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.

Healthcare provider and drug dispenser knowledge and adherence to guidelines for the case management of malaria in pregnancy in the context of multiple first-line artemisinin-based combination therapy in western Kenya.

BACKGROUND: Concerns about emerging resistance to artemether-lumefantrine (AL) in Africa prompted the pilot introduction of multiple first-line therapies (MFT) in Western Kenya, potentially exposing women-of-childbearing-age (WOCBA) to anti-malarials with unknown safety profiles in the first trimester. The study assessed healthcare provider knowledge and adherence to national guidelines for managing malaria in pregnancy in the context of the MFT pilot. METHODS: From March to April 2022, a cross-sectional study was conducted in 50 health facilities (HF) and 40 drug outlets (DO) using structured questionnaires to assess pregnancy detection, malaria diagnosis, and treatment choices by trimester. Differences between HF and DO providers and between MFT and non-MFT HFs were assessed using Chi-square tests. RESULTS: Of 174 providers (77% HF, 23% DO), 56% were from MFT pilot facilities. Most providers had tertiary education; 5% HF and 20% DO had only primary or secondary education. More HF than DO providers had knowledge of malaria treatment guidelines (62% vs. 40%, p = 0.023), received training in malaria in pregnancy (49% vs. 20%, p = 0.002), and reported assessing for pregnancy in WOCBA (98% vs. 78%, p < 0.001). Most providers insisted on parasitological diagnosis, with 59% HF using microscopy and 85% DO using rapid diagnostic tests. More HF than DO providers could correctly name the drugs for treating uncomplicated malaria in the first trimester (oral quinine, or AL if quinine is unavailable) (90% vs. 58%, p < 0.001), second and third trimesters (artemisinin-based combination therapy) (84% vs. 70%, p = 0.07), and for severe malaria (parenteral artesunate/artemether) (94% vs. 60%, p < 0.001). Among HF providers, those in the MFT pilot had more knowledge of malaria treatment guidelines (67% vs. 49%, p = 0.08) and had received training on treatment of malaria in pregnancy (56% vs. 32%, p = 0.03). Few providers (10% HF and 12% DO) had adequate knowledge of malaria treatment in pregnancy, defined as the correct drug and dose for uncomplicated and severe malaria in all trimesters. CONCLUSIONS: Knowledge of national malaria in pregnancy treatment guidelines among providers in Western Kenya is suboptimal. Robust training on appropriate anti-malarial and dosage is needed, particularly given the recent change in recommendation for artemether-lumefantrine use in the first trimester. Supervision of DO and HF practices is essential for correct treatment of malaria in pregnancy in the context of MFT programmes.

Perceptions and drivers of healthcare provider and drug dispenser practices for the treatment of malaria in pregnancy in the context of multiple first-line therapies in western Kenya: a qualitative study.

BACKGROUND: Emergence of Plasmodium falciparum resistance to artemether-lumefantrine in Africa prompted the pilot introduction of multiple first-line therapies (MFT) against malaria in Kenya, potentially exposing women-of-childbearing-age (WOCBAs) to anti-malarials with unknown safety profiles in the first trimester. This qualitative study explored knowledge and perceptions among healthcare providers providing malaria treatment to WOCBAs and pregnant women. METHODS: In-depth interviews were conducted with purposively selected public and private health facility (HF) and drug outlet (DO) providers within and outside the pilot-MFT area. County health managers were interviewed about their knowledge of the national treatment guidelines. Transcripts were coded by content analysis using the World Health Organization health system building blocks (leadership/governance, financing, health workforce, health information systems, access to medicines, and service delivery). RESULTS: Thirty providers (HF:21, DO:9) and three health managers were interviewed. Eighteen providers were from HFs in the pilot-MFT area; the remaining three and all nine DOs were outside the pilot-MFT area. The analysis revealed that providers had not been trained in malaria case management in the previous twelve months. DO providers were unfamiliar with national treatment guidelines in pregnancy and reported having no pregnancy tests. Health managers were unable to supervise DOs due to resource limitations. Providers from HFs and DOs noted poor sensitivity of malaria rapid diagnostic tests (RDTs) and hesitancy among patients who associated malaria-RDTs with HIV testing. Almost all providers reported anti-malarial stock-outs, with quinine most affected. Patient preference was a major factor in prescribing anti-malarials. Providers in HFs and DOs reported preferentially using artemether-lumefantrine in the first trimester due to the side effects and unavailability of quinine. CONCLUSION: Knowledge of malaria case management in drug outlets and health facilities remains poor. Improved regulation of DO providers is warranted. Optimizing treatment of malaria in pregnancy requires training, availability of malaria commodities, and pregnancy tests.

First trimester use of artemisinin-based combination therapy and the risk of low birth weight and small for gestational age.

BACKGROUND: While there is increasing evidence on the safety of artemisinin-based combination therapy (ACT) for the case management of malaria in early pregnancy, little is known about the association between exposure to ACT during the first trimester and the effect on fetal growth. METHODS: Data were analysed from prospective studies of pregnant women enrolled in Mozambique, Burkina Faso and Kenya designed to determine the association between anti-malarial drug exposure in the first trimester and pregnancy outcomes, including low birth weight (LBW) and small for gestational age (SGA). Exposure to anti-malarial drugs was ascertained retrospectively by record linkage using a combination of data collected from antenatal and adult outpatient clinic registries, prescription records and self-reported medication usage by the women. Site-level data synthesis (fixed effects and random effects) was conducted as well as individual-level analysis (fixed effects by site). RESULTS: Overall, 1915 newborns were included with 92 and 26 exposed to ACT (artemether-lumefantrine) and quinine, respectively. In Burkina Faso, Mozambique and Kenya at recruitment, the mean age (standard deviation) was 27.1 (6.6), 24.2 (6.2) and 25.7 (6.5) years, and the mean gestational age was 24.0 (6.2), 21.2 (5.7) and 17.9 (10.2) weeks, respectively. The LBW prevalence among newborns born to women exposed to ACT and quinine (QNN) during the first trimester was 10/92 (10.9%) and 7/26 (26.9%), respectively, compared to 9.5% (171/1797) among women unexposed to any anti-malarials during pregnancy. Compared to those unexposed to anti-malarials, ACT and QNN exposed women had the pooled LBW prevalence ratio (PR) of 1.13 (95% confidence interval (CI) 0.62-2.05, p-value 0.700) and 2.03 (95% CI 1.09-3.78, p-value 0.027), respectively. Compared to those unexposed to anti-malarials ACT and QNN-exposed women had the pooled SGA PR of 0.85 (95% CI 0.50-1.44, p-value 0.543) and 1.41 (95% CI 0.71-2.77, p-value 0.322), respectively. Whereas compared to ACT-exposed, the QNN-exposed had a PR of 2.14 (95% CI 0.78-5.89, p-value 0.142) for LBW and 8.60 (95% CI 1.29-57.6, p-value 0.027) for SGA. The level of between sites heterogeneity was moderate to high. CONCLUSION: ACT exposure during the first trimester was not associated with an increased occurrence of LBW or SGA. However, the data suggest a higher prevalence of LBW and SGA for children born to QNN-exposed pregnancies. The findings support the use of ACT (artemether-lumefantrine) for the treatment of uncomplicated malaria during the first trimester of pregnancy.

First-trimester artemisinin derivatives and quinine treatments and the risk of adverse pregnancy outcomes in Africa and Asia: A meta-analysis of observational studies.

BACKGROUND: Animal embryotoxicity data, and the scarcity of safety data in human pregnancies, have prevented artemisinin derivatives from being recommended for malaria treatment in the first trimester except in lifesaving circumstances. We conducted a meta-analysis of prospective observational studies comparing the risk of miscarriage, stillbirth, and major congenital anomaly (primary outcomes) among first-trimester pregnancies treated with artemisinin derivatives versus quinine or no antimalarial treatment. METHODS AND FINDINGS: Electronic databases including Medline, Embase, and Malaria in Pregnancy Library were searched, and investigators contacted. Five studies involving 30,618 pregnancies were included; four from sub-Saharan Africa (n = 6,666 pregnancies, six sites) and one from Thailand (n = 23,952). Antimalarial exposures were ascertained by self-report or active detection and confirmed by prescriptions, clinic cards, and outpatient registers. Cox proportional hazards models, accounting for time under observation and gestational age at enrollment, were used to calculate hazard ratios. Individual participant data (IPD) meta-analysis was used to combine the African studies, and the results were then combined with those from Thailand using aggregated data meta-analysis with a random effects model. There was no difference in the risk of miscarriage associated with the use of artemisinins anytime during the first trimester (n = 37/671) compared with quinine (n = 96/945; adjusted hazard ratio [aHR] = 0.73 [95% CI 0.44, 1.21], I2 = 0%, p = 0.228), in the risk of stillbirth (artemisinins, n = 10/654; quinine, n = 11/615; aHR = 0.29 [95% CI 0.08-1.02], p = 0.053), or in the risk of miscarriage and stillbirth combined (pregnancy loss) (aHR = 0.58 [95% CI 0.36-1.02], p = 0.099). The corresponding risks of miscarriage, stillbirth, and pregnancy loss in a sensitivity analysis restricted to artemisinin exposures during the embryo sensitive period (6-12 wk gestation) were as follows: aHR = 1.04 (95% CI 0.54-2.01), I2 = 0%, p = 0.910; aHR = 0.73 (95% CI 0.26-2.06), p = 0.551; and aHR = 0.98 (95% CI 0.52-2.04), p = 0.603. The prevalence of major congenital anomalies was similar for first-trimester artemisinin (1.5% [95% CI 0.6%-3.5%]) and quinine exposures (1.2% [95% CI 0.6%-2.4%]). Key limitations of the study include the inability to control for confounding by indication in the African studies, the paucity of data on potential confounders, the limited statistical power to detect differences in congenital anomalies, and the lack of assessment of cardiovascular defects in newborns. CONCLUSIONS: Compared to quinine, artemisinin treatment in the first trimester was not associated with an increased risk of miscarriage or stillbirth. While the data are limited, they indicate no difference in the prevalence of major congenital anomalies between treatment groups. The benefits of 3-d artemisinin combination therapy regimens to treat malaria in early pregnancy are likely to outweigh the adverse outcomes of partially treated malaria, which can occur with oral quinine because of the known poor adherence to 7-d regimens. REVIEW REGISTRATION: PROSPERO CRD42015032371.

Malaria, malnutrition, and birthweight: A meta-analysis using individual participant data.

BACKGROUND: Four studies previously indicated that the effect of malaria infection during pregnancy on the risk of low birthweight (LBW; <2,500 g) may depend upon maternal nutritional status. We investigated this dependence further using a large, diverse study population. METHODS AND FINDINGS: We evaluated the interaction between maternal malaria infection and maternal anthropometric status on the risk of LBW using pooled data from 14,633 pregnancies from 13 studies (6 cohort studies and 7 randomized controlled trials) conducted in Africa and the Western Pacific from 1996-2015. Studies were identified by the Maternal Malaria and Malnutrition (M3) initiative using a convenience sampling approach and were eligible for pooling given adequate ethical approval and availability of essential variables. Study-specific adjusted effect estimates were calculated using inverse probability of treatment-weighted linear and log-binomial regression models and pooled using a random-effects model. The adjusted risk of delivering a baby with LBW was 8.8% among women with malaria infection at antenatal enrollment compared to 7.7% among uninfected women (adjusted risk ratio [aRR] 1.14 [95% confidence interval (CI): 0.91, 1.42]; N = 13,613), 10.5% among women with malaria infection at delivery compared to 7.9% among uninfected women (aRR 1.32 [95% CI: 1.08, 1.62]; N = 11,826), and 15.3% among women with low mid-upper arm circumference (MUAC <23 cm) at enrollment compared to 9.5% among women with MUAC ≥ 23 cm (aRR 1.60 [95% CI: 1.36, 1.87]; N = 9,008). The risk of delivering a baby with LBW was 17.8% among women with both malaria infection and low MUAC at enrollment compared to 8.4% among uninfected women with MUAC ≥ 23 cm (joint aRR 2.13 [95% CI: 1.21, 3.73]; N = 8,152). There was no evidence of synergism (i.e., excess risk due to interaction) between malaria infection and MUAC on the multiplicative (p = 0.5) or additive scale (p = 0.9). Results were similar using body mass index (BMI) as an anthropometric indicator of nutritional status. Meta-regression results indicated that there may be multiplicative interaction between malaria infection at enrollment and low MUAC within studies conducted in Africa; however, this finding was not consistent on the additive scale, when accounting for multiple comparisons, or when using other definitions of malaria and malnutrition. The major limitations of the study included availability of only 2 cross-sectional measurements of malaria and the limited availability of ultrasound-based pregnancy dating to assess impacts on preterm birth and fetal growth in all studies. CONCLUSIONS: Pregnant women with malnutrition and malaria infection are at increased risk of LBW compared to women with only 1 risk factor or none, but malaria and malnutrition do not act synergistically.

A cross-sectional study of the availability and price of anti-malarial medicines and malaria rapid diagnostic tests in private sector retail drug outlets in rural Western Kenya, 2013.

BACKGROUND: Although anti-malarial medicines are free in Kenyan public health facilities, patients often seek treatment from private sector retail drug outlets. In mid-2010, the Affordable Medicines Facility-malaria (AMFm) was introduced to make quality-assured artemisinin-based combination therapy (ACT) accessible and affordable in private and public sectors. METHODS: Private sector retail drug outlets stocking anti-malarial medications within a surveillance area of approximately 220,000 people in a malaria perennial high-transmission area in rural western Kenya were identified via a census in September 2013. A cross-sectional study was conducted in September-October 2013 to determine availability and price of anti-malarial medicines and malaria rapid diagnostic tests (RDTs) in drug outlets. A standardized questionnaire was administered to collect drug outlet and personnel characteristics and availability and price of anti-malarials and RDTs. RESULTS: Of 181 drug outlets identified, 179 (99 %) participated in the survey. Thirteen percent were registered pharmacies, 25 % informal drug shops, 46 % general shops, 13 % homesteads and 2 % other. One hundred sixty-five (92 %) had at least one ACT type: 162 (91 %) had recommended first-line artemether-lumefantrine (AL), 22 (12 %) had recommended second-line dihydroartemisinin-piperaquine (DHA-PPQ), 85 (48 %) had sulfadoxine-pyrimethamine (SP), 60 (34 %) had any quinine (QN) formulation, and 14 (8 %) had amodiaquine (AQ) monotherapy. The mean price (range) of an adult treatment course for AL was $1.01 ($0.35-4.71); DHA-PPQ was $4.39 ($0.71-7.06); QN tablets were $2.24 ($0.12-4.71); SP was $0.62 ($0.24-2.35); AQ monotherapy was $0.42 ($0.24-1.06). The mean AL price with or without the AMFm logo did not differ significantly ($1.01 and 1.07, respectively; p = 0.45). Only 17 (10 %) drug outlets had RDTs; 149 (84 %) never stocked RDTs. The mean RDT price was $0.92 ($0.24-2.35). CONCLUSIONS: Most outlets never stocked RDTs; therefore, testing prior to treatment was unlikely for customers seeking treatment in the private retail sector. The recommended first-line treatment, AL, was widely available. Although SP and AQ monotherapy are not recommended for treatment, both were less expensive than AL, which might have caused preferential use by customers. Interventions that create community demand for malaria diagnostic testing prior to treatment and that increase RDT availability should be encouraged.

Effectiveness of the delivery of interventions to prevent malaria in pregnancy in Kenya.

BACKGROUND: Coverage with malaria in pregnancy interventions remains unacceptably low. Implementation research is needed to identify and quantify the bottlenecks for the delivery and use of these life-saving interventions through antenatal clinics (ANC). METHODS: A cross-sectional study was carried out in ANC across nine health facilities in western Kenya. Data were collected for an individual ANC visit through structured observations and exit interviews with the same ANC clients. The cumulative and intermediate systems effectiveness for the delivery of intermittent preventive treatment (IPTp) and insecticide-treated nets (ITNs) to eligible pregnant women on this one specific visit to ANC were estimated. RESULTS: Overall the ANC systems effectiveness for delivering malaria in pregnancy interventions was suboptimal. Only 40 and 53 % of eligible women received IPTp by directly observed therapy as per policy in hospitals and health centres/dispensaries respectively. The overall systems effectiveness for the receipt of IPTp disregarding directly observed therapy was 62 and 72 % for hospitals and lower level health facilities, respectively. The overall systems effectiveness for ITNs for first ANC visit was 63 and 67 % for hospitals and lower level facilities, respectively. CONCLUSION: This study found that delivery of IPTp and ITNs through ANC was ineffective and more so for higher-level facilities. This illustrates missed opportunities and provider level bottlenecks to the scale up and use of interventions to control malaria in pregnancy delivered through ANC. The high level of clustering within health facilities suggest that future studies should assess the feasibility of implementing interventions to improve systems effectiveness tailored to the health facility level.

Global Call to Action: maximize the public health impact of intermittent preventive treatment of malaria in pregnancy in sub-Saharan Africa.

Intermittent preventive treatment of malaria in pregnancy is a highly cost-effective intervention which significantly improves maternal and birth outcomes among mothers and their newborns who live in areas of moderate to high malaria transmission. However, coverage in sub-Saharan Africa remains unacceptably low, calling for urgent action to increase uptake dramatically and maximize its public health impact. The 'Global Call to Action' outlines priority actions that will pave the way to success in achieving national and international coverage targets. Immediate action is needed from national health institutions in malaria-endemic countries, the donor community, the research community, members of the pharmaceutical industry and private sector, along with technical partners at the global and local levels, to protect pregnant women and their babies from the preventable, adverse effects of malaria in pregnancy.

Global Call to Action to scale-up coverage of intermittent preventive treatment of malaria in pregnancy: seminar report.

In 2014, a global 'Call to Action' seminar for the scale-up of intermittent preventive treatment of malaria in pregnancy was held during the 63rd Annual Meeting of the American Society of Tropical Medicine and Hygiene. This report summarizes the presentations and main discussion points from the meeting.

Risks of miscarriage and inadvertent exposure to artemisinin derivatives in the first trimester of pregnancy: a prospective cohort study in western Kenya.

BACKGROUND: The artemisinin anti-malarials are widely deployed as artemisinin-based combination therapy (ACT). However, they are not recommended for uncomplicated malaria during the first trimester because safety data from humans are scarce. METHODS: This was a prospective cohort study of women of child-bearing age carried out in 2011-2013, evaluating the relationship between inadvertent ACT exposure during first trimester and miscarriage. Community-based surveillance was used to identify 1134 early pregnancies. Cox proportional hazard models with left truncation were used. RESULTS: The risk of miscarriage among pregnancies exposed to ACT (confirmed + unconfirmed) in the first trimester, or during the embryo-sensitive period (≥6 to <13 weeks gestation) was higher than among pregnancies unexposed to anti-malarials in the first trimester: hazard ratio (HR) = 1.70, 95 % CI (1.08-2.68) and HR = 1.61 (0.96-2.70). For confirmed ACT-exposures (primary analysis) the corresponding values were: HR = 1.24 (0.56-2.74) and HR = 0.73 (0.19-2.82) relative to unexposed women, and HR = 0.99 (0.12-8.33) and HR = 0.32 (0.03-3.61) relative to quinine exposure, but the numbers of quinine exposures were very small. CONCLUSION: ACT exposure in early pregnancy was more common than quinine exposure. Confirmed inadvertent artemisinin exposure during the potential embryo-sensitive period was not associated with increased risk of miscarriage. Confirmatory studies are needed to rule out a smaller than three-fold increase in risk.

Barriers and facilitators to antenatal and delivery care in western Kenya: a qualitative study.

BACKGROUND: In western Kenya, maternal mortality is a major public health problem estimated at 730/100,000 live births, higher than the Kenyan national average of 488/100,000 women. Many women do not attend antenatal care (ANC) in the first trimester, half do not receive 4 ANC visits. A high proportion use traditional birth attendants (TBA) for delivery and 1 in five deliver unassisted. The present study was carried out to ascertain why women do not fully utilise health facility ANC and delivery services. METHODS: A qualitative study using 8 focus group discussions each consisting of 8-10 women, aged 15-49 years. Thematic analysis identified the main barriers and facilitators to health facility based ANC and delivery. RESULTS: Attending health facility for ANC was viewed positively. Three elements of care were important; testing for disease including HIV, checking the position of the foetus, and receiving injections and / or medications. Receiving a bed net and obtaining a registration card were also valuable. Four barriers to attending a health facility for ANC were evident; attitudes of clinic staff, long clinic waiting times, HIV testing and cost, although not all women felt the cost was prohibitive being worth it for the health of the child. Most women preferred to deliver in a health facility due to better management of complications. However cost was a barrier, and a reason to visit a TBA because of flexible payment. Other barriers were unpredictable labour and transport, staff attitudes and husbands' preference. CONCLUSIONS: Our findings suggest that women in western Kenya are amenable to ANC and would be willing and even prefer to deliver in a healthcare facility, if it were affordable and accessible to them. However for this to happen there needs to be investment in health promotion, and transport, as well as reducing or removing all fees associated with antenatal and delivery care. Yet creating demand for service will need to go alongside investment in antenatal services at organisational, staffing and facility level in order to meet both current and future increase in demand.

Assessment of the safety of antimalarial drug use during early pregnancy (ASAP): protocol for a multicenter prospective cohort study in Burkina Faso, Kenya and Mozambique.

BACKGROUND: A major unresolved safety concern for malaria case management is the use of artemisinin combination therapies (ACTs) in the first trimester of pregnancy. There is a need for human data to inform policy makers and treatment guidelines on the safety of artemisinin combination therapies (ACT) when used during early pregnancy. METHODS: The overall goal of this paper is to describe the methods and implementation of a study aimed at developing surveillance systems for identifying exposures to antimalarials during early pregnancy and for monitoring pregnancy outcomes using health and demographic surveillance platforms. This was a multi-center prospective observational cohort study involving women at health and demographic surveillance sites in three countries in Africa: Burkina Faso, Kenya and Mozambique [(ClinicalTrials.gov Identifier: NCT01232530)]. The study was designed to identify pregnant women with artemisinin exposure in the first trimester and compare them to: 1) pregnant women without malaria, 2) pregnant women treated for malaria, but exposed to other antimalarials, and 3) pregnant women with malaria and treated with artemisinins in the 2nd or 3rd trimesters from the same settings. Pregnant women were recruited through community-based surveys and attendance at health facilities, including antenatal care clinics and followed until delivery. Data from the three sites will be pooled for analysis at the end of the study. Results are forthcoming. DISCUSSION: Despite few limitations, the methods described here are relevant to the development of sustainable pharmacovigilance systems for drugs used by pregnant women in the tropics using health and demographic surveillance sites to prospectively ascertain drug safety in early pregnancy. TRIAL REGISTRATION: NCT01232530.

Perspectives of men on antenatal and delivery care service utilisation in rural western Kenya: a qualitative study.

BACKGROUND: Poor utilisation of facility-based antenatal and delivery care services in Kenya hampers reduction of maternal mortality. Studies suggest that the participation of men in antenatal and delivery care is associated with better health care seeking behaviour, yet many reproductive health programs do not facilitate their involvement. This qualitative study conducted in rural Western Kenya, explored men's perceptions of antenatal and delivery care services and identified factors that facilitated or constrained their involvement. METHODS: Eight focus group discussions were conducted with 68 married men between 20-65 years of age in May 2011. Participants were of the Luo ethnic group residing in Asembo, western Kenya. The area has a high HIV-prevalence and polygamy is common. A topic guide was used to guide the discussions and a thematic framework approach for data analysis. RESULTS: Overall, men were positive in their views of antenatal and delivery care, as decision makers they often encouraged, some even 'forced', their wives to attend for antenatal or delivery care. Many reasons why it was beneficial to accompany their wives were provided, yet few did this in practice unless there was a clinical complication. The three main barriers relating to cultural norms identified were: 1) pregnancy support was considered a female role; and the male role that of provider; 2) negative health care worker attitudes towards men's participation, and 3) couple unfriendly antenatal and delivery unit infrastructure. CONCLUSION: Although men reported to facilitate their wives' utilisation of antenatal and delivery care services, this does not translate to practice as adherence to antenatal-care schedules and facility based delivery is generally poor. Equally, reasons proffered why they should accompany their wives are not carried through into practice, with barriers outweighing facilitators. Recommendations to improve men involvement and potentially increase services utilisation include awareness campaigns targeting men, exploring promotion of joint HIV testing and counselling, staff training, and design of couple friendly antenatal and delivery units.

Global estimates of the number of pregnancies at risk of malaria from 2007 to 2020: a demographic study.

BACKGROUND: The most recent global estimates of the number of pregnancies at risk of Plasmodium falciparum and Plasmodium vivax malaria infection are from 2007. To inform global malaria prevention and control efforts, we aimed to estimate the global distribution of pregnancies at risk of malaria infection from 2007 to 2020. METHODS: We used estimates from the Malaria Atlas Project on the total population living in areas of P falciparum and P vivax transmission, combined with country-specific demographic data on women of reproductive age, fertility rates, induced abortions, and stillbirths, to derive the annual number of pregnancies overall, by parasite species, and by endemicity strata from 2007 to 2020. The definition of endemicity strata was based on the parasite point prevalence in individuals aged 2-10 years for P falciparum and 1-99 years for P vivax. We also did a sensitivity analysis in which we considered most of sub-Saharan Africa endemic for P vivax. FINDINGS: In 2020, 121·9 million pregnancies occurred in malaria transmission areas, resulting in an estimated 70·9 million (58·1%) livebirths. The total number of pregnancies at risk of malaria was 52·9 million in the WHO South-East Asia (SEARO) region, 5·1 million in the Western Pacific (WPRO) region, 46·1 million in the Africa (AFRO) region, 11·1 million in the Eastern Mediterranean (EMRO) region, and 6·7 million in the Americas (AMRO) region. Between 2007 and 2020, pregnancies in areas of P falciparum transmission declined by 11·4% globally, despite an overall 7·0% increase in pregnancies, representing a decrease of 100·0% in the WHO Europe (EURO) region, 52·6% in WPRO, 51·5% in AMRO, 23·9% in EMRO, and 17·2% in SEARO, and a 25·4% increase in AFRO. Pregnancies in P vivax transmission areas fell by 42·8%, representing a decrease of 100·0% in EURO, 89·8% in WPRO, 48·4% in AMRO, 32·4% in EMRO, and 10·0% in SEARO, and a 25·8% increase in AFRO. Our sensitivity analysis suggests that the number of pregnancies at risk of P vivax infection could be seven-fold higher for AFRO if the whole of sub-Saharan Africa was considered endemic for P vivax. INTERPRETATION: Between 2007 and 2020, substantial declines in the number of pregnancies at risk of malaria were seen globally. However, in AFRO, 25·4% more pregnancies were at risk of P falciparum or P vivax malaria than in 2007. This increase in the number at risk in AFRO comes despite the decline in malaria rates due to the rapidly rising population and the corresponding number of pregnancies in endemic areas. These estimates should guide priority setting for resource allocation to control malaria in pregnancy. FUNDING: Bill & Melinda Gates Foundation and Telethon Trust.

Quantifying the number of pregnancies at risk of malaria in 2007: a demographic study.

BACKGROUND: Comprehensive and contemporary estimates of the number of pregnancies at risk of malaria are not currently available, particularly for endemic areas outside of Africa. We derived global estimates of the number of women who became pregnant in 2007 in areas with Plasmodium falciparum and P. vivax transmission. METHODS AND FINDINGS: A recently published map of the global limits of P. falciparum transmission and an updated map of the limits of P. vivax transmission were combined with gridded population data and growth rates to estimate total populations at risk of malaria in 2007. Country-specific demographic data from the United Nations on age, sex, and total fertility rates were used to estimate the number of women of child-bearing age and the annual rate of live births. Subregional estimates of the number of induced abortions and country-specific stillbirths rates were obtained from recently published reviews. The number of miscarriages was estimated from the number of live births and corrected for induced abortion rates. The number of clinically recognised pregnancies at risk was then calculated as the sum of the number of live births, induced abortions, spontaneous miscarriages, and stillbirths among the population at risk in 2007. In 2007, 125.2 million pregnancies occurred in areas with P. falciparum and/or P. vivax transmission resulting in 82.6 million live births. This included 77.4, 30.3, 13.1, and 4.3 million pregnancies in the countries falling under the World Health Organization (WHO) regional offices for South-East-Asia (SEARO) and the Western-Pacific (WPRO) combined, Africa (AFRO), Europe and the Eastern Mediterranean (EURO/EMRO), and the Americas (AMRO), respectively. Of 85.3 million pregnancies in areas with P. falciparum transmission, 54.7 million occurred in areas with stable transmission and 30.6 million in areas with unstable transmission (clinical incidence <1 per 10,000 population/year); 92.9 million occurred in areas with P. vivax transmission, 53.0 million of which occurred in areas in which P. falciparum and P. vivax co-exist and 39.9 million in temperate regions with P. vivax transmission only. CONCLUSIONS: In 2007, 54.7 million pregnancies occurred in areas with stable P. falciparum malaria and a further 70.5 million in areas with exceptionally low malaria transmission or with P. vivax only. These represent the first contemporary estimates of the global distribution of the number of pregnancies at risk of P. falciparum and P. vivax malaria and provide a first step towards a more informed estimate of the geographical distribution of infection rates and the corresponding disease burden of malaria in pregnancy.

Monitoring and evaluation of malaria in pregnancy - developing a rational basis for control.

Monitoring and evaluation of malaria control in pregnancy is essential for assessing the efficacy and effectiveness of health interventions aimed at reducing the major burden of this disease on women living in endemic areas. Yet there is no currently integrated strategic approach on how this should be achieved. Malaria control in pregnancy is formulated in relation to epidemiological patterns of exposure. Current emphasis is on intermittent preventive treatment (IPTp) during pregnancy with sulphadoxine-pyrimethamine in higher transmission areas, combined with insecticide treated bed nets (ITNs) and case management. Emphasis in lower transmission areas is primarily on case management. This paper discusses a rational basis for monitoring and evaluation based on: assessments of therapeutic and prophylactic drug efficacy; proportional reductions in parasite prevalence; seasonal effects; rapid assessment methodologies; birthweight and/or anaemia nomograms; case-coverage methods; maternal mortality indices; operational and programmatic indicators; and safety and pharmacovigilance of antimalarials in pregnancy. These approaches should be incorporated more effectively within National Programmes in order to facilitate surveillance and improve identification of high-risk women. Systems for utilizing routinely collected data should be strengthened, with greater attention to safety and pharmacovigilance with the advent of artemisinin combination therapies, and prospects of inadvertent exposures to artemisinins in the first trimester. Integrating monitoring activities within malaria control, reproductive health and adolescent-friendly services will be critical for implementation. Large-scale operational research is required to further evaluate the validity of currently proposed indicators, and in order to clarify the breadth and scale of implementation to be deployed.

Knowledge and Adherence to the National Guidelines for Malaria Diagnosis in Pregnancy among Health-Care Providers and Drug-Outlet Dispensers in Rural Western Kenya.

Prompt diagnosis and effective treatment of acute malaria in pregnancy (MiP) is important for the mother and fetus; data on health-care provider adherence to diagnostic guidelines in pregnancy are limited. From September to November 2013, a cross-sectional survey was conducted in 51 health facilities and 39 drug outlets in Western Kenya. Provider knowledge of national diagnostic guidelines for uncomplicated MiP were assessed using standardized questionnaires. The use of parasitologic testing was assessed in health facilities via exit interviews with febrile women of childbearing age and in drug outlets via simulated-client scenarios, posing as pregnant women or their spouses. Overall, 93% of providers tested for malaria or accurately described signs and symptoms consistent with clinical malaria. Malaria was parasitologically confirmed in 77% of all patients presenting with febrile illness at health facilities and 5% of simulated clients at drug outlets. Parasitological testing was available in 80% of health facilities; 92% of patients evaluated at these facilities were tested. Only 23% of drug outlets had malaria rapid diagnostic tests (RDTs); at these outlets, RDTs were offered in 17% of client simulations. No differences were observed in testing rates by pregnancy trimester. The study highlights gaps among health providers in diagnostic knowledge and practice related to MiP, and the lack of malaria diagnostic capacity, particularly in drug outlets. The most important factor associated with malaria testing of pregnant women was the availability of diagnostics at the point of service. Interventions that increase the availability of malaria diagnostic services might improve malaria case management in pregnant women.

Systematic review: Impact of meningococcal vaccination on pharyngeal carriage of meningococci.

OBJECTIVE: To investigate the effect of meningococcal vaccines on pharyngeal carriage of meningococci. METHODS: Systematic review. MEDLINE and EMBASE were searched for relevant studies. Controlled trials and observational studies which used comparison groups or compared carriage rates before and after vaccination were included in the review. RESULTS: Twenty-nine studies satisfied the inclusion criteria. Twenty-five studies reported the effect of a polysaccharide vaccine, one the effect of a serogroup C conjugate vaccine and three the impact of serogroup B outer-membrane vaccines on overall and/or serogroup-specific meningococcal carriage rates. Ten studies of meningococcal polysaccharide vaccines found reduced serogroup-specific carriage; seven of these focussed on high-risk groups and had a short follow-up period. Only one of five studies of civilian populations in Africa showed a significantly reduced carriage. Many studies had methodological shortcomings. The one study which assessed the effect of a meningococcal conjugate vaccine on carriage showed a significant impact. Three studies of serogroup B outer-membrane protein vaccines showed no effect on carriage. CONCLUSIONS: A few well-designed trials of the impact of meningococcal vaccines on carriage have been undertaken. Such studies should be an essential component of the evaluation of new meningococcal vaccines, particularly those introduced to control epidemic meningococcal disease in Africa.

The safety of artemisinins during pregnancy: a pressing question.

BACKGROUND: An increasing number of countries in sub-Saharan Africa are changing to artemisinins combination therapy (ACT) as first or second line treatment for malaria. There is an urgent need to assess the safety of these drugs in pregnant women who may be inadvertently exposed to or actively treated with ACTs. OBJECTIVES: To examine existing published evidence on the relationship between artemisinin compounds and adverse pregnancy outcomes and consider the published evidence with regard to the safety of these compounds when administered during pregnancy. METHODS: Studies on ACT use in pregnancy were identified via searches of MEDLINE, EMBASE, Cochrane and Current Contents databases. Data on study characteristics, maternal adverse events, pregnancy outcomes and infant follow up were extracted. RESULTS: Fourteen relevant studies (nine descriptive/case reports and five controlled trials) were identified. Numbers of participants in these studies ranged from six to 461. Overall there were reports on 945 women exposed to an artemisinin during pregnancy, 123 in the 1st trimester and 822 in 2nd or 3rd trimesters. The primary end points for these studies were drug efficacy and parasite clearance. Secondary endpoints were birth outcomes including low birth weight, pre-term birth, pregnancy loss, congenital anomalies and developmental milestones. While none of the studies found evidence for an association between the use of artemisinin compounds and increased risk of adverse pregnancy outcomes, none were of sufficient size to detect small differences in event rates that could be of public health importance. Heterogeneity between studies in the artemisinin and comparator drugs used, and in definitions of adverse pregnancy outcomes, limited any pooled analysis. CONCLUSION: The limited data available suggest that artemisinins are effective and unlikely to be cause of foetal loss or abnormalities, when used in late pregnancy. However, none of these studies had adequate power to rule out rare serious adverse events, even in 2nd and 3rd trimesters and there is not enough evidence to effectively assess the risk-benefit profile of artemisinin compounds for pregnant women particularly for 1st trimester exposure. Methodologically rigorous, larger studies and post-marketing pharmacovigilance are urgently required.