Assessing the Role of Echocardiography in Pregnancy in First Nations Australian Women: Is It an Underutilised Resource?

BACKGROUND: Rheumatic heart disease (RHD) remains prevalent within First Nations Australian communities. RHD is more common in females and peak prevalence corresponds with childbearing age. Significant valvular disease can complicate pregnancy. Current practice in Northern Australia is to refer pregnant women for echocardiography if there are signs or symptoms of possible cardiac pathology or a history of acute rheumatic fever (ARF) or RHD. It is not currently routine practice to offer echocardiographic screening for all pregnant women at high risk of RHD. AIM: This study aimed to assess the current referral practices for echocardiography and disease patterns in pregnant women in the Northern Territory, Australia-a region with a known high prevalence of RHD in the First Nations population. METHOD: A retrospective analysis of all echocardiography referrals of pregnant women over a 4-year period was performed. Data included indication for echocardiography, clinical history, echocardiographic findings, and location of delivery. Comparisons were made using Fisher's exact and Mann-Whitney U tests. RESULTS: A total of 322 women underwent echocardiography during pregnancy: 195 First Nations and 127 non-Indigenous women (median age, 25 vs 30 years, respectively; p<0.01). Indications for echocardiography differed by ethnicity, with history of ARF or RHD being the most common indication in First Nations women, and incidental murmur the most common in non-Indigenous women. First Nations women were more likely to have abnormal echocardiograms (35.9% vs 11.0% in non-Indigenous women; p<0.01) or a history of ARF or RHD (39.4% vs 0.8%; p<0.01), but less likely to have documented cardiac symptoms as an indication for echocardiography (8.2% vs 20.5%; p<0.01). New cardiac diagnoses were made during pregnancy in 11 (5.6%) First Nations and two (1.6%) non-Indigenous women (p=0.02). Moderate or severe valve lesions were detected in 26 (13.3%) First Nations women (all previously diagnosed), and 11 (5.6%) had previous cardiac surgery. No severe valve lesions were identified in the non-Indigenous group. Interstate transfer to a tertiary centre with valve intervention services was required during pregnancy or the puerperium for 12 (6.2%) First Nations women and no non-Indigenous women. CONCLUSIONS: Amongst pregnant women in the Northern Territory who had an indication for echocardiography, First Nations women were more likely to have abnormal echocardiograms. This was mainly due to valvular disease secondary to RHD. Cardiac symptoms were infrequently recorded as an indication for echocardiography in First Nations women, suggesting possible underappreciation of symptoms. Having a low threshold for echocardiographic investigation, including consideration of universal screening during pregnancy, is important in a high RHD-burden setting such as ours. A better understanding of the true prevalence and spectrum of disease severity in this population would enable health services to invest in appropriate resources.

Pregnancy and malaria: the perfect storm.

PURPOSE OF REVIEW: Malaria in pregnancy continues to exert a toll on pregnant women and their offspring. RECENT FINDINGS: The burden of Plasmodium falciparum infection is especially large in Africa, and new data show lasting effects of maternal infection on the infant's neurocognitive development. Elsewhere, P. vivax infection causes relapsing infections that are challenging to prevent. Infection in first trimester of pregnancy is an area of increasing focus, and its adverse effects on pregnancy outcome are increasingly recognised. First-trimester infection is common and frequently acquired prior to conception. Although newer rapid diagnostic tests still have limited sensitivity, they may be useful in detection of early pregnancy malaria for treatment. Artemisinin-based combination therapies are efficacious in later pregnancy but have yet to be recommended in first trimester because of limited safety data. In Africa, intermittent preventive treatment in pregnancy (IPTp) with monthly sulfadoxine-pyrimethamine improves pregnancy outcomes, but sulfadoxine-pyrimethamine resistance is worsening. The alternative, IPTp with dihydroartemisinin-piperaquine, has greater antimalarial efficacy, but does not appear to improve pregnancy outcomes, because sulfadoxine-pyrimethamine has poorly understood nonmalarial benefits on birthweight. SUMMARY: Novel IPTp regimens must be combined with interventions to strengthen protection from malaria infection acquired before and in early pregnancy.

Associations of maternal iron deficiency with malaria infection in a cohort of pregnant Papua New Guinean women.

BACKGROUND: Iron deficiency (ID) is common in malaria-endemic settings. Intermittent preventative treatment of malaria in pregnancy (IPTp) and iron supplementation are core components of antenatal care in endemic regions to prevent adverse pregnancy outcomes. ID has been associated with reduced risk of malaria infection, and correspondingly, iron supplementation with increased risk of malaria infection, in some studies. METHODS: A secondary analysis was conducted amongst 1888 pregnant women enrolled in a malaria prevention trial in Papua New Guinea. Maternal ID was defined as inflammation-corrected plasma ferritin levels < 15 µg/L at antenatal enrolment. Malaria burden (Plasmodium falciparum, Plasmodium vivax) was determined by light microscopy, polymerase chain reaction, and placental histology. Multiple logistic and linear regression analyses explored the relationship of ID or ferritin levels with indicators of malaria infection. Models were fitted with interaction terms to assess for modification of iron-malaria relationships by gravidity or treatment arm. RESULTS: Two-thirds (n = 1226) and 13.7% (n = 258) of women had ID and peripheral parasitaemia, respectively, at antenatal enrolment (median gestational age: 22 weeks), and 18.7% (120/1,356) had evidence of malaria infection on placental histology. Overall, ID was associated with reduced odds of peripheral parasitaemia at enrolment (adjusted odds ratio [aOR] 0.50; 95% confidence interval [95% CI] 0.38, 0.66, P < 0.001); peripheral parasitaemia at delivery (aOR 0.68, 95% CI 0.46, 1.00; P = 0.050); and past placental infection (aOR 0.35, 95% CI 0.24, 0.50; P < 0.001). Corresponding increases in the odds of infection were observed with two-fold increases in ferritin levels. There was effect modification of iron-malaria relationships by gravidity. At delivery, ID was associated with reduced odds of peripheral parasitaemia amongst primigravid (AOR 0.44, 95% CI 0.25, 0.76; P = 0.003), but not multigravid women (AOR 1.12, 95% CI 0.61, 2.05; P = 0.720). A two-fold increase in ferritin associated with increased odds of placental blood infection (1.44, 95% CI 1.06, 1.96; P = 0.019) and active placental infection on histology amongst primigravid women only (1.24, 95% CI 1.00, 1.54; P = 0.052). CONCLUSIONS: Low maternal ferritin at first antenatal visit was associated with a lower risk of malaria infection during pregnancy, most notably in primigravid women. The mechanisms by which maternal iron stores influence susceptibility to infection with Plasmodium species require further investigation.

The relationship between markers of antenatal iron stores and birth outcomes differs by malaria prevention regimen-a prospective cohort study.

BACKGROUND: Iron deficiency (ID) has been associated with adverse pregnancy outcomes, maternal anaemia, and altered susceptibility to infection. In Papua New Guinea (PNG), monthly treatment with sulphadoxine-pyrimethamine plus azithromycin (SPAZ) prevented low birthweight (LBW; <2500 g) through a combination of anti-malarial and non-malarial effects when compared to a single treatment with SP plus chloroquine (SPCQ) at first antenatal visit. We assessed the relationship between ID and adverse birth outcomes in women receiving SPAZ or SPCQ, and the mediating effects of malaria infection and haemoglobin levels during pregnancy. METHODS: Plasma ferritin levels measured at antenatal enrolment in a cohort of 1892 women were adjusted for concomitant inflammation using C-reactive protein and α-1-acid glycoprotein. Associations of ID (defined as ferritin <15 µg/L) or ferritin levels with birth outcomes (birthweight, LBW, preterm birth, small-for-gestational-age birthweight [SGA]) were determined using linear or logistic regression analysis, as appropriate. Mediation analysis assessed the degree of mediation of ID-birth outcome relationships by malaria infection or haemoglobin levels. RESULTS: At first antenatal visit (median gestational age, 22 weeks), 1256 women (66.4%) had ID. Overall, ID or ferritin levels at first antenatal visit were not associated with birth outcomes. There was effect modification by treatment arm. Amongst SPCQ recipients, ID was associated with a 81-g higher mean birthweight (95% confidence interval [CI] 10, 152; P = 0.025), and a twofold increase in ferritin levels was associated with increased odds of SGA (adjusted odds ratio [aOR] 1.25; 95% CI 1.06, 1.46; P = 0.007). By contrast, amongst SPAZ recipients, a twofold increase in ferritin was associated with reduced odds of LBW (aOR 0.80; 95% CI 0.67, 0.94; P = 0.009). Mediation analyses suggested that malaria infection or haemoglobin levels during pregnancy do not substantially mediate the association of ID with birth outcomes amongst SPCQ recipients. CONCLUSIONS: Improved antenatal iron stores do not confer a benefit for the prevention of adverse birth outcomes in the context of malaria chemoprevention strategies that lack the non-malarial properties of monthly SPAZ. Research to determine the mechanisms by which ID protects from suboptimal foetal growth is needed to guide the design of new malaria prevention strategies and to inform iron supplementation policy in malaria-endemic settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT01136850 .

Blood cytokine, chemokine and growth factor profiling in a cohort of pregnant women from tropical countries.

The immune status of women changes during and after pregnancy, differs between blood compartments at delivery and is affected by environmental factors particularly in tropical areas endemic for multiple infections. We quantified the plasma concentration of a set of thirty-one TH1, TH2, TH17 and regulatory cytokines, pro-inflammatory and anti-inflammatory cytokines and chemokines, and growth factors (altogether biomarkers), in a cohort of 540 pregnant women from five malaria-endemic tropical countries. Samples were collected at recruitment (first antenatal visit), delivery (periphery, cord and placenta) and postpartum, allowing a longitudinal analysis. We found the lowest concentration of biomarkers at recruitment and the highest at postpartum, with few exceptions. Among them, IL-6, HGF and TGF-ß had the highest levels at delivery, and even higher concentrations in the placenta compared to peripheral blood. Placental concentrations were generally higher than peripheral, except for eotaxin that was lower. We also compared plasma biomarker concentrations between the tropical cohort and a control group from Spain at delivery, presenting overall higher biomarker levels the tropical cohort, particularly pro-inflammatory cytokines and growth factors. Only IL-6 presented lower levels in the tropical group. Moreover, a principal component analysis of biomarker concentrations at delivery showed that women from Spain grouped more homogenously, and that IL-6 and IL-8 clustered together in the tropical cohort but not in the Spanish one. Plasma cytokine concentrations correlated with Plasmodium antibody levels at postpartum but not during pregnancy. This basal profiling of immune mediators over gestation and in different compartments at delivery is important to subsequently understand response to infections and clinical outcomes in mothers and infants in tropical areas.

Microscopic and submicroscopic Plasmodium falciparum infection, maternal anaemia and adverse pregnancy outcomes in Papua New Guinea: a cohort study.

BACKGROUND: Infection during pregnancy with Plasmodium falciparum is associated with maternal anaemia and adverse birth outcomes including low birth weight (LBW). Studies using polymerase chain reaction (PCR) techniques indicate that at least half of all infections in maternal venous blood are missed by light microscopy or rapid diagnostic tests. The impact of these subpatent infections on maternal and birth outcomes remains unclear. METHODS: In a cohort of women co-enrolled in a clinical trial of intermittent treatment with sulfadoxine-pyrimethamine (SP) plus azithromycin for the prevention of LBW (< 2500 g) in Papua New Guinea (PNG), P. falciparum infection status at antenatal enrolment and delivery was assessed by routine light microscopy and real-time quantitative PCR. The impact of infection status at enrolment and delivery on adverse birth outcomes and maternal haemoglobin at delivery was assessed using logistic and linear regression models adjusting for potential confounders. Together with insecticide-treated bed nets, women had received up to 3 monthly intermittent preventive treatments with SP plus azithromycin or a single clearance treatment with SP plus chloroquine. RESULTS: A total of 9.8% (214/2190) of women had P. falciparum (mono-infection or mixed infection with Plasmodium vivax) detected in venous blood at antenatal enrolment at 14-26 weeks' gestation. 4.7% of women had microscopic, and 5.1% submicroscopic P. falciparum infection. At delivery (n = 1936), 1.5% and 2.0% of women had submicroscopic and microscopic P. falciparum detected in peripheral blood, respectively. Submicroscopic P. falciparum infections at enrolment or at delivery in peripheral or placental blood were not associated with maternal anaemia or adverse birth outcomes such as LBW. Microscopic P. falciparum infection at antenatal enrolment was associated with anaemia at delivery (adjusted odds ratio [aOR] 2.00, 95% confidence interval [CI] 1.09, 3.67; P = 0.025). Peripheral microscopic P. falciparum infection at delivery was associated with LBW (aOR 2.75, 95% CI 1.27; 5.94, P = 0.010) and preterm birth (aOR 6.58, 95% CI 2.46, 17.62; P < 0.001). CONCLUSIONS: A substantial proportion of P. falciparum infections in pregnant women in PNG were submicroscopic. Microscopic, but not submicroscopic, infections were associated with adverse outcomes in women receiving malaria preventive treatment and insecticide-treated bed nets. Current malaria prevention policies that combine insecticide-treated bed nets, intermittent preventive treatment and prompt treatment of symptomatic infections appear to be appropriate for the management of malaria in pregnancy in settings like PNG.

Strategies to reduce and maintain low perinatal mortality in resource-poor settings - Findings from a four-decade observational study of birth records from a large public maternity hospital in Papua New Guinea.

BACKGROUND: In many low- to middle-income countries (LMIC) assisted vaginal birth rates have fallen, while caesarean section (CS) rates have increased, with potentially deleterious consequences for maternal and perinatal mortality. AIMS: To review birth mode and perinatal mortality in a large LMIC hospital with strict labour management protocols and expertise in vacuum extraction. MATERIALS AND METHODS: We conducted a retrospective observational study at Port Moresby General Hospital in Papua New Guinea. Birth registers from 1977 to 2015 (39 years) were reviewed. Overall and modified (fresh stillbirths and early neonatal deaths ≥500 g) perinatal mortality rates (PMRs) were calculated by birthweight/birth mode. RESULTS: There were 365 056 births (5215 in 1977; 14 927 in 2015), of which 14 179 (3.9%) were vacuum extractions, 609 (0.2%) forceps births and 14 747 (4.4%) CS (increase from 2% to 5%). The failure rate of vacuum extraction was 2.5% (range 0.5-5.4%). Symphysiotomy was employed for 184 births. From 1989 to 2015, the modified mean PMR for babies ≥2500 g was 8.1/1000 births (range 5.6-12.1; 6.9 in 2015), 9.1/1000 for babies ≥1500 g (7.3-14.8; 9.1 in 2015) and 7.5/1000 (0-21.7; 9.0 in 2015) for vacuum extractions (98% were ≥2500 g). The overall PMR for these years was 29.7/1000 births. CONCLUSIONS: In an LMIC with rapidly increasing birth numbers a comparatively low PMR can be achieved while maintaining low CS rates. This may be in part accomplished through strict use of second-stage protocols, perinatal audit, and supportive training that promotes judicious and proficient use of vacuum extraction and CS.

Intermittent Preventive Therapy in Pregnancy and Incidence of Low Birth Weight in Malaria-Endemic Countries.

OBJECTIVES: To estimate the impact of hypothetical antimalarial and nutritional interventions (which reduce the prevalence of low midupper arm circumference [MUAC]) on the incidence of low birth weight (LBW). METHODS: We analyzed data from 14 633 pregnancies from 13 studies conducted across Africa and the Western Pacific from 1996 to 2015. We calculated population intervention effects for increasing intermittent preventive therapy in pregnancy (IPTp), full coverage with bed nets, reduction in malaria infection at delivery, and reductions in the prevalence of low MUAC. RESULTS: We estimated that, compared with observed IPTp use, administering 3 or more doses of IPTp to all women would decrease the incidence of LBW from 9.9% to 6.9% (risk difference = 3.0%; 95% confidence interval = 1.7%, 4.0%). The intervention effects for eliminating malaria at delivery, increasing bed net ownership, and decreasing low MUAC prevalence were all modest. CONCLUSIONS: Increasing IPTp uptake to at least 3 doses could decrease the incidence of LBW in malaria-endemic countries. The impact of IPTp on LBW was greater than the effect of prevention of malaria, consistent with a nonmalarial effect of IPTp, measurement error, or selection bias.

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.

Awareness, attitudes and perceptions regarding HIV and PMTCT amongst pregnant women in Guinea-Bissau- a qualitative study.

BACKGROUND: The human immunodeficiency virus (HIV) continues to be a major cause of maternal and infant mortality and morbidity in sub-Saharan Africa. Prevention of mother-to-child transmission of HIV (PMTCT) strategies have proven effective in decreasing the number of children infected in utero, intrapartum and during the breastfeeding period. This qualitative study explores knowledge and perceptions of HIV amongst pregnant women, healthcare workers' experiences of the national PMTCT services, and barriers to PMTCT, during a period of programme scale-up in urban Guinea-Bissau (2010-11). METHODS: In-depth interviews were undertaken amongst 27 women and 19 key informants at local antenatal clinics and the national maternity ward in Bissau, Guinea-Bissau. RESULTS: Amongst women who had been tested for HIV, awareness and knowledge of HIV and PMTCT remained low. Testing without informed consent was reported in some cases, in particular when the test was performed around the time of delivery. Possible drivers of inadequate counselling included lack of confidentiality, suboptimal healthcare worker training, lack of time, and perceived occupational risk. Demand-side barriers to PMTCT included lack of HIV and PMTCT knowledge, customary and cultural beliefs associated with HIV and ill-health, HIV stigma and discrimination, and fear of partnership dissolution. CONCLUSIONS: Socio-cultural and operational challenges, including HIV testing without informed consent, present significant barriers to the scale-up of PMTCT services in Bissau. Strengthening local capacity for effective counselling and testing in the antenatal setting is paramount. Further research into local customary beliefs relating to HIV is warranted.

Impact of Placental Malaria and Hypergammaglobulinemia on Transplacental Transfer of Respiratory Syncytial Virus Antibody in Papua New Guinea.

BACKGROUND: Passively acquired respiratory syncytial virus (RSV) neutralizing antibody protects against RSV-associated lower respiratory infections, but placental malaria (PM) and maternal hypergammaglobulinemia might interfere with transplacental immunoglobulin transport. METHODS: We measured RSV plaque-reduction neutralization (PRN) antibody in 300 full-term maternal/cord serum pairs in 2 cohorts in malaria-endemic Papua New Guinea: Alexishafen (2005-2008) and the Fetal Immunity Study (FIS) (2011-2013). We defined impaired transport as a cord-to-maternal titer ratio <1.0 and a protective RSV PRN titer (PRNT) ≥1:200. RESULTS: PM and hypergammaglobulinemia occurred in 60% and 54% of Alexishafen mothers versus 8% and 9% of FIS mothers, respectively. 34% of Alexishafen and 32% of FIS pairs demonstrated impaired transport. Multivariate modeling revealed significant associations between increasing maternal IgG (log2) and impaired transport (adjusted OR, Alexishafen: 2.68 [1.17-6.14], FIS: 6.94 [1.94-24.8]) but no association with PM. 34% of Alexishafen and 31% of FIS cord PRNTs were <1:200. CONCLUSIONS: Impaired RSV antibody transport was observed in approximately one-third of maternal/cord pairs. Hypergammaglobulinemia, but not PM, was associated with impaired transport, particularly among women with low RSV PRNT. Detection of RSV PRNT <1:200 in one-third of cord sera confirms the need to increase levels of RSV neutralizing antibody in pregnant women through maternal immunization.

Undernutrition and malaria in pregnancy - a dangerous dyad?

BACKGROUND: In low-resource settings, malaria and macronutrient undernutrition are major health problems in pregnancy, contributing significantly to adverse pregnancy outcomes such as preterm birth and fetal growth restriction. Affected pregnancies may result in stillbirth and neonatal death, and surviving children are at risk of poor growth and infection in infancy, and of non-communicable diseases in adulthood. Populations exposed to macronutrient undernutrition frequently reside in malaria-endemic areas, and seasonal peaks of low food supply and malaria transmission tend to coincide. Despite these geographic and temporal overlaps, integrated approaches to these twin challenges are infrequent. DISCUSSION: This opinion article examines the current evidence for malaria-macronutrition interactions and discusses possible mechanisms whereby macronutrient undernutrition and malaria may interact to worsen pregnancy outcomes. Macronutrient undernutrition dysregulates the immune response. In pregnant women, undernutrition may worsen the already increased susceptibility to malarial infection and could impair development of protective immunity to malaria, and is likely to exacerbate the impact of placental malaria on fetal growth. Malarial infection, in turn, can drive nutritional depletion; poor gestational weight gain and weight loss in pregnancy increases the risk of adverse pregnancy outcomes. Despite a commendable number of studies and trials that, in isolation, attempt to address the challenges of malaria and undernutrition in pregnancy, few dare to venture beyond the 'single disease - single solution' paradigm. We believe that this may be a lost opportunity: researching malaria-nutrition interactions, and designing and implementing integrated interventions to prevent and treat these commonly co-existing and intertwining conditions, may markedly reduce the high burden of preterm birth and fetal growth restriction in affected areas. CONCLUSION: We call for more collaboration between researchers studying malaria and nutrition in pregnancy, and propose a research agenda to address this important twin health problem.

Azithromycin-containing intermittent preventive treatment in pregnancy affects gestational weight gain, an important predictor of birthweight in Papua New Guinea - an exploratory analysis.

In Papua New Guinea, intermittent preventive treatment with sulphadoxine-pyrimethamine and azithromycin (SPAZ-IPTp) increased birthweight despite limited impact on malaria and sexually transmitted infections. To explore possible nutrition-related mechanisms, we evaluated associations between gestational weight gain (GWG), enrolment body mass index (BMI) and mid-upper arm circumference (MUAC), and birthweight. We investigated whether the increase in birthweight associated with SPAZ-IPTp may partly be driven by a treatment effect on GWG. The mean GWG rate was 393 g/week (SD 250; n = 948). A 100 g/week increase in GWG was associated with a 14 g (95% CI 2.6, 25.4) increase in birthweight (P = 0.016). Enrolment BMI and MUAC also positively correlated with birthweight. SPAZ-IPTp was associated with increased GWG [58 g/week (26, 900), P < 0.001, n = 948] and with increased birthweight [48 g, 95% CI (8, 880), P = 0.019] when all eligible women were considered (n = 1947). Inclusion of GWG reduced the birthweight coefficient associated with SPAZ-IPTp by 18% from 44 to 36 g (n = 948), although SPAZ-IPTp was not significantly associated with birthweight among women for whom GWG data were available (P = 0.13, n = 948). One month post-partum, fewer women who had received SPAZ-IPTp had a low post-partum BMI (<18.5 kg m(-2) ) [adjusted risk ratio: 0.55 (95% CI 0.36, 0.82), P = 0.004] and their babies had a reduced risk of wasting [risk ratio 0.39 (95% CI 0.21, 0.72), P = 0.003]. SPAZ-IPTp increased GWG, which could explain its impact on birthweight and maternal post-partum BMI. Future trials of SPAZ-IPTp must incorporate detailed anthropometric evaluations to investigate mechanisms of effects on maternal and child health.

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).

Impact of intermittent preventive treatment in pregnancy with azithromycin-containing regimens on maternal nasopharyngeal carriage and antibiotic sensitivity of Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus: a cross-sectional survey at delivery.

Sulfadoxine-pyrimethamine (SP) plus azithromycin (AZ) (SPAZ) has the potential for intermittent preventive treatment of malaria in pregnancy (IPTp), but its use could increase circulation of antibiotic-resistant bacteria associated with severe pediatric infections. We evaluated the effect of monthly SPAZ-IPTp compared to a single course of SP plus chloroquine (SPCQ) on maternal nasopharyngeal carriage and antibiotic susceptibility of Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus at delivery among 854 women participating in a randomized controlled trial in Papua New Guinea. Serotyping was performed, and antibiotic susceptibility was evaluated by disk diffusion and Etest. Potential risk factors for carriage were examined. Nasopharyngeal carriage at delivery of S. pneumoniae (SPAZ, 7.2% [30/418], versus SPCQ, 19.3% [84/436]; P<0.001) and H. influenzae (2.9% [12/418] versus 6.0% [26/436], P=0.028), but not S. aureus, was significantly reduced among women who had received SPAZ-IPTp. The number of macrolide-resistant pneumococcal isolates was small but increased in the SPAZ group (13.3% [4/30], versus SPCQ, 2.2% [2/91]; P=0.033). The proportions of isolates with serotypes covered by the 13-valent pneumococcal conjugate vaccine were similar (SPAZ, 10.3% [3/29], versus SPCQ, 17.6% [16/91]; P=0.352). Although macrolide-resistant isolates were rare, they were more commonly detected in women who had received SPAZ-IPTp, despite the significant reduction of maternal carriage of S. pneumoniae and H. influenzae observed in this group. Future studies on SPAZ-IPTp should evaluate carriage and persistence of macrolide-resistant S. pneumoniae and other pathogenic bacteria in both mothers and infants and assess the clinical significance of their circulation.

Malaria preventive therapy in pregnancy and its potential impact on immunity to malaria in an area of declining transmission.

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.

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.

Determining effects of areca (betel) nut chewing in a prospective cohort of pregnant women in Madang Province, Papua New Guinea.

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).

The impact of tubal ectopic pregnancy in Papua New Guinea--a retrospective case review.

BACKGROUND: Ectopic pregnancy (EP) is an important cause of morbidity and mortality amongst women of reproductive age. Tubal EP is well described in industrialised countries, but less is known about its impact in low-resource countries, in particular in the South Pacific Region. METHODS: We undertook a retrospective review of women with tubal EP treated at a provincial referral hospital in coastal Papua New Guinea over a period of 56 months. Demographic and clinical variables were obtained from patients' medical records and analysed. The institutional rate of tubal EP was calculated, and diagnosis and management reviewed. Potential risk factors for tubal EP were identified, and delays contributing to increased morbidity described. RESULTS: A total of 73 women had tubal EP. The institutional rate of tubal EP over the study period was 6.3 per 1,000 deliveries. There were no maternal deaths due to EP. The mean age of women was 31.5+/-5.7 years, 85% were parous, 67% were rural dwellers and 62% had a history of sub-fertility. The most commonly used diagnostic aid was culdocentesis. One third of women had clinical evidence of shock on arrival. All women with tubal EP were managed by open salpingectomy. Tubal rupture was confirmed for 48% of patients and was more common amongst rural dwellers. Forty-three percent of women had macroscopic evidence of pelvic infection. Two-thirds of patients received blood transfusions, and post-operative recovery lasted six days on average. Late presentation, lack of clinical suspicion, and delays with receiving appropriate treatments were observed. CONCLUSIONS: Tubal EP is a common gynaecological emergency in a referral hospital in coastal PNG, and causes significant morbidity, in particular amongst women residing in rural areas. Sexually transmitted infections are likely to represent the most important risk factor for tubal EP in PNG. Interventions to reduce the morbidity due to tubal EP include the prevention, detection and treatment of sexually transmitted infections, identification and reduction of barriers to prompt presentation, increasing health workers' awareness of ectopic pregnancy, providing pregnancy test kits to rural health centres, and strengthening hospital blood transfusion services, including facilities for autotransfusion.

A case of ultrasound-guided prenatal diagnosis of prune belly syndrome in Papua New Guinea--implications for management.

BACKGROUND: Prune belly syndrome is a rare congenital malformation of unknown aetiology and is characterised by abnormalities of the urinary tract, a deficiency of abdominal musculature and bilateral cryptorchidism in males. We report a case of prune belly syndrome from Papua New Guinea, which was suspected on pregnancy ultrasound scan and confirmed upon delivery. CASE PRESENTATION: A 26-year-old married woman, Gravida 3 Para 2, presented to antenatal clinic in Madang, Papua New Guinea, at 21(+5) weeks' gestation by dates. She was well with no past medical or family history of note. She gave consent to participate in a clinical trial on prevention of malaria in pregnancy and underwent repeated ultrasound examinations which revealed a live fetus with persistent megacystis and anhydramnios. Both mother and clinicians agreed on conservative management of the congenital abnormality. The mother spontaneously delivered a male fetus weighing 2010 grams at 34 weeks' gestation with grossly abnormal genitalia including cryptorchidism, penile aplasia and an absent urethral meatus, absent abdominal muscles and hypoplastic lungs. The infant passed away two hours after delivery. This report discusses the implications of prenatal detection of severe congenital abnormalities in PNG. CONCLUSION: This first, formally reported, case of prune belly syndrome from a resource-limited setting in the Oceania region highlights the importance of identifying and documenting congenital abnormalities. Women undergoing antenatal ultrasound examinations must be carefully counseled on the purpose and the limitations of the scan. The increasing use of obstetric ultrasound in PNG will inevitably result in a rise in prenatal detection of congenital abnormalities. This will need to be met with adequate training, referral mechanisms and better knowledge of women's attitudes and beliefs on birth defects and ultrasound. National medicolegal guidance regarding induced abortion and resuscitation of a fetus with severe congenital abnormalities may be required.