The effect and control of malaria in pregnancy and lactating women in the Asia-Pacific region.

Half of all pregnancies at risk of malaria worldwide occur in the Asia-Pacific region, where Plasmodium falciparum and Plasmodium vivax co-exist. Despite substantial reductions in transmission, malaria remains an important cause of adverse health outcomes for mothers and offspring, including pre-eclampsia. Malaria transmission is heterogeneous, and infections are commonly subpatent and asymptomatic. High-grade antimalarial resistance poses a formidable challenge to malaria control in pregnancy in the region. Intermittent preventive treatment in pregnancy reduces infection risk in meso-endemic New Guinea, whereas screen-and-treat strategies will require more sensitive point-of-care tests to control malaria in pregnancy. In the first trimester, artemether-lumefantrine is approved, and safety data are accumulating for other artemisinin-based combinations. Safety of novel antimalarials to treat artemisinin-resistant P falciparum during pregnancy, and of 8-aminoquinolines during lactation, needs to be established. A more systematic approach to the prevention of malaria in pregnancy in the Asia-Pacific is required.

The association of intraleucocytic malaria pigment and disease severity in Papua New Guinean children with severe P. falciparum malaria.

BACKGROUND: Plasmodium falciparum pigment-containing leucocytes (PCLs) are associated with adverse clinical manifestations of severe malaria in African children. However, limited data exist on the association of PCLs in settings outside of Africa. METHODS: Thin films on peripheral blood slides obtained from children ages 6 months-10 y with severe malaria were examined for PCLs. The intraleucocytic pigment data were correlated with clinical phenotypic data such as severe anaemia, metabolic acidosis and coma to determine the association of PCLs with clinical phenotypes of severe malaria and outcome. RESULTS: Of the 169 children with severe P. falciparum malaria confirmed by microscopy, 76% (129/169) had PCLs. Compared with children without PCLs, the presence (adjusted odds ratio [AOR] 3.2 [95% confidence interval {CI} 1.5 to 6.9], p≤0.01) and quantity (AOR 1.0 [95% CI 1.0 to 1.1], p=0.04) of pigment-containing monocytes (PCMs) was significantly associated with severe anaemia, while the quantity of both PCMs (AOR 1.0 [95% CI 1.0 to 1.1], p≤0.01) and pigment-containing neutrophils (AOR 1.0 [95% CI 1.0 to 1.1], p=0.01) was significantly associated with metabolic acidosis. Plasma P. falciparum histidine-rich protein-2 level negatively correlated with the platelet count (r=-0.5, p≤0.01) in patients with PCLs and no PCLs. CONCLUSIONS: In Papua New Guinean children with severe P. falciparum malaria, the presence and quantity of PCLs are predictors of disease severity, severe anaemia and metabolic acidosis.

Incidence of self-induced abortion with misoprostol, admitted to a provincial hospital in Papua New Guinea: A prospective observational study.

BACKGROUND: Misoprostol is a life-savingmedication in obstetric practice but the prevalence of misoprostol-related self-induced abortion is increasing in many communities. AIMS: To investigate the hospital incidence, clinical management, and legal framework of self-induced abortions with misoprostol. MATERIALS AND METHODS: This was a prospective observational study conducted over 18 months. All patients <20 weeks pregnant who were admitted with a diagnosis of misoprostol-induced abortion were included in the study. RESULTS: Of 186 women with abortion-related admissions during the study period, 51 (27.4%) women reported using misoprostol to induce abortion. The majority were young (27.8 ± 5.5) married women (32/51: 62.7%), particularly educated (27/51: 52.9%) employed women (27/51: 52.9%), who were not on any contraception (46/51: 90.1%). Most abortions were induced in the first trimester (39/51: 76.5%) and patients were admitted because of prolonged bleeding (23/51: 45.1%). A significant proportion of participants who did not receive the correct dose of misoprostol developed sepsis compared to those who received a correct dose (6/18 (33.3%) vs 1/30 (3.3%); P = 0.008). CONCLUSION: The use of misoprostol as an abortifacient is increasing in Papua New Guinea, particularly among educated and employed women. A review of the laws to meet the demand for abortion services and to limit complications of unsafe abortion practices is required.

Safety and efficacy of an oral misoprostol standard-dose regimen vs a low-dose regimen for induction of labour in Papua New Guinean women: An open-label randomised controlled trial.

BACKGROUND: Oral misoprostol is widely used for induction of labour (IOL) in developing countries because of its many advantages. However, limited data exist concerning its safety and efficacy when lower doses are used. AIM: To determine the safety and efficacy of a low-dose oral misoprostol regimen (commencing at 12 µg) compared to a standard-dose regimen (commencing at 25 µg) in Papua New Guinea (PNG) women undergoing IOL. MATERIALS AND METHODS: This was an open-label non-inferiority randomised controlled trial conducted at a provincial hospital in PNG. Women with singleton pregnancies ≥36 weeks with cephalic presentation and a Bishops score of <6, requiring IOL were enrolled. Both regimens were incremented second-hourly to a maximum required dose within 24 h or until commencement of labour. The primary outcome was the proportion of women who delivered within 24 h of drug administration without any severe adverse events. RESULTS: Of the 262 women induced (130 standard-dose vs 132 low-dose), rates of successful induction were high for both regimens (120/130 (92%) vs 118/132 (89%); P = 0.52). Fourteen women (11%) in the standard-dose regimen and 20 (15%) in the low-dose regimen had severe adverse events. There was no significant difference in the safety profile of the two regimens (106/130 (82%) vs 98/132 (74%); P = 0.18). The induction-to-delivery time was significantly shorter in the standard-dose arm (15.2 ± 8.7 h vs 18.0 ± 9.1 h; P = 0.01). CONCLUSION: The standard-dose regimen for IOL has greater efficacy in reducing induction-to-delivery time compared to the low-dose regimen. There was no significant difference in the number of adverse events between the two regimens.

Mortality and morbidity after emergency peripartum hysterectomy in a provincial referral hospital in Papua New Guinea: A seven-year audit.

BACKGROUND: Emergency peripartum hysterectomy (EPH) is a life-saving surgical procedure performed at the time of caesarean section or within 24 h of vaginal delivery and is usually a procedure of last resort in obstetric haemorrhage when other interventions fail. AIM: To investigate the incidence, indications, risk factors and complications of EPH in a provincial referral hospital in Papua New Guinea (PNG). MATERIALS AND METHODS: This was a seven-year retrospective observational study investigating the rate of EPH at a provincial hospital between January 2012 and December 2018. Patient medical records that included socio-demographics, obstetric risk factors, indications for EPH and maternal and perinatal outcomes were reviewed. RESULTS: Of the 19 215 deliveries during the study period, 26 women had EPH, giving an incidence of 1.35 per 1000 deliveries. The majority of women (18/26) were referred from peripheral health facilities. Overall, 21 women survived and five died (mortality index, 19%). Uterine rupture was the most common indication for EPH (13/26), and it was associated with a high maternal death rate of 15.4% (2/13) and significantly higher perinatal deaths when compared to babies born to mothers with other indications (13/13 (100%) versus 5/13 (38.5%); P = 0.002). Neonates born to mothers with uterine atony were more likely to survive (8/11 (72.7%) versus 0/15 (0%); P < 0.001), although maternal mortality was higher at 27.3% (3/11). CONCLUSION: Uterine rupture and uterine atony after prolonged labour are common indications of EPH and associated with significant maternal and perinatal mortality. Improving pre-hospital management of prolonged labour remains critical in PNG.

The burden of presumed tuberculosis in hospitalized children in a resource-limited setting in Papua New Guinea: a prospective observational study.

Background: In Papua New Guinea, TB is considered to be a major public health problem, but little is known about the prevalence and prognosis of presumed TB in children. Methods: As part of a prospective hospital-based surveillance on the northern coast of mainland Papua New Guinea, the authors investigated the admission prevalence and case fatality rate associated with presumed TB over a 6-year period (2011-2016). All children admitted who were diagnosed with TB were followed-up until discharge or death. Results: Of 8992 paediatric admissions, 734 patients (8.2%) were diagnosed with presumed TB and there were 825 deaths, with TB accounting for 102 (12.4%). Extrapulmonary TB was the final diagnosis in 384 admissions {prevalence 4.3% [384/8992 (95% CI 3.9-4.7)]} with a case fatality rate of 21.4% [82/384 (95% CI 17.4-25.9)]. TB meningitis, disseminated TB and pericardial TB had high case fatality rates of 29.0% (53/183), 28.9% (11/38) and 25% (4/16), respectively. Severe malnutrition was more common in patients with pulmonary compared with extrapulmonary TB (25.4% vs 15.6%; p<0.01). Conclusions: Improved community-based case detection strategies, routine BCG vaccinations and other effective forms of TB control need revitalization and sustainability to reduce the high case fatality rates associated with childhood TB in Papua New Guinea.

Risk factors and pregnancy outcomes associated with placental malaria in a prospective cohort of Papua New Guinean women.

BACKGROUND: Plasmodium falciparum in pregnancy results in substantial poor health outcomes for both mother and child, particularly in young, primigravid mothers who are at greatest risk of placental malaria (PM) infection. Complications of PM include maternal anaemia, low birth weight and preterm delivery, which contribute to maternal and infant morbidity and mortality in coastal Papua New Guinea (PNG). METHODS: Placental biopsies were examined from 1451 pregnant women who were enrolled in a malaria prevention study at 14-26 weeks gestation. Clinical and demographic information were collected at first antenatal clinic visits and women were followed until delivery. Placental biopsies were collected and examined for PM using histology. The presence of infected erythrocytes and/or the malaria pigment in monocytes or fibrin was used to determine the type of placental infection. RESULTS: Of 1451 placentas examined, PM infection was detected in 269 (18.5%), of which 54 (3.7%) were acute, 55 (3.8%) chronic, and 160 (11.0%) were past infections. Risk factors for PM included residing in rural areas (adjusted odds ratio (AOR) 3.65, 95% CI 1.76-7.51; p ≤ 0.001), being primigravid (AOR 2.45, 95% CI 1.26-4.77; p = 0.008) and having symptomatic malaria during pregnancy (AOR 2.05, 95% CI 1.16-3.62; p = 0.013). After adjustment for covariates, compared to uninfected women, acute infections (AOR 1.97, 95% CI 0.98-3.95; p = 0.056) were associated with low birth weight babies, whereas chronic infections were associated with preterm delivery (AOR 3.92, 95% CI 1.64-9.38; p = 0.002) and anaemia (AOR 2.22, 95% CI 1.02-4.84; p = 0.045). CONCLUSIONS: Among pregnant PNG women receiving at least one dose of intermittent preventive treatment in pregnancy and using insecticide-treated bed nets, active PM infections were associated with adverse outcomes. Improved malaria prevention is required to optimize pregnancy outcomes.

The Burden of Child Maltreatment Leading to Hospitalization in a Provincial Setting in Papua New Guinea.

INTRODUCTION: Child maltreatment is prevalent globally. In Papua New Guinea (PNG), child maltreatment remains an under-reported problem. METHODS: As part of a 10 month prospective observational study conducted at Modilon Hospital in PNG, we investigated the burden of child maltreatment in the form of sexual abuse, physical abuse and neglect, leading to hospitalization in children ≤14 years. RESULTS: Of 1061 screened admissions, 107 (10%) fulfilled the definition of child maltreatment. The in-hospital admission prevalence of sexual abuse was 5.7% [60 of 1061; 95% confidence interval (CI): 4.4-7.3]. Neglect accounted for 3.4% (36 of 1061; 95% CI: 2.4-4.7) of admissions, while physical abuse accounted for 1.0% (11 of 1061; 95% CI: 0.6-1.9). Mortality was highest in the neglected group, with severe acute malnutrition accounting for 89% of deaths. CONCLUSION: Improved awareness, establishment of appropriate channels for addressing child maltreatment and enforcement of child protection laws in PNG and other epidemiologically similar settings are urgently needed.

Accuracy of an HRP-2/panLDH rapid diagnostic test to detect peripheral and placental Plasmodium falciparum infection in Papua New Guinean women with anaemia or suspected malaria.

BACKGROUND: The diagnosis of malaria during pregnancy is complicated by placental sequestration, asymptomatic infection, and low-density peripheral parasitaemia. Where intermittent preventive treatment (IPT) with sulfadoxine-pyrimethamine is threatened by drug resistance, or is inappropriate due to low transmission, intermittent screening and treatment (ISTp) with rapid diagnostic tests for malaria (RDT) could be a valuable alternative. Therefore, the accuracy of RDTs to detect peripheral and placental infection was assessed in a declining transmission setting in Papua New Guinea (PNG). METHODS: The performance of a combination RDT detecting histidine-rich protein-2 (HRP-2) and Plasmodium lactate dehydrogenase (pLDH), and light microscopy (LM), to diagnose peripheral Plasmodium falciparum and Plasmodium vivax infections during pregnancy, were assessed using quantitative real-time PCR (qPCR) as the reference standard. Participants in a malaria prevention trial in PNG with a haemoglobin ≤90 g/L, or symptoms suggestive of malaria, were tested. Ability of RDT and LM to detect active placental infection on histology was evaluated in some participants. RESULTS: Among 876 women, 1162 RDTs were undertaken (anaemia: 854 [73.5 %], suspected malaria: 308 [26.5 %]). qPCR detected peripheral infection during 190 RDT episodes (165 P. falciparum, 19 P. vivax, 6 mixed infections). Overall, RDT detected peripheral P. falciparum infection with 45.6 % sensitivity (95 % CI 38.0-53.4), a specificity of 96.4 % (95.0-97.4), a positive predictive value of 68.4 % (59.1-76.8), and a negative predictive value of 91.1 % (89.2-92.8). RDT performance to detect P. falciparum was inferior to LM, more so amongst anaemic women (18.6 vs 45.3 % sensitivity, Liddell's exact test, P < 0.001) compared to symptomatic women (72.9 vs 82.4 % sensitivity, P = 0.077). RDT and LM missed 88.0 % (22/25) and 76.0 % (19/25) of P. vivax infections, respectively. In a subset of women tested at delivery and who had placental histology (n = 158) active placental infection was present in 19.6 %: all three peripheral blood infection detection methods (RDT, LM, qPCR) missed >50 % of these infections. CONCLUSIONS: In PNG, HRP-2/pLDH RDTs may be useful to diagnose peripheral P. falciparum infections in symptomatic pregnant women. However, they are not sufficiently sensitive for use in intermittent screening amongst asymptomatic (anaemic) women. These findings have implications for the management of malaria in pregnancy. The adverse impact of infections undetected by RDT or LM on pregnancy outcomes needs further evaluation.

Sulphadoxine-pyrimethamine plus azithromycin for the prevention of low birthweight in Papua New Guinea: a randomised controlled trial.

BACKGROUND: Intermittent preventive treatment in pregnancy has not been evaluated outside of Africa. Low birthweight (LBW, <2,500 g) is common in Papua New Guinea (PNG) and contributing factors include malaria and reproductive tract infections. METHODS: From November 2009 to February 2013, we conducted a parallel group, randomised controlled trial in pregnant women (≤ 26 gestational weeks) in PNG. Sulphadoxine-pyrimethamine (1,500/75 mg) plus azithromycin (1 g twice daily for 2 days) (SPAZ) monthly from second trimester (intervention) was compared against sulphadoxine-pyrimethamine and chloroquine (450 to 600 mg, daily for three days) (SPCQ) given once, followed by SPCQ placebo (control). Women were assigned to treatment (1:1) using a randomisation sequence with block sizes of 32. Participants were blinded to assignments. The primary outcome was LBW. Analysis was by intention-to-treat. RESULTS: Of 2,793 women randomised, 2,021 (72.4%) were included in the primary outcome analysis (SPCQ: 1,008; SPAZ: 1,013). The prevalence of LBW was 15.1% (305/2,021). SPAZ reduced LBW (risk ratio [RR]: 0.74, 95% CI: 0.60-0.91, P = 0.005; absolute risk reduction (ARR): 4.5%, 95% CI: 1.4-7.6; number needed to treat: 22), and preterm delivery (0.62, 95% CI: 0.43-0.89, P = 0.010), and increased mean birthweight (41.9 g, 95% CI: 0.2-83.6, P = 0.049). SPAZ reduced maternal parasitaemia (RR: 0.57, 95% CI: 0.35-0.95, P = 0.029) and active placental malaria (0.68, 95% CI: 0.47-0.98, P = 0.037), and reduced carriage of gonorrhoea (0.66, 95% CI: 0.44-0.99, P = 0.041) at second visit. There were no treatment-related serious adverse events (SAEs), and the number of SAEs (intervention 13.1% [181/1,378], control 12.7% [174/1,374], P = 0.712) and AEs (intervention 10.5% [144/1,378], control 10.8% [149/1,374], P = 0.737) was similar. A major limitation of the study was the high loss to follow-up for birthweight. CONCLUSIONS: SPAZ was efficacious and safe in reducing LBW, possibly acting through multiple mechanisms including the effect on malaria and on sexually transmitted infections. The efficacy of SPAZ in the presence of resistant parasites and the contribution of AZ to bacterial antibiotic resistance require further study. The ability of SPAZ to improve pregnancy outcomes warrants further evaluation. TRIAL REGISTRATION: ClinicalTrials.gov NCT01136850 (06 April 2010).

Does malaria affect placental development? Evidence from in vitro models.

BACKGROUND: Malaria in early pregnancy is difficult to study but has recently been associated with fetal growth restriction (FGR). The pathogenic mechanisms underlying malarial FGR are poorly characterized, but may include impaired placental development. We used in vitro methods that model migration and invasion of placental trophoblast into the uterine wall to investigate whether soluble factors released into maternal blood in malaria infection might impair placental development. Because trophoblast invasion is enhanced by a number of hormones and chemokines, and is inhibited by pro-inflammatory cytokines, many of which are dysregulated in malaria in pregnancy, we further compared concentrations of these factors in blood between malaria-infected and uninfected pregnancies. METHODOLOGY/PRINCIPAL FINDINGS: We measured trophoblast invasion, migration and viability in response to treatment with serum or plasma from two independent cohorts of Papua New Guinean women infected with Plasmodium falciparum or Plasmodium vivax in early pregnancy. Compared to uninfected women, serum and plasma from women with P. falciparum reduced trophoblast invasion (P = .06) and migration (P = .004). P. vivax infection did not alter trophoblast migration (P = .64). The P. falciparum-specific negative effect on placental development was independent of trophoblast viability, but associated with high-density infections. Serum from P. falciparum infected women tended to have lower levels of trophoblast invasion promoting hormones and factors and higher levels of invasion-inhibitory inflammatory factors. CONCLUSION/SIGNIFICANCE: We demonstrate that in vitro models of placental development can be adapted to indirectly study the impact of malaria in early pregnancy. These infections could result in impaired trophoblast invasion with reduced transformation of maternal spiral arteries due to maternal hormonal and inflammatory disturbances, which may contribute to FGR by limiting the delivery of maternal blood to the placenta. Future prevention strategies for malaria in pregnancy should include protection in the first half of pregnancy.