Can the date of last menstrual period be trusted in the first trimester? Comparisons of gestational age measures from a prospective cohort study in six low-income to middle-income countries.

OBJECTIVES: We examined gestational age (GA) estimates for live and still births, and prematurity rates based on last menstrual period (LMP) compared with ultrasonography (USG) among pregnant women at seven sites in six low-resource countries. DESIGN: Prospective cohort study SETTING AND PARTICIPANTS: This study included data from the Global Network's population-based Maternal and Newborn Health Registry which follows pregnant women in six low-income and middle-income countries (Democratic Republic of the Congo, Guatemala, India, Kenya, Pakistan and Zambia). Participants in this analysis were 42 803 women, including their 43 230 babies, who registered for the study in their first trimester based on GA estimated either by LMP or USG and had a live or stillbirth with an estimated GA of 20-42 weeks. OUTCOME MEASURES: GA was estimated in weeks and days based on LMP and/or USG. Prematurity was defined as GA of 20 weeks+0 days through 36 weeks+6 days, calculated by both USG and LMP. RESULTS: Overall, average GA varied ≤1 week between LMP and USG. Mean GA for live births by LMP was lower than by USG (adjusted mean difference (95% CI) = -0.23 (-0.29 to -0.17) weeks). Among stillbirths, a higher GA was estimated by LMP than USG (adjusted mean difference (95% CI)= 0.42 (0.11 to 0.72) weeks). Preterm birth rates for live births were significantly higher when dated by LMP (adjusted rate difference (95% CI)= 4.20 (3.56 to 4.85)). There was no significant difference in preterm birth rates for stillbirths. CONCLUSION: The small differences in GA for LMP versus USG in the Guatemalan and Indian sites suggest that LMP may be a useful alternative to USG for GA dating during the first trimester until availability of USG improves in those areas. Further research is needed to assess LMP for first-trimester GA dating in other regions with limited access to USG. TRIAL REGISTRATION NUMBER: NCT01073475.

Prevention of maternal and neonatal death/infections with a single oral dose of azithromycin in women in labour in low-income and middle-income countries (A-PLUS): a study protocol for a multinational, randomised placebo-controlled clinical trial.

INTRODUCTION: Maternal and neonatal infections are among the most frequent causes of maternal and neonatal mortality, and current antibiotic strategies have been ineffective in preventing many of these deaths. A randomised clinical trial conducted in a single site in The Gambia showed that treatment with an oral dose of 2 g azithromycin versus placebo for all women in labour reduced certain maternal and neonatal infections. However, it is unknown if this therapy reduces maternal and neonatal sepsis and mortality. In a large, multinational randomised trial, we will evaluate the impact of azithromycin given in labour to improve maternal and newborn outcomes. METHODS AND ANALYSIS: This randomised, placebo-controlled, multicentre clinical trial includes two primary hypotheses, one maternal and one neonatal. The maternal hypothesis is to test whether a single, prophylactic intrapartum oral dose of 2 g azithromycin given to women in labour will reduce maternal death or sepsis. The neonatal hypothesis will test whether this intervention will reduce intrapartum/neonatal death or sepsis. The intervention is a single, prophylactic intrapartum oral dose of 2 g azithromycin, compared with a single intrapartum oral dose of an identical appearing placebo. A total of 34 000 labouring women from 8 research sites in sub-Saharan Africa, South Asia and Latin America will be randomised with a one-to-one ratio to intervention/placebo. In addition, we will assess antimicrobial resistance in a sample of women and their newborns. ETHICS AND DISSEMINATION: The study protocol has been reviewed and ethics approval obtained from all the relevant ethical review boards at each research site. The results will be disseminated via peer-reviewed journals and national and international scientific forums. TRIAL REGISTRATION NUMBER: NCT03871491 (https://clinicaltrials.gov/ct2/show/NCT03871491?term=NCT03871491&draw=2&rank=1).

Prescription patterns and compliance with World Health Organization recommendations for the management of uncomplicated and severe malaria: A prospective, real-world study in sub-Saharan Africa.

BACKGROUND: This study aimed to evaluate the gap between guidelines and local clinical practice for diagnosis and treatment of uncomplicated and severe malaria, the patient characteristics, diagnostic approach, treatment, and compliance to standard guideline recommendations. METHODS: This was a multicentre, observational study conducted between October 2020 and March 2021 in which patients of all ages with symptoms suggestive of malaria and who visited a healthcare facility were prospectively enrolled in six countries in sub-Saharan Africa (The Democratic Republic of the Congo, Mozambique, Nigeria, Rwanda, The United Republic of Tanzania, and Zambia). RESULTS: Of 1001 enrolled patients, 735 (73.4%) patients had confirmed malaria (based on overall judgment by investigator) at baseline (uncomplicated malaria: 598 [81.4%] and severe malaria: 137 [18.6%]). Of the confirmed malaria patients, 533 (72.5%) were administered a malaria rapid diagnostic test. The median age of patients was 11 years (range: 2 weeks-91 years) with more patients coming from rural (44.9%) than urban (30.6%) or suburban areas (24.5%). At the community level, 57.8% of patients sought advice or received treatment for malaria and 56.9% of patients took one or more drugs for their illness before coming to the study site. In terms of early access to care, 44.1% of patients came to the study site for initial visit ≥ 48 h after symptom onset. In patients with uncomplicated malaria, the most prescribed treatments were artemisinin-based combination therapy (ACT; n = 564 [94.3%]), primarily using artemether-lumefantrine (82.3%), in line with the World Health Organization (WHO) treatment guidelines. In addition, these patients received antipyretics (85.6%) and antibiotics (42.0%). However, in those with severe malaria, only 66 (48.2%) patients received parenteral treatment followed by oral ACT as per WHO guidelines, whereas 62 (45.3%) received parenteral treatment only. After receiving ambulatory care, 88.6% of patients with uncomplicated malaria were discharged and 83.2% of patients with severe malaria were discharged after hospitalization. One patient with uncomplicated malaria having multiple co-morbidities and three patients with severe malaria died. CONCLUSIONS: The findings of this study suggest that the prescribed treatment in most patients with uncomplicated malaria, but not of those with severe malaria, was in alignment with the WHO recommended guidelines.

Fetal sex and risk of pregnancy-associated malaria in Plasmodium falciparum-endemic regions: a meta-analysis.

In areas of moderate to intense Plasmodium falciparum transmission, malaria in pregnancy remains a significant cause of low birth weight, stillbirth, and severe anaemia. Previously, fetal sex has been identified to modify the risks of maternal asthma, pre-eclampsia, and gestational diabetes. One study demonstrated increased risk of placental malaria in women carrying a female fetus. We investigated the association between fetal sex and malaria in pregnancy in 11 pregnancy studies conducted in sub-Saharan African countries and Papua New Guinea through meta-analysis using log binomial regression fitted to a random-effects model. Malaria infection during pregnancy and delivery was assessed using light microscopy, polymerase chain reaction, and histology. Five studies were observational studies and six were randomised controlled trials. Studies varied in terms of gravidity, gestational age at antenatal enrolment and bed net use. Presence of a female fetus was associated with malaria infection at enrolment by light microscopy (risk ratio 1.14 [95% confidence interval 1.04, 1.24]; P = 0.003; n = 11,729). Fetal sex did not associate with malaria infection when other time points or diagnostic methods were used. There is limited evidence that fetal sex influences the risk of malaria infection in pregnancy.

Diagnostic accuracy of ASQ for screening of neurodevelopmental delays in low resource countries.

OBJECTIVE: The Bayley Scales of Infant Development (BSID) is the most used diagnostic tool to identify neurodevelopmental disorders in children under age 3 but is challenging to use in low-resource countries. The Ages and Stages Questionnaire (ASQ) is an easy-to-use, low-cost clinical tool completed by parents/caregivers that screens children for developmental delay. The objective was to determine the performance of ASQ as a screening tool for neurodevelopmental impairment when compared with BSID second edition (BSID-II) for the diagnosis of moderate-to-severe neurodevelopmental impairment among infants at 12 and 18 months of age in low-resource countries. METHODS: Study participants were recruited as part of the First Bites Complementary Feeding trial from the Democratic Republic of Congo, Zambia, Guatemala and Pakistan between October 2008 and January 2011. Study participants underwent neurodevelopmental assessment by trained personnel using the ASQ and BSID-II at 12 and 18 months of age. RESULTS: Data on both ASQ and BSID-II assessments of 1034 infants were analysed. Four of five ASQ domains had specificities greater than 90% for severe neurodevelopmental delay at 18 months of age. Sensitivities ranged from 23% to 62%. The correlations between ASQ communications subscale and BSID-II Mental Development Index (MDI) (r=0.38) and between ASQ gross motor subscale and BSID-II Psychomotor Development Index (PDI) (r=0.33) were the strongest correlations found. CONCLUSION: At 18 months, ASQ had high specificity but moderate-to-low sensitivity for BSID-II MDI and/or PDI <70. ASQ, when administered by trained healthcare workers, may be a useful screening tool to detect severe disability in infants from rural low-income to middle-income settings. TRIAL REGISTRATION NUMBER: NCT01084109.

Prereferral rectal artesunate and referral completion among children with suspected severe malaria in the Democratic Republic of the Congo, Nigeria and Uganda.

INTRODUCTION: Children who receive prereferral rectal artesunate (RAS) require urgent referral to a health facility where appropriate treatment for severe malaria can be provided. However, the rapid improvement of a child's condition after RAS administration may influence a caregiver's decision to follow this recommendation. Currently, the evidence on the effect of RAS on referral completion is limited. METHODS: An observational study accompanied the roll-out of RAS in three malaria endemic settings in the Democratic Republic of the Congo (DRC), Nigeria and Uganda. Community health workers and primary health centres enrolled children under 5 years with suspected severe malaria before and after the roll-out of RAS. All children were followed up 28 days after enrolment to assess their treatment-seeking pathways. RESULTS: Referral completion was 67% (1408/2104) in DRC, 48% (287/600) in Nigeria and 58% (2170/3745) in Uganda. In DRC and Uganda, RAS users were less likely to complete referral than RAS non-users in the pre-roll-out phase (adjusted OR (aOR)=0.48, 95% CI 0.30 to 0.77 and aOR=0.72, 95% CI 0.58 to 0.88, respectively). Among children seeking care from a primary health centre in Nigeria, RAS users were less likely to complete referral compared with RAS non-users in the post-roll-out phase (aOR=0.18, 95% CI 0.05 to 0.71). In Uganda, among children who completed referral, RAS users were significantly more likely to complete referral on time than RAS non-users enrolled in the pre-roll-out phase (aOR=1.81, 95% CI 1.17 to 2.79). CONCLUSIONS: The findings of this study raise legitimate concerns that the roll-out of RAS may lead to lower referral completion in children who were administered prereferral RAS. To ensure that community-based programmes are effectively implemented, barriers to referral completion need to be addressed at all levels. Alternative effective treatment options should be provided to children unable to complete referral. TRIAL REGISTRSTION NUMBER: NCT03568344; ClinicalTrials.gov.

Factors associated with adherence to COVID-19 prevention measures in the Democratic Republic of the Congo (DRC): results of an online survey.

OBJECTIVES: We aimed to assess the level of adherence to COVID-19 preventive measures in the Democratic Republic of the Congo (DRC) and to identify factors associated with non-adherence. DESIGN: A cross-sectional population-based online survey. SETTINGS: The study was conducted in 22 provinces of the DRC. Five provinces with a satisfactory number of respondents were included in the analysis: Haut Katanga, Kasaï-Central, Kasaï-Oriental, Kinshasa and North Kivu. PARTICIPANTS: The participants were people aged ≥18 years, living in the DRC. A total of 3268 participants were included in the study analysis. INTERVENTIONS: Both convenience sampling (surveyors themselves contacted potential participants in different districts) and snowball sampling (the participants were requested to share the link of the questionnaire with their contacts) methods were used. PRIMARY AND SECONDARY OUTCOME MEASURES: We computed adherence scores using responses to 10 questions concerning COVID-19 preventive measures recommended by the WHO and the DRC Ministry of Health. We used logistic regression analysis with generalised estimating equations to identify factors of poor adherence. We also asked about the presence or absence of flu-like symptoms during the preceding 14 days, whether a COVID-19 test was done and the test result. RESULTS: Data from 3268 participants were analysed. Face masks were not used by 1789 (54.7%) participants. Non-adherence to physical distancing was reported by 1364 (41.7%) participants. 501 (15.3%) participants did not observe regular handwashing. Five variables were associated with poor adherence: lower education level, living with other people at home, being jobless/students, living with a partner and not being a healthcare worker. CONCLUSION: Despite compulsory restrictions imposed by the government, only about half of the respondents adhered to COVID-19 preventive measures in the DRC. Disparities across the provinces are remarkable. There is an urgent need to further explore the reasons for these disparities and factors associated with non-adherence.

Spatial and epidemiological drivers of Plasmodium falciparum malaria among adults in the Democratic Republic of the Congo.

BACKGROUND: Adults are frequently infected with malaria and may serve as a reservoir for further transmission, yet we know relatively little about risk factors for adult infections. In this study, we assessed malaria risk factors among adults using samples from the nationally representative, cross-sectional 2013-2014 Demographic and Health Survey (DHS) conducted in the Democratic Republic of the Congo (DRC). We further explored differences in risk factors by urbanicity. METHODS: Plasmodium falciparum infection was determined by PCR. Covariates were drawn from the DHS to model individual, community and environmental-level risk factors for infection. Additionally, we used deep sequencing data to estimate the community-level proportions of drug-resistant infections and included these estimates as potential risk factors. All identified factors were assessed for differences in associations by urbanicity. RESULTS: A total of 16 126 adults were included. Overall prevalence of malaria was 30.3% (SE=1.1) by PCR; province-level prevalence ranged from 6.7% to 58.3%. Only 17% of individuals lived in households with at least one bed-net for every two people, as recommended by the WHO. Protective factors included increasing within-household bed-net coverage (Prevalence Ratio=0.85, 95% CI=0.76-0.95) and modern housing (PR=0.58, 95% CI=0.49-0.69). Community-level protective factors included increased median wealth (PR=0.87, 95% CI=0.83-0.92). Education, wealth, and modern housing showed protective associations in cities but not in rural areas. CONCLUSIONS: The DRC continues to suffer from a high burden of malaria; interventions that target high-risk groups and sustained investment in malaria control are sorely needed. Areas of high prevalence should be prioritised for interventions to target the largest reservoirs for further transmission.

The World Health Organization Fetal Growth Charts: A Multinational Longitudinal Study of Ultrasound Biometric Measurements and Estimated Fetal Weight.

BACKGROUND: Perinatal mortality and morbidity continue to be major global health challenges strongly associated with prematurity and reduced fetal growth, an issue of further interest given the mounting evidence that fetal growth in general is linked to degrees of risk of common noncommunicable diseases in adulthood. Against this background, WHO made it a high priority to provide the present fetal growth charts for estimated fetal weight (EFW) and common ultrasound biometric measurements intended for worldwide use. METHODS AND FINDINGS: We conducted a multinational prospective observational longitudinal study of fetal growth in low-risk singleton pregnancies of women of high or middle socioeconomic status and without known environmental constraints on fetal growth. Centers in ten countries (Argentina, Brazil, Democratic Republic of the Congo, Denmark, Egypt, France, Germany, India, Norway, and Thailand) recruited participants who had reliable information on last menstrual period and gestational age confirmed by crown-rump length measured at 8-13 wk of gestation. Participants had anthropometric and nutritional assessments and seven scheduled ultrasound examinations during pregnancy. Fifty-two participants withdrew consent, and 1,387 participated in the study. At study entry, median maternal age was 28 y (interquartile range [IQR] 25-31), median height was 162 cm (IQR 157-168), median weight was 61 kg (IQR 55-68), 58% of the women were nulliparous, and median daily caloric intake was 1,840 cal (IQR 1,487-2,222). The median pregnancy duration was 39 wk (IQR 38-40) although there were significant differences between countries, the largest difference being 12 d (95% CI 8-16). The median birthweight was 3,300 g (IQR 2,980-3,615). There were differences in birthweight between countries, e.g., India had significantly smaller neonates than the other countries, even after adjusting for gestational age. Thirty-one women had a miscarriage, and three fetuses had intrauterine death. The 8,203 sets of ultrasound measurements were scrutinized for outliers and leverage points, and those measurements taken at 14 to 40 wk were selected for analysis. A total of 7,924 sets of ultrasound measurements were analyzed by quantile regression to establish longitudinal reference intervals for fetal head circumference, biparietal diameter, humerus length, abdominal circumference, femur length and its ratio with head circumference and with biparietal diameter, and EFW. There was asymmetric distribution of growth of EFW: a slightly wider distribution among the lower percentiles during early weeks shifted to a notably expanded distribution of the higher percentiles in late pregnancy. Male fetuses were larger than female fetuses as measured by EFW, but the disparity was smaller in the lower quantiles of the distribution (3.5%) and larger in the upper quantiles (4.5%). Maternal age and maternal height were associated with a positive effect on EFW, particularly in the lower tail of the distribution, of the order of 2% to 3% for each additional 10 y of age of the mother and 1% to 2% for each additional 10 cm of height. Maternal weight was associated with a small positive effect on EFW, especially in the higher tail of the distribution, of the order of 1.0% to 1.5% for each additional 10 kg of bodyweight of the mother. Parous women had heavier fetuses than nulliparous women, with the disparity being greater in the lower quantiles of the distribution, of the order of 1% to 1.5%, and diminishing in the upper quantiles. There were also significant differences in growth of EFW between countries. In spite of the multinational nature of the study, sample size is a limiting factor for generalization of the charts. CONCLUSIONS: This study provides WHO fetal growth charts for EFW and common ultrasound biometric measurements, and shows variation between different parts of the world.

Monitoring parasite diversity for malaria elimination in sub-Saharan Africa.

The African continent continues to bear the greatest burden of malaria and the greatest diversity of parasites, mosquito vectors, and human victims. The evolutionary plasticity of malaria parasites and their vectors is a major obstacle to eliminating the disease. Of current concern is the recently reported emergence of resistance to the front-line drug, artemisinin, in South-East Asia in Plasmodium falciparum, which calls for preemptive surveillance of the African parasite population for genetic markers of emerging drug resistance. Here we describe the Plasmodium Diversity Network Africa (PDNA), which has been established across 11 countries in sub-Saharan Africa to ensure that African scientists are enabled to work together and to play a key role in the global effort for tracking and responding to this public health threat.