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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.

Knowledge of accurate gestational age is required for comprehensive pregnancy care and is an essential component of research evaluating causes of preterm birth. In industrialised countries gestational age is determined with the help of fetal biometry in early pregnancy. Lack of ultrasound and late presentation to antenatal clinic limits this practice in low-resource settings. Instead, clinical estimators of gestational age are used, but their accuracy remains a matter of debate. In a cohort of 688 singleton pregnancies from rural Papua New Guinea, delivery gestational age was calculated from Ballard score, last menstrual period, symphysis-pubis fundal height at first visit and quickening as well as mid- and late pregnancy fetal biometry. Published models using sequential fundal height measurements and corrected last menstrual period to estimate gestational age were also tested. Novel linear models that combined clinical measurements for gestational age estimation were developed. Predictions were compared with the reference early pregnancy ultrasound (<25 gestational weeks) using correlation, regression and Bland-Altman analyses and ranked for their capability to predict preterm birth using the harmonic mean of recall and precision (F-measure). Average bias between reference ultrasound and clinical methods ranged from 0-11 days (95% confidence levels: 14-42 days). Preterm birth was best predicted by mid-pregnancy ultrasound (F-measure: 0.72), and neuromuscular Ballard score provided the least reliable preterm birth prediction (F-measure: 0.17). The best clinical methods to predict gestational age and preterm birth were last menstrual period and fundal height (F-measures 0.35). A linear model combining both measures improved prediction of preterm birth (F-measure: 0.58). Estimation of gestational age without ultrasound is prone to significant error. In the absence of ultrasound facilities, last menstrual period and fundal height are among the more reliable clinical measures. This study underlines the importance of strengthening ultrasound facilities and developing novel ways to estimate gestational age.

In persistent infections that are accompanied by chronic immune activation, such as human immunodeficiency virus, hepatitis C virus, and malaria, there is an increased frequency of a phenotypically distinct subset of memory B cells lacking the classic memory marker CD27 and showing a reduced capacity to produce antibodies. However, critical knowledge gaps remain on specific B cell changes and immune adaptation in chronic infections. We hypothesized that expansion of atypical memory B cells (aMBCs) and reduction of activated peripheral marginal zone (MZ)-like B cells in constantly exposed individuals might be accompanied by phenotypic changes that would confer a tolerogenic profile, helping to establish tolerance to infections. To better understand malaria-associated phenotypic abnormalities on B cells, we analyzed peripheral blood mononuclear cells from 55 pregnant women living in a malaria-endemic area of Papua Nueva Guinea and 9 Spanish malaria-naïve individuals using four 11-color flow cytometry panels. We assessed the expression of markers of B cell specificity (IgG and IgM), activation (CD40, CD80, CD86, b220, TACI, and CD150), inhibition (PD1, CD95, and CD71), and migration (CCR3, CXCR3, and CD62l). We found higher frequencies of active and resting aMBC and marked reduction of MZ-like B cells, although changes in absolute cell counts could not be assessed. Highly exposed women had higher PD1 -, CD95 -, CD40 -, CD71 -, and CD80 -activated aMBC frequencies than non-exposed subjects. Malaria exposure increased frequencies of b220 and proapoptotic markers PD1 and CD95, and decreased expression of the activation marker TACI on MZ-like B cells. The increased frequencies of inhibitory and apoptotic markers on activated aMBCs and MZ-like B cells in malaria-exposed adults suggest an immune-homeostatic mechanism for maintaining B cell development and function while simultaneously downregulating hyperreactive B cells. This mechanism would keep the B cell activation threshold high enough to control infection but impaired enough to tolerate it, preventing systemic inflammation.

Despite that over 90 million pregnancies are at risk of Plasmodium vivax infection annually, little is known about the epidemiology and impact of the infection in pregnancy. We undertook a health facility-based prospective observational study in pregnant women from Guatemala (GT), Colombia (CO), Brazil (BR), India (IN) and Papua New Guinea PNG). Malaria and anemia were determined during pregnancy and fetal outcomes assessed at delivery. A total of 9388 women were enrolled at antennal care (ANC), of whom 53% (4957) were followed until delivery. Prevalence of P. vivax monoinfection in maternal blood at delivery was 0.4% (20/4461) by microscopy [GT 0.1%, CO 0.5%, BR 0.1%, IN 0.2%, PNG 1.2%] and 7% (104/1488) by PCR. P. falciparum monoinfection was found in 0.5% (22/4463) of women by microscopy [GT 0%, CO 0.5%, BR 0%, IN 0%, PNG 2%]. P. vivax infection was observed in 0.4% (14/3725) of placentas examined by microscopy and in 3.7% (19/508) by PCR. P. vivax in newborn blood was detected in 0.02% (1/4302) of samples examined by microscopy [in cord blood; 0.05% (2/4040) by microscopy, and 2.6% (13/497) by PCR]. Clinical P. vivax infection was associated with increased risk of maternal anemia (Odds Ratio-OR, 5.48, [95% CI 1.83-16.41]; p = 0.009), while submicroscopic vivax infection was not associated with increased risk of moderate-severe anemia (Hb<8g/dL) (OR, 1.16, [95% CI 0.52-2.59]; p = 0.717), or low birth weight (<2500g) (OR, 0.52, [95% CI, 0.23-1.16]; p = 0.110). In this multicenter study, the prevalence of P. vivax infection in pregnancy by microscopy was overall low across all endemic study sites; however, molecular methods revealed a significant number of submicroscopic infections. Clinical vivax infection in pregnancy was associated with maternal anemia, which may be deleterious for infant's health. These results may help to guide maternal health programs in settings where vivax malaria is endemic; they also highlight the need of addressing a vulnerable population such as pregnant women while embracing malaria elimination in endemic countries.

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. viva x, 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.

Background Chewing areca nut (AN), also known as betel nut, is common in Asia and the South Pacific and the habit has been linked to a number of serious health problems including oral cancer. Use of AN in pregnancy has been associated with a reduction in mean birthweight in some studies, but this association and the relationship between AN chewing and other adverse pregnancy outcomes remain poorly understood. Methods We assessed the impact of AN chewing on adverse outcomes including stillbirth, low birthweight (LBW, <2,500 g) and anaemia at delivery (haemoglobin <11.0 g/dL) in a longitudinal cohort of 2,700 pregnant women residing in rural lowland Papua New Guinea (PNG) from November 2009 until February 2013. Chewing habits and participant characteristics were evaluated at first antenatal visit and women were followed until delivery. Results 83.3 % [2249/2700] of pregnant women used AN, and most chewed on a daily basis (86.2 % [1939/2249]. Smoking and alcohol use was reported by 18.9 % (511/2700) and 5.0 % (135/2688) of women, respectively. AN use was not associated with pregnancy loss or congenital abnormalities amongst women with a known pregnancy outcome ( n  = 2215). Analysis of 1769 birthweights did not demonstrate an association between AN and LBW (chewers: 13.7 % [200/1459] vs. non-chewers: 14.5 % [45/310], P  = 0.87) or reduced mean birthweight (2957 g vs. 2966 g; P  = 0.76). Women using AN were more likely to be anaemic (haemoglobin <11 g/dL) at delivery (75.2 % [998/1314] vs. 63.9 % [182/285], adjusted odds ratio [95 % CI]: 1.67 [1.27, 2.20], P  < 0.001). Chewers more commonly had male babies than non-chewers (46.1 % [670/1455] vs. 39.8 % [123/309], P  = 0.045). Conclusions AN chewing may contribute to anaemia. Although not associated with other adverse pregnancy outcome in this cohort gestational AN use should be discouraged, given the potential adverse effects on haemoglobin and well-established long-term health risk including oral cancer. Future research evaluating the potential association of AN use and anaemia may be warranted. Trial registration ClinicalTrials.gov NCT01136850 (06 April 2010).

Background Doppler velocimetry studies of umbilical artery (UA) and middle cerebral artery (MCA) flow help to determine the presence and severity of fetal growth restriction. Increased UA resistance and reduced MCA pulsatility may indicate increased placental resistance and intrafetal blood flow redistribution. Malaria causes low birth weight and fetal growth restriction, but few studies have assessed its effects on uteroplacental and fetoplacental blood flow. Methods Colour-pulsed Doppler ultrasound was used to assess UA and MCA flow in 396 Papua New Guinean singleton fetuses. Abnormal flow was defined as an UA resistance index above the 90th centile, and/or a MCA pulsatility index and cerebroplacental ratio (ratio of MCA and UA pulsatility index) below the 10th centile of population-specific models fitted to the data. Associations between malaria (peripheral infection prior to and at ultrasound examination, and any gestational infection, i.e., ‘exposure’) and abnormal flow, and between abnormal flow and birth outcomes, were estimated. Results Of 78 malaria infection episodes detected before or at the ultrasound visit, 62 (79.5%) were Plasmodium falciparum (34 sub-microscopic infections), and 16 were Plasmodium vivax . Plasmodium falciparum infection before or at Doppler measurement was associated with increased UA resistance (adjusted odds ratio (aOR) 2.3 95% CI 1.0–5.2, P  = 0.047). When assessed by ‘exposure’, P. falciparum infection was significantly associated with increased UA resistance (all infections: 2.4, 1.1–4.9, P  = 0.024; sub-microscopic infections 2.6, 1.0–6.6, P  = 0.051) and a reduced MCA pulsatility index (all infections: 2.6, 1.2–5.3, P  = 0.012; sub-microscopic infections: 2.8, 1.1–7.5, P  = 0.035). Sub-microscopic P. falciparum infections were additionally associated with a reduced cerebroplacental ratio (3.64, 1.22–10.88, P  = 0.021). There were too few P. vivax infections to draw robust conclusions. An increased UA resistance index was associated with histological evidence of placental malaria (5.1, 2.3–10.9, P  < 0.001; sensitivity 0.26, specificity 0.93). A low cerebroplacental Doppler ratio was associated with concurrently measuring small-for-gestational-age, and with low birth weight. Discussion/conclusion Both microscopic and sub-microscopic P. falciparum infections impair fetoplacental and intrafetal flow, at least temporarily. Increased UA resistance has high specificity but low sensitivity for the detection of placental infection. These findings suggest that interventions to protect the fetus should clear and prevent both microscopic and sub-microscopic malarial infections. Trial Registration ClinicalTrials.gov NCT01136850. Registered 06 April 2010

Background Regular anti-malarial therapy in pregnancy, a pillar of malaria control, may affect malaria immunity, with therapeutic implications in regions of reducing transmission. Methods Plasma antibodies to leading vaccine candidate merozoite antigens and opsonizing antibodies to endothelial-binding and placental-binding infected erythrocytes were quantified in pregnant Melanesian women receiving sulfadoxine-pyrimethamine (SP) with chloroquine taken once, or three courses of SP with azithromycin. Results Malaria prevalence was low. Between enrolment and delivery, antibodies to recombinant antigens declined in both groups ( p  < 0.0001). In contrast, median levels of opsonizing antibodies did not change, although levels for some individuals changed significantly. In multivariate analysis, the malaria prevention regimen did not influence antibody levels. Conclusion Different preventive anti-malarial chemotherapy regimens used during pregnancy had limited impact on malarial-immunity in a low-transmission region of Papua New Guinea. Trial registrations NCT01136850

P. vivax infection during pregnancy has been associated with poor outcomes such as anemia, low birth weight and congenital malaria, thus representing an important global health problem. However, no vaccine is currently available for its prevention. Vir genes were the first putative virulent factors associated with P. vivax infections, yet very few studies have examined their potential role as targets of immunity. We investigated the immunogenic properties of five VIR proteins and two long synthetic peptides containing conserved VIR sequences (PvLP1 and PvLP2) in the context of the PregVax cohort study including women from five malaria endemic countries: Brazil, Colombia, Guatemala, India and Papua New Guinea (PNG) at different timepoints during and after pregnancy. Antibody responses against all antigens were detected in all populations, with PNG women presenting the highest levels overall. P. vivax infection at sample collection time was positively associated with antibody levels against PvLP1 (fold-increase: 1.60 at recruitment -first antenatal visit-) and PvLP2 (fold-increase: 1.63 at delivery), and P. falciparum co-infection was found to increase those responses (for PvLP1 at recruitment, fold-increase: 2.25). Levels of IgG against two VIR proteins at delivery were associated with higher birth weight (27 g increase per duplicating antibody levels, p<0.05). Peripheral blood mononuclear cells from PNG uninfected pregnant women had significantly higher antigen-specific IFN-γ TH1 responses (p=0.006) and secreted less pro-inflammatory cytokines TNF and IL-6 after PvLP2 stimulation than P. vivax-infected women (p<0.05). These data demonstrate that VIR antigens induce the natural acquisition of antibody and T cell memory responses that might be important in immunity to P. vivax during pregnancy in very diverse geographical settings.

Background Fetal growth restriction (FGR) is associated with increased infant mortality rates and ill-health in adulthood. Evaluation of fetal growth requires ultrasound. As a result, ultrasound-assisted evaluations of causes of FGR in malaria-endemic developing countries are rare. We aimed to determine factors associated with indicators of abnormal fetal growth in rural lowland Papua New Guinea (PNG). Methods Weights and growth of 671 ultrasound-dated singleton pregnancies (<25 gestational weeks) were prospectively monitored using estimated fetal weights and birthweights. Maternal nutritional status and haemoglobin levels were assessed at enrolment, and participants were screened for malaria on several occasions. FGR was suspected upon detection of an estimated fetal weight or birthweight <10 th centile (small-for-gestational age) and/or low fetal weight gain, defined as a change in weight z-score in the first quartile. Factors associated with fetal weight and fetal weight gain were additionally assessed by evaluating differences in weight z-scores and change in weight z-scores. Log-binomial and linear mixed effect models were used to determine factors associated with indicators of FGR. Results SGA and low weight gain were detected in 48.3% and 37.0% of pregnancies, respectively. Of participants, 13.8%, 21.2%, and 22.8% had a low mid-upper arm circumference (MUAC, <22 cms), short stature (<150 cms) and anaemia (haemoglobin <90 g/L) at first antenatal visit. 24.0% (161/671) of women had at least one malaria infection detected in peripheral blood. A low MUAC (adjusted risk ratio [aRR] 1.51, 95% CI 1.29, 1.76, P  < 0.001), short stature (aRR 1.27, 95% CI 1.04, 1.55, P  = 0.009), and anaemia (aRR 1.27, 95% CI 1.06, 1.51, P  = 0.009) were associated with SGA, and a low body mass index was associated with low fetal weight gain (aRR 2.10, 95% CI 1.62, 2.71, P  < 0.001). Additionally, recent receipt of intermittent preventive treatment in pregnancy was associated with increased weight z-scores, and anaemia with reduced change in weight z-scores. Malaria infection was associated with SGA on crude but not adjusted analyses (aRR 1.13, 95% CI 0.95, 1.34, P  = 0.172). Conclusion Macronutrient undernutrition and anaemia increased the risk of FGR. Antenatal nutritional interventions and malaria prevention could improve fetal growth in PNG.