. A minimum sample size of 80 participants was determined for each group. However, to allow for an attrition/non-response and loss to follow-up rate of 20%, a sample size of 100 participants in each group was estimated. Completion of the study was defined by availability of enrolment, delivery and postpartum data and all blood film samples. Randomisation was done using a computer-generated table of random numbers, and randomisation numbers were labelled against either of the intervention drugs. The labelled intervention drugs were concealed in opaque envelopes labelled with randomisation number. The attending physicians and laboratory scientist were blinded to the intervention drug being administered to the participants.

The primary outcome measure was to determine the occurrence of malaria infection – parasitaemia in the participants during pregnancy and at delivery; placental and cord blood malaria parasite of the new-born at delivery. The secondary outcome measures were foetal outcomes, drug tolerability and adverse reactions. The data were analysed with the Statistical Package for Social Sciences, version 16 (SPSS Inc., Chicago, IL, USA). The data analysis was based on a per-protocol analysis, rather than an intention-to-treat analysis. Analysis was done using Chi-square test for categorical variables (Fisher's exact test was used as appropriate) and Student's t-test for continuous variables. Statistical significance was set at P<0.05.

  Results Top

A total of 200 participants were enrolled into the study with 100 participants allocated into each study group [Figure 1]. One hundred and sixty-six participants (83.0%) completed the study; 34 (17.0%) participants were lost to follow-up. Eighty-six (86.0%) of the participants in the SP group and 80 (80.0%) in the AZ group (P = 0.26) completed the study.
Figure 1: Flow of participants through the study. SP: Sulphadoxine--pyrimethamine, IPTp: Intermittent preventive treatment for malaria in pregnancy

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The sociodemographic and baseline characteristics of the participants in the study were comparable [Table 1]. The mean age of participants in the two groups was 30.62 ± 4.03 and 31.45 ± 4.87 years for the SP and AZ groups, respectively. Majority of the participants were in their first or second pregnancy, and there was no difference in the mean gestational age at enrolment for either study group with 24.74 weeks and 24.64 weeks for the SP and AZ groups, respectively (P = 0.86). The participants tolerated the drugs in both study groups; 3 (3.5%) and 1 (1.2%) of the participants had adverse drug reaction in the SP and AZ groups, respectively (P = 0.35). The drug reactions seen in the SP group included skin rashes, haematuria and weakness, whereas fever was seen in the AZ. There was no known history of allergy to SP and previous exposure or reaction to sulphonamide could not be ascertained.
Table 1: Comparison of sociodemographic characteristics of participants

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Only 9 (5.4%) of the participants had malaria infection during the antenatal period [Table 2]. The mean gestational age at which participants in each group were diagnosed of malaria was slightly different but not statistically significant (P = 0.56), neither was the mean gestational age at delivery (P = 0.18). A comparison of malaria parasite detection at delivery in the two study groups is shown in [Table 3]. The peripheral blood film parasitisation, the placental parasitisation and cord blood parasitisation were not significantly different for participants in either study group. Placental parasitisation was demonstrated in 2 (2.3%) participants in the SP group compared with 1 (1.2%) in the AZ group, whereas a positive cord blood film was demonstrated in 1 (1.2%) participant in the SP group compared with 2 (2.5%) in the AZ group.
Table 2: Comparison of malaria infection during pregnancy and the mean gestational ages at malaria detection and delivery

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Table 3: Comparison of malaria parasitisation at delivery in the two groups

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[Table 4] shows the foetal outcomes in terms of birth weight, Apgar scores at 1 and 5 min, placental weight, intrauterine foetal death, live birth and stillbirth. The Apgar score at 1 min was statistically significant with a mean Apgar score of 8.38 (±0.96) and 7.90 (±1.80) in the SP and AZ groups, respectively (P = 0.03). All other parameters were similar in the two study groups. One (1.2%) foetal anomaly was seen in the SP group and none in the AZ group (P = 0.33). The anomaly included prominent, patent anterior fontanelle, low set ears, talipes equinovalgus deformity and skin discolouration.
Table 4: Comparison of foetal outcomes between the two study groups

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  Discussion Top

According to the Nigeria Demographic and Health Survey 2013, about two-thirds of women receive antenatal care from a skilled provider and only about one-third deliver in the health-care facility.[29] This may explain the loss to follow-up among some of the study participants as well as the desire to deliver in faith-based maternity homes or other facilities rather than health-care facilities despite booking for antenatal care at these facilities.

The study compared the use of SP with AZ for IPTp. The results from this study suggest the similar efficacy of AZ compared with the efficacy of SP in the prevention of malaria in pregnancy. There was no significant difference in peripheral parasitaemia, placenta parasitaemia and cord blood parasitaemia between the two groups. This is similar to a study comparing a control cohort to AZ in which AZ was found to be effective in 100% of cohorts who had AZ [18] and in another study in which AZ was compared to doxycycline.[25] The degree of parasitaemia at delivery in this study was low. This may suggest the efficacy of SP and AZ in clearance of peripheral parasitaemia thus reducing density of peripheral parasite for placental sequestration. Both study drugs were tolerated by most of the participants. However, there were few reported cases of adverse effects such as haematuria in the SP group. This is similar to findings in other studies demonstrating good tolerability and few adverse reactions with use of AZ [18],[25] or SP-AZ combination.[24]

The mean gestational age at delivery in both study groups was also comparable to findings in a study conducted in Malawi with a mean duration of pregnancy of 38.5 ± 2.4 weeks in SP group, 38.8 ± 2.1 weeks in the AZ-SP group and 38.4 ± 2.2 weeks in the control group.[30] The birth weights were comparable for both study groups. The mean Apgar scores of infants in both study groups were normal, as defined by Apgar score of 7–10.

An advantage of AZ is its safety in all trimesters of pregnancy. Another advantage is its dosing regimen, which is more likely to encourage compliance. SP (costs $0.40–$1.50 per 3 tablets, using the exchange rate at the time of the study, of $1 to N160) is cheaper than AZ (costs $3.00–$20.00 per 3 tablets). The cost of AZ compared to SP may also discourage indiscriminate use of AZ either as an effective antibiotic or antimalarial agent. This may help prevent the development of resistance to AZ in the nearest future or at least slow down the rate of development of resistant strains.

The limitations of the study include inability to ensure other strategies of malaria prevention and their impact in the study population; inability to prevent the use of herbal self-medications which may interfere with the pharmacodynamics and pharmacokinetics of the antimalarial drugs being studied and loss to follow-up.

  Conclusion Top

The results of this study suggest that AZ is as effective as SP in the IPTp and may therefore be used as chemoprophylaxis against malaria in pregnancy in place of IPTp-SP in patients who do not tolerate SP, or in whom SP is contraindicated, or in patients who require IPTp in the first trimester.

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Conflicts of Interest

There are no conflicts of interest.

  References Top

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  [Figure 1]

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

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