Pregnancy outcomes after first-trimester treatment with artemisinin derivatives versus non-artemisinin antimalarials: a systematic review and individual patient data meta-analysis.

BACKGROUND: Malaria in the first trimester of pregnancy is associated with adverse pregnancy outcomes. Artemisinin-based combination therapies (ACTs) are a highly effective, first-line treatment for uncomplicated Plasmodium falciparum malaria, except in the first trimester of pregnancy, when quinine with clindamycin is recommended due to concerns about the potential embryotoxicity of artemisinins. We compared adverse pregnancy outcomes after artemisinin-based treatment (ABT) versus non-ABTs in the first trimester of pregnancy. METHODS: For this systematic review and individual patient data (IPD) meta-analysis, we searched MEDLINE, Embase, and the Malaria in Pregnancy Library for prospective cohort studies published between Nov 1, 2015, and Dec 21, 2021, containing data on outcomes of pregnancies exposed to ABT and non-ABT in the first trimester. The results of this search were added to those of a previous systematic review that included publications published up until November, 2015. We included pregnancies enrolled before the pregnancy outcome was known. We excluded pregnancies with missing estimated gestational age or exposure information, multiple gestation pregnancies, and if the fetus was confirmed to be unviable before antimalarial treatment. The primary endpoint was adverse pregnancy outcome, defined as a composite of either miscarriage, stillbirth, or major congenital anomalies. A one-stage IPD meta-analysis was done by use of shared-frailty Cox models. This study is registered with PROSPERO, number CRD42015032371. FINDINGS: We identified seven eligible studies that included 12 cohorts. All 12 cohorts contributed IPD, including 34 178 pregnancies, 737 with confirmed first-trimester exposure to ABTs and 1076 with confirmed first-trimester exposure to non-ABTs. Adverse pregnancy outcomes occurred in 42 (5·7%) of 736 ABT-exposed pregnancies compared with 96 (8·9%) of 1074 non-ABT-exposed pregnancies in the first trimester (adjusted hazard ratio [aHR] 0·71, 95% CI 0·49-1·03). Similar results were seen for the individual components of miscarriage (aHR=0·74, 0·47-1·17), stillbirth (aHR=0·71, 0·32-1·57), and major congenital anomalies (aHR=0·60, 0·13-2·87). The risk of adverse pregnancy outcomes was lower with artemether-lumefantrine than with oral quinine in the first trimester of pregnancy (25 [4·8%] of 524 vs 84 [9·2%] of 915; aHR 0·58, 0·36-0·92). INTERPRETATION: We found no evidence of embryotoxicity or teratogenicity based on the risk of miscarriage, stillbirth, or major congenital anomalies associated with ABT during the first trimester of pregnancy. Given that treatment with artemether-lumefantrine was associated with fewer adverse pregnancy outcomes than quinine, and because of the known superior tolerability and antimalarial effectiveness of ACTs, artemether-lumefantrine should be considered the preferred treatment for uncomplicated P falciparum malaria in the first trimester. If artemether-lumefantrine is unavailable, other ACTs (except artesunate-sulfadoxine-pyrimethamine) should be preferred to quinine. Continued active pharmacovigilance is warranted. FUNDING: Medicines for Malaria Venture, WHO, and the Worldwide Antimalarial Resistance Network funded by the Bill & Melinda Gates Foundation.

Feasibility and cost of using mobile phones for capturing drug safety information in peri-urban settlement in Ghana: a prospective cohort study of patients with uncomplicated malaria.

BACKGROUND: The growing need to capture data on health and health events using faster and efficient means to enable prompt evidence-based decision-making is making the use of mobile phones for health an alternative means to capture anti-malarial drug safety data. This paper examined the feasibility and cost of using mobile phones vis-à-vis home visit to monitor adverse events (AEs) related to artemisinin-based combination therapy (ACT) for treatment of uncomplicated malaria in peri-urban Ghana. METHODS: A prospective, observational, cohort study conducted on 4270 patients prescribed ACT in 21 health facilities. The patients were actively followed by telephone or home visit to document AEs associated with anti-malarial drugs. Call duration and travel distances of each visit were recorded. Pre-paid call cards and fuel for motorbike travels were used to determine cost of conducting both follow-ups. Ms-Excel 2010 and STATA 11.2 were used for analysis. RESULTS: Of the 4270 patients recruited, 4124 (96.6 %) were successfully followed up and analyzed. Of these, 1126/4124 (27.3 %) were children under 5 years. Most 3790/4124 (91.9 %) follow-ups were done within 7 days of ACT intake. Overall, follow up by phone (2671/4124-64.8 %) was almost two times the number done by home visits (1453/4124-35.2 %). Duration of telephone calls ranged from 38 s to 53 min, costing between GH¢0.26 (0.20USD) and GH¢41.70 (27.USD). On the average, the calls lasted 3 min 51 s (SD = 3 min, 21 s) costing GH¢2.70 (0.77USD). Distance travelled for home visit ranged from 0.65 to 62 km costing GH¢0.29 (0.20USD) and GH¢279.00 (79.70USD). Thirty-two per cent (1128/4124) of patients reported AEs. In total, 1831 AE were reported, 1016/1831(55.5 %) by telephone and 815/1831 (44.5 %) by home visits. Events such as nausea, dizziness, diarrhoea, and vomiting were commonly reported. CONCLUSION: Majority of patients was successfully followed up by telephone and reported the most AEs. The cost of telephone interviewing was almost two times less than the cost of home visit. Telephone follow up should be considered for monitoring drug adverse events in low resource settings.

Influences on participant reporting in the World Health Organisation drugs exposure pregnancy registry; a qualitative study.

BACKGROUND: The World Health Organisation has designed a pregnancy registry to investigate the effect of maternal drug use on pregnancy outcomes in resource-limited settings. In this sentinel surveillance system, detailed health and drug use data are prospectively collected from the first antenatal clinic visit until delivery. Over and above other clinical records, the registry relies on accurate participant reports about the drugs they use. Qualitative methods were incorporated into a pilot registry study during 2010 and 2011 to examine barriers to women reporting these drugs and other exposures at antenatal clinics, and how they might be overcome. METHODS: Twenty-seven focus group discussions were conducted in Ghana, Kenya and Uganda with a total of 208 women either enrolled in the registry or from its source communities. A question guide was designed to uncover the types of exposure data under- or inaccurately reported at antenatal clinics, the underlying reasons, and how women prefer to be asked questions. Transcripts were analysed thematically. RESULTS: Women said it was important for them to report everything they had used during pregnancy. However, they expressed reservations about revealing their consumption of traditional, over-the-counter medicines and alcohol to antenatal staff because of anticipated negative reactions. Some enrolled participants' improved relationship with registry staff facilitated information sharing and the registry tools helped overcome problems with recall and naming of medicines. Decisions about where women sought care, which influenced medicines used and antenatal clinic attendance, were influenced by pressure within and outside of the formal healthcare system to conform to conflicting behaviours. Conversations also reflected women's responsibilities for producing a healthy baby. CONCLUSIONS: Women in this study commonly take traditional medicines in pregnancy, and to a lesser extent over-the-counter medicines and alcohol. The World Health Organisation pregnancy registry shows potential to enhance their reporting of these substances at the antenatal clinic. However, more work is needed to find optimal techniques for eliciting accurate reports, especially where the detail of constituents may never be known. It will also be important to find ways of sustaining such drug exposure surveillance systems in busy antenatal clinics.

The essential role of infection-detection technologies for malaria elimination and eradication.

Recent emphasis on malaria elimination and eradication (E&E) goals is changing the way that experts evaluate malaria diagnostic tools and tactics. As prevalence declines, the focus of malaria management is pivoting toward low-density, subclinical infections and geographically and demographically concentrated reservoirs. These and other changes present challenges and opportunities for innovations in malaria diagnostics aimed at meeting the needs of malaria elimination programs. Developing such technologies requires a review of the operational approaches to detecting malaria infections in areas of declining prevalence. Here we review recent research on epidemiology and biology related to malaria elimination and operational factors that influence E&E strategies. We further propose use-scenarios and a target product profile framework to define and prioritize the required attributes of infection-detection technologies.

Protocol for a drugs exposure pregnancy registry for implementation in resource-limited settings.

BACKGROUND: The absence of robust evidence of safety of medicines in pregnancy, particularly those for major diseases provided by public health programmes in developing countries, has resulted in cautious recommendations on their use. We describe a protocol for a Pregnancy Registry adapted to resource-limited settings aimed at providing evidence on the safety of medicines in pregnancy. METHODS/DESIGN: Sentinel health facilities are chosen where women come for prenatal care and are likely to come for delivery. Staff capacity is improved to provide better care during the pregnancy, to identify visible birth defects at delivery and refer infants with major anomalies for surgical or clinical evaluation and treatment. Consenting women are enrolled at their first antenatal visit and careful medical, obstetric and drug-exposure histories taken; medical record linkage is encouraged. Enrolled women are followed up prospectively and their histories are updated at each subsequent visit. The enrolled woman is encouraged to deliver at the facility, where she and her baby can be assessed. DISCUSSION: In addition to data pooling into a common WHO database, the WHO Pregnancy Registry has three important features: First is the inclusion of pregnant women coming for antenatal care, enabling comparison of birth outcomes of women who have been exposed to a medicine with those who have not. Second is its applicability to resource-poor settings regardless of drug or disease. Third is improvement of reproductive health care during pregnancies and at delivery. Facility delivery enables better health outcomes, timely evaluation and management of the newborn, and the collection of reliable clinical data. The Registry aims to improves maternal and neonatal care and also provide much needed information on the safety of medicines in pregnancy.

One Health concept for strengthening public health surveillance and response through Field Epidemiology and Laboratory Training in Ghana.

The lack of highly trained field epidemiologists in the public health system in Ghana has been known since the 1970s when the Planning Unit was established in the Ghana Ministry of Health. When the Public Health School was started in 1994, the decision was taken to develop a 1 academic-year general MPH course. The persisting need for well-trained epidemiologists to support the public health surveillance, outbreak investigation and response system made the development of the Field Epidemiology and Laboratory Training Programme (FELTP) a national priority. The School of Public health and the Ministry of Health therefore requested the technical and financial assistance of the United States Centers for Disease Control and Prevention (CDC) in organizing the Programme. The collaboration started by organizing short courses in disease outbreak investigations and response for serving Ghana Health Service staff. The success of the short courses led to development of the FELTP. By October 2007, the new FELTP curriculum for the award of a Masters of Philosophy in Applied Epidemiology and Disease Control was approved by the Academic Board of the University of Ghana and the programme started that academic year. Since then five cohorts of 37 residents have been enrolled in the two tracks of the programme. They consist of 12 physicians, 12 veterinarians and 13 laboratory scientists. The first two cohorts of 13 residents have graduated. The third cohort of seven has submitted dissertations and is awaiting the results. The fourth cohort has started the second year of field placement while the fifth cohort has just started the first semester. The field activities of the graduates have included disease outbreak investigations and response, evaluation of disease surveillance systems at the national level and analysis of datasets on diseases at the regional level. The residents have made a total of 25 oral presentations and 39 poster presentations at various regional and global scientific conferences. The Ghana FELTP (GFELTP) has promoted the introduction of the One Health concept into FELTP. It hosted the first USAID-supported workshop in West Africa to further integrate and strengthen collaboration of the animal and human health sectors in the FETP model. GFELTP has also taken the lead in hosting the first AFENET Center for Training in Public Health Leadership and Management, through which the short course on Management for Improving Public Health Interventions was developed for AFENET member countries. The GFELTP pre-tested the Integrated Avian Influenza Outbreak and Pandemic Influenza course in preparation for introducing the materials into the curriculum of other FELTP in the network. The leadership positions to which the graduates of the program have been appointed in the human and animal Public Health Services, improvement in disease surveillance, outbreak investigation and response along with the testimony of the health authorities about their appreciation of the outputs of the graduates at various fora, is a strong indication that the GFELTP is meeting its objectives.

The use of placebo in a trial of rectal artesunate as initial treatment for severe malaria patients en route to referral clinics: ethical issues.

Placebo-controlled trials are controversial when individuals might be denied existing beneficial medical interventions. In the case of malaria, most patients die in rural villages without healthcare facilities. An artesunate suppository that can be given by minimally skilled persons might be of value when patients suddenly become too ill for oral treatment but are several hours from a facility that can give injectable treatment for severe disease. In such situations, by default, no treatment is (or can be) given until the patient reaches a facility, making the placebo control design clinically relevant; alternative bioequivalence designs at the facility would misrepresent reality and risk incorrect conclusions. We describe the ethical issues underpinning a placebo-controlled trial in severe malaria. To protect patients and minimise risk, all patients were referred immediately to hospital so that each had a higher chance of prompt treatment through participation. There was no difference between artesunate and placebo in patients who reached clinic rapidly; among those who could not, a single artesunate suppository significantly reduced death or permanent disability, a finding of direct and indirect benefit to patients in participating villages and elsewhere.

The epidemiology of malaria among pregnant women attending antenatal clinics in an area with intense and highly seasonal malaria transmission in northern Ghana.

OBJECTIVE: To describe the factors associated with malaria infection and anaemia in pregnancy in northern Ghana. METHOD: We studied 3642 pregnant women of all gravidities and gestational age of 18-32 weeks who attended an antenatal clinic in the Kassena-Nankana district of Ghana between June 2004 and July 2006. Blood samples were examined for haemoglobin concentrations and parasitaemia, and we obtained socio-demographic data, an obstetric history, information on their past and current state of health and bed net use. RESULTS: The overall prevalence of malaria parasitaemia during pregnancy was 47%. Older age [adjusted odds ratio (AOR) 0.65, 95% CI 0.54-0.78], multigravidity (AOR 0.51, 95% CI 0.42-0.61) and third trimester of pregnancy (AOR 0.85, 95% CI 0.73-0.99) were associated with a decreased risk of parasitaemia. Enrollment during the rainy or post-rainy season was associated with an increased risk of parasitaemia (AOR 2.59, 95% CI 2.20-3.04 and AOR 3.12, 95% CI, 2.60-3.74 respectively). Malaria infection was associated with an increased risk of anaemia among young women. The prevalences of anaemia (Hb<11.0 g/dl) and severe anaemia (Hb<7.0 g/dl) during pregnancy were 72% and 2% respectively. The risk of anaemia was lower in older women (AOR 0.79, 95% CI, 0.64-0.97), multigravidae (AOR 0.67, 95% CI 0.55-0.83) and in educated women (AOR 0.81, 0.68-0.98). CONCLUSION: The prevalence of malaria parasitaemia and anaemia among pregnant women in Kassena-Nankana district is high with marked seasonal variation. Targeting of interventions to the high transmission season and to paucigravidae may be appropriate in this setting.

A randomized, controlled trial of intermittent preventive treatment with sulfadoxine-pyrimethamine, amodiaquine, or the combination in pregnant women in Ghana.

BACKGROUND: The use of sulfadoxine-pyrimethamine (SP) for intermittent preventive treatment in pregnancy (IPTp) is threatened by the spread of resistance to SP. Therefore, we studied the efficacy, safety, and tolerance of amodiaquine (AQ) or the combination of AQ and SP (SPAQ) as possible alternative treatments. METHODS: The study was performed in Ghana from June 2004 through February 2007. Women were individually randomized to receive IPTp with SP (n=1328), AQ (n= 986), or SPAQ (n=1328). Incidences of anemia, peripheral anemia, and placental parasitemia at delivery were assessed for paucigravidae, as were the birth weights of their infants. Delivery outcomes and the incidence of adverse events were investigated for all women. RESULTS: The prevalences of anemia (as defined by a hemoglobin concentration of <11.0 g/dL) at delivery were comparable between the SP and AQ groups and between the SP and SPAQ groups. Similarly, there was no significant difference between the SP and AQ groups or between the SP and SPAQ groups with regard to the incidences of low birth weight (LBW). Women who received AQ or SPAQ were more likely to report adverse events than were those who received SP. CONCLUSION: The effects of IPTp with AQ or SPAQ on maternal anemia and LBW were comparable to the effects of IPTp with SP; however, IPTp regimens that contain AQ are unlikely to be useful as an alternative to IPTp with SP in Ghana, because of a high frequency of associated adverse events. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00146783 .

Review of Antenatal-Linked Voluntary Counseling and HIV Testing in Sub-Saharan Africa: Lessons and Options for Ghana.

SummaryVoluntary counselling and HIV testing has become an integral part of HIV prevention and care programs in many countries in sub-Saharan Africa. A number of interventions offer potential to reduce mother-to-child HIV transmission. These interventions, including antenatal and or intrapartum administration of antiretroviral drugs require the integration of voluntary counselling and HIV testing for pregnant women into antenatal care. Ghana's strategic framework for HIV control calls for the integration of voluntary counselling and HIV testing to antenatal care nationwide. It sets as target, the year 2005 when VCT would be widely available and accessible in the country. This paper reviews medline-indexed publications on antenatal-linked VCT programs of sub-Saharan Africa. Four critical themes were used in the medline search. These are acceptability, rates of return for test, disclosure of results vis-à-vis confidentiality and cost effectiveness. The growing consensuses on these issues are discussed in relations to the findings of a recent study conducted among 270 pregnant women in Navrongo in the Kassena-Nankana district of northern Ghana. Suggestions are made to guide the on-going pilot VCT and prevention of mother-to-child programs in Ghana. It is also suggested on the basis of the review and the findings of the Navrongo study that Ghana should explore options likely to promote universal access and overall acceptability. These include couple counselling, guarantee of confidentiality, free testing and continuum of care for mothers who are test positive.

Perception of university students in Ghana about emergency contraception.

Emergency contraception (EC) refers to methods that women can use to prevent pregnancy after unprotected sexual intercourse, method failure, or incorrect use. There is growing worldwide acceptance and promotion of EC as a measure to reduce the level of unwanted pregnancies and, hence, unsafe abortions. The potential effect of EC in this regard could be most evident in sub-Saharan Africa. In Ghana, the Ministry of Health has since 1996 included EC in its reproductive health service policy and standards. The Planned Parenthood Association of Ghana is the only agency involved in the promotion of EC in the country. Very little is known about societal perception of EC. We undertook a study to assess knowledge and attitude toward EC among a sample of students at the University of Ghana. We used a two-page, self-administered questionnaire in a cross-sectional study among students chosen by random sampling. The aspects of EC assessed included level of knowledge, extent of use, common traditional methods of emergency contraception, as well as socially and culturally acceptable ways to promote EC in Ghana. We also assessed how the availability of EC could influence the use of condoms among male respondents. Less than half (43.2%) of the 194 respondents (88 males and 106 females) had heard of modern emergency contraceptive methods. Postinor-2, a dedicated emergency contraceptive product, which was already on the Ghanaian market, was known to 1.5% of respondents. Only 11.3% of respondents indicated correctly the recommended time within which emergency contraceptive pills (ECPs) are to be taken after unprotected sex. Taking concentrated sugar solutions, having an enema, and douching were commonly used traditional methods of EC. More than half (55.0%) of the male respondents indicated that they would either "certainly" or "probably" reduce how often they used condoms once they knew that EC was available. Almost all (97.4%) the respondents wanted to learn more about EC. The indications from this study are that the promotion of EC in Ghana is desired and must be encouraged. The fact that EC does not offer protection against sexually transmitted infections should always be emphasized.