A Bioplex Analysis of Cytokines and Chemokines in First Trimester Maternal Plasma to Screen for Predictors of Miscarriage

Background

We have previously shown in two independent cohorts that circulating first trimester Macrophage Inhibitory Cytokine-1 (MIC-1) levels are lower in women in early pregnancy who are destined to miscarriage. While promising, the diagnostic performance of measuring MIC-1 alone was not sufficient for it to be a useful predictive test for miscarriage. Besides MIC-1, there are other cytokines, as well as chemokines, involved in facilitating early pregnancy. We reasoned that screening these factors in maternal plasma could uncover other predictive markers of miscarriage.

Methods

This was a nested case control study, of 78 women from a prospective study of 462 attending the Early Pregnancy Assessment Unit in the first trimester (EPAU) with a threatened miscarriage; 34 of these subsequently miscarried (cases) and 44 went on to have a normal delivery (controls) Cytokines IL-1β, IL-6 and IL-10, and the chemokines, CXCL8, CCL2, CCL5, CCL7 and CX3CL1 were measured in plasma from our cohort.

Results

The cytokines IL-1β, IL-6, IL-10 and the chemokine CXCL8 were not detectable in first trimester plasma. The chemokines CCL2, CCL5, CCL7 and CX3CL1 were detectable in all samples but levels did not vary across 5–12 weeks of gestation among controls. Plasma levels of these chemokines were no different in the miscarriage cohort compared to controls.

Conclusion

The chemokines CCL2, CCL5, CCL7 and CX3CL1 were detectable in plasma during the first trimester while IL-1β, IL-6, IL-10 and CXCL8 were not. However, none of the cytokines and chemokines screened were different in maternal plasma in cases or controls. These therefore do not appear to have potential for application as predictive biomarkers of miscarriage.     

Using Plasma Viral Load to Guide Antiretroviral Therapy Initiation to Prevent HIV-1 Transmission

Background

Current WHO guidelines recommend antiretroviral therapy (ART) initiation at CD4 counts ≤350 cells/µL. Increasing this threshold has been proposed, with a primary goal of reducing HIV-1 infectiousness. Because the quantity of HIV-1 in plasma is the primary predictor of HIV-1 transmission, consideration of plasma viral load in ART initiation guidelines is warranted.

Methods

Using per-sex-act infectivity estimates and cross-sectional sexual behavior data from 2,484 HIV-1 infected persons with CD4 counts >350 enrolled in a study of African heterosexual HIV-1 serodiscordant couples, we calculated the number of transmissions expected and the number potentially averted under selected scenarios for ART initiation: i) CD4 count <500 cells/µL, ii) viral load ≥10,000 or ≥50,000 copies/mL and iii) universal treatment. For each scenario, we estimated the proportion of expected infections that could be averted, the proportion of infected persons initiating treatment, and the ratio of these proportions.

Results

Initiating treatment at viral load ≥50,000 copies/mL would require treating 19.8% of infected persons with CD4 counts >350 while averting 40.5% of expected transmissions (ratio 2.0); treating at viral load ≥10,0000 copies/mL had a ratio of 1.5. In contrast, initiation at CD4 count <500 would require treating 41.8%, while averting 48.4% (ratio 1.1).

Conclusion

Inclusion of viral load in ART initiation guidelines could permit targeting ART resources to HIV-1 infected persons who have a higher risk of transmitting HIV-1. Further work is needed to estimate costs and feasibility.     

Increasing Transfers-Out from an Antiretroviral Treatment Service in South Africa: Patient Characteristics and Rates of Virological Non-Suppression

Objectives

To determine the proportion, characteristics and outcomes of patients who transfer-out from an antiretroviral therapy (ART) service in a South African township.

Methods

This retrospective cohort study included all patients aged ≥15 years who enrolled between September 2002 and December 2009. Follow-up data were censored in December 2010. Kaplan-Meier survival analysis was used to describe time to transfer-out and cox proportional hazard analysis was used to determine associated risk factors.

Results

4511 patients (4003 ART-naïve and 508 non-naïve at baseline) received ART during the study period. Overall, 597 (13.2%) transferred out. The probability of transferring out by one year of ART steadily increased from 1.4% in 2002/2004 cohort to 8.9% for the 2009 cohort. Independent risk factors for transfer-out were more recent calendar year of enrolment, younger age (≤25 years) and being ART non-naïve at baseline (i.e., having previously transferred into this clinic from another facility). The proportions of patients transferred out who had a CD4 cell count <200 cells/µL and/or a viral load ≥1000 copies/mL were 19% and 20%, respectively.

Conclusions

With scale-up of ART over time, an increasing proportion of patients are transferring between ART services and information systems are needed to track patients. Approximately one-fifth of these have viral loads >1000 copies/mL around the time of transfer, suggesting the need for careful adherence counseling and assessment of medication supplies among those planning transfer.     

Semen Abnormalities,Sperm DNA Damage and Global Hypermethylation in Health Workers Occupationally Exposed to Ionizing Radiation

Background

Cytogenetic studies have demonstrated that low levels of chronic radiation exposure can potentially increase the frequency of chromosomal aberrations and aneuploidy in somatic cells. Epidemiological studies have shown that health workers occupationally exposed to ionizing radiation bear an increased risk of hematological malignancies.

Objectives

To find the influence of occupational radiation exposure on semen characteristics, including genetic and epigenetic integrity of spermatozoa in a chronically exposed population.

Methods

This cross sectional study included 134 male volunteers of which 83 were occupationally exposed to ionizing radiation and 51 were non-exposed control subjects. Semen characteristics, sperm DNA fragmentation, aneuploidy and incidence of global hypermethylation in the spermatozoa were determined and compared between the non-exposed and the exposed group.

Results

Direct comparison of the semen characteristics between the non-exposed and the exposed population revealed significant differences in motility characteristics, viability, and morphological abnormalities (P<0.05–0.0001). Although, the level of sperm DNA fragmentation was significantly higher in the exposed group as compared to the non-exposed group (P<0.05–0.0001), the incidence of sperm aneuploidy was not statistically different between the two groups. However, a significant number of hypermethylated spermatozoa were observed in the exposed group in comparison to non-exposed group (P<0.05).

Conclusions

We provide the first evidence on the detrimental effects of occupational radiation exposure on functional, genetic and epigenetic integrity of sperm in health workers. However, further studies are required to confirm the potential detrimental effects of ionizing radiation in these subjects.     

The Impact of Antiretroviral Therapy on Mortality in HIV Positive People during Tuberculosis Treatment: A Systematic Review and Meta-Analysis

Objective

To quantify the impact of antiretroviral therapy (ART) on mortality in HIV-positive people during tuberculosis (TB) treatment.

Design

We conducted a systematic literature review and meta-analysis. Studies published from 1996 through February 15, 2013, were identified by searching electronic resources (Pubmed and Embase) and conference books, manual searches of references, and expert consultation. Pooled estimates for the outcome of interest were acquired using random effects meta-analysis.

Subjects

The study population included individuals receiving ART before or during TB treatment.

Main Outcome Measures

Main outcome measures were: (i) TB-case fatality ratio (CFR), defined as the proportion of individuals dying during TB treatment and, if mortality in HIV-positive people not on ART was also reported, (ii) the relative risk of death during TB treatment by ART status.

Results

Twenty-one studies were included in the systematic review. Random effects pooled meta-analysis estimated the CFR between 8% and 14% (pooled estimate 11%). Among HIV-positive TB cases, those receiving ART had a reduction in mortality during TB treatment of between 44% and 71% (RR = 0.42, 95%CI: 0.29–0.56).

Conclusion

Starting ART before or during TB therapy reduces the risk of death during TB treatment by around three-fifths in clinical settings. National programmes should continue to expand coverage of ART for HIV positive in order to control the dual epidemic.     

Characteristics and Outcomes among Older HIV-Positive Adults Enrolled in HIV Programs in Four Sub-Saharan African Countries

Background

Limited information exists on adults ≥50 years receiving HIV care in sub-Saharan Africa.

Methodology

Using routinely-collected longitudinal patient-level data among 391,111 adults ≥15 years enrolling in HIV care from January 2005–December 2010 and 184,689 initiating ART, we compared characteristics and outcomes between older (≥50 years) and younger adults at 199 clinics in Kenya, Mozambique, Rwanda, and Tanzania. We calculated proportions over time of newly enrolled and active adults receiving HIV care and initiating ART who were ≥50 years; cumulative incidence of loss to follow-up (LTF) and recorded death one year after enrollment and ART initiation, and CD4+ response following ART initiation.

Findings

From 2005–2010, the percentage of adults ≥50 years newly enrolled in HIV care remained stable at 10%, while the percentage of adults ≥50 years newly initiating ART (10% [2005]-12% [2010]), active in follow-up (10% [2005]-14% (2010]), and active on ART (10% [2005]-16% [2010]) significantly increased. One year after enrollment, older patients had significantly lower incidence of LTF (33.1% vs. 32.6%[40–49 years], 40.5%[25–39 years], and 56.3%[15–24 years]; p-value<0.0001), but significantly higher incidence of recorded death (6.0% vs. 5.0% [40–49 years], 4.1% [25–39 years], and 2.8% [15–24 years]; p-valve<0.0001). LTF was lower after vs. before ART initiation for all ages, with older adults experiencing less LTF than younger adults. Among 85,763 ART patients with baseline and follow-up CD4+ counts, adjusted average 12-month CD4+ response for older adults was 20.6 cells/mm³ lower than for adults 25–39 years of age (95% CI: 17.1–24.1).

Conclusions

The proportion of patients who are ≥50 years has increased over time and been driven by aging of the existing patient population. Older patients experienced less LTF, higher recorded mortality and less robust CD4+ response after ART initiation. Increased programmatic attention on older adults receiving HIV care in sub-Saharan Africa is warranted.     

Informatics enhanced SNP microarray analysis of 30 miscarriage samples compared to routine cytogenetics

Purpose

The metaphase karyotype is often used as a diagnostic tool in the setting of early miscarriage; however this technique has several limitations. We evaluate a new technique for karyotyping that uses single nucleotide polymorphism microarrays (SNP). This technique was compared in a blinded, prospective fashion, to the traditional metaphase karyotype.

Methods

Patients undergoing dilation and curettage for first trimester miscarriage between February and August 2010 were enrolled. Samples of chorionic villi were equally divided and sent for microarray testing in parallel with routine cytogenetic testing.

Results

Thirty samples were analyzed, with only four discordant results. Discordant results occurred when the entire genome was duplicated or when a balanced rearrangement was present. Cytogenetic karyotyping took an average of 29 days while microarray-based karytoyping took an average of 12 days.

Conclusions

Molecular karyotyping of POC after missed abortion using SNP microarray analysis allows for the ability to detect maternal cell contamination and provides rapid results with good concordance to standard cytogenetic analysis.     

The Differences in Homocysteine Level between Obstructive Sleep Apnea Patients and Controls: A Meta-Analysis

Background

Studies have reported inconsistent findings regarding the relationship between obstructive sleep apnea (OSA) and homocysteine (HCY) level. This study aimed to assess the difference in plasma HCY level between OSA patients and controls by conducting a meta-analysis of published studies.

Methods

Database of PubMed, SCI, and China National Knowledge Internet (CNKI) were comprehensively searched. Eligible studies regarding plasma HCY level in OSA patients were identified by two independent reviewers. RevMan (version 5.2) and STATA (version 12.0) were employed for data synthesis.

Results

A total of 10 studies involving 432 subjects were included. Meta-analysis showed that plasma HCY levels in OSA group were 3.11 µmol/l higher than that in control group (95% confidence interval: 2.08 to 4.15, P<0.01). Subgroup analysis revealed a more significant differences between OSA patients and controls when average body mass index ≥30 (the total weighted mean difference (WMD) was 3.64), average age<50 (the total WMD was 3.96) and average apnea hypopnea index ≥35 (the total WMD was 4.54).

Conclusions

In this meta-analysis, plasma HCY levels were found to be higher in OSA patients compared to control subjects.     

Outcome of Assisted Reproductive Technology (ART) and Subsequent Self-Reported Life Satisfaction

Objective

To compare life satisfaction between women with successful or unsuccessful outcome after assisted reproductive treatment (ART) by taking into account the time since the last ART.

Design

Cohort study.

Setting

Tertiary hospital.

Patients

A total of 987 consecutive women who had undergone ART during 1996–2007 were invited and altogether 505 women participated in the study.

Interventions

A postal enquiry with a life satisfaction scale.

Main Outcome Measure

Self-reported life satisfaction in respect to the time since the last ART.

Results

In general, women who achieved a live birth after ART had a significantly higher life satisfaction than those who had unsuccessful ART, especially when compared in the first three years. The difference disappeared in the time period of 6–9 years after ART. The unsuccessfully treated women who had a child by some other means before or after the unsuccessful ART had comparable life satisfaction with successfully treated women even earlier.

Conclusions

Even if unsuccessful ART outcome is associated with subsequent lower level of life satisfaction, it does not seem to threaten the long-term wellbeing.     

Metabolomics Profiling for Identification of Novel Potential Markers in Early Prediction of Preeclampsia

Objective

The first aim was to investigate specific signature patterns of metabolites that are significantly altered in first-trimester serum of women who subsequently developed preeclampsia (PE) compared to healthy pregnancies. The second aim of this study was to examine the predictive performance of the selected metabolites for both early onset [EO-PE] and late onset PE [LO-PE].

Methods

This was a case-control study of maternal serum samples collected between 8+0 and 13+6 weeks of gestation from 167 women who subsequently developed EO-PE n = 68; LO-PE n = 99 and 500 controls with uncomplicated pregnancies. Metabolomics profiling analysis was performed using two methods. One has been optimized to target eicosanoids/oxylipins, which are known inflammation markers and the other targets compounds containing a primary or secondary biogenic amine group. Logistic regression analyses were performed to predict the development of PE using metabolites alone and in combination with first trimester mean arterial pressure (MAP) measurements.

Results

Two metabolites were significantly different between EO-PE and controls (taurine and asparagine) and one in case of LO-PE (glycylglycine). Taurine appeared the most discriminative biomarker and in combination with MAP predicted EO-PE with a detection rate (DR) of 55%, at a false-positive rate (FPR) of 10%.

Conclusion

Our findings suggest a potential role of taurine in both PE pathophysiology and first trimester screening for EO-PE.     

The “hypertriglyceridemic waist” phenotype and glucose intolerance in pregnancy

Background

Abdominal visceral adiposity in early pregnancy has been associated with impaired glucose tolerance in later pregnancy. The “hypertriglyceridemic waist” phenotype (i.e., abdominal obesity in combination with hyper-triglyceridemia) is a clinical marker of visceral obesity. Our study aimed to assess the association between the hyper-triglyceridemic-waist phenotype in early pregnancy and glucose intolerance in later pregnancy.

Methods

Plasma triglycerides and waist girth were measured at 11–14 weeks of gestation among 144 white pregnant women. Glycemia was measured following a 75-g oral glucose tolerance test performed at 24–28 weeks of gestation.

Results

A waist girth greater than 85 cm in combination with a triglyceride level ≥ 1.7 mmol/L in the first trimester was associated with an increased risk of two-hour glucose ≥ 7.8 mmol/L following the 75-g oral glucose tolerance test (odds ratio [OR] 6.1, p = 0.002). This risk remained significant even after we controlled for maternal age, fasting glucose at first trimester and previous history of gestational diabetes (OR 4.7, p = 0.02).

Interpretation

Measurement of waist girth in combination with measurement of triglyceride concentrations in the first trimester of pregnancy could improve early screening for gestational glucose intolerance.Early and accessible screening tools for gestational diabetes mellitus are needed to improve pregnancy-related outcomes for women and children.¹ Diagnostic tools currently used for gestational diabetes (most commonly the fasting oral glucose tolerance test) are expensive, time-consuming, uncomfortable for pregnant women and do not allow diagnosis before the end of the second trimester of pregnancy.² Some earlier screening tools have been suggested, such as a 50-g glucose load followed by a one-hour plasma glucose analysis that can be performed at any time of the day and early in pregnancy. Although this test is less uncomfortable than the fasting oral glucose tolerance test, it remains time-consuming and unpleasant for women. Its use is therefore restricted mainly to women at risk for gestational diabetes.Several attempts have been made to simplify these tests to promote wider use. However, no results have yet identified the means to carry out early and widely accessible screening. Interesting positive and negative predictive values have been obtained for first-trimester fasting glucose and insulin for subsequent gestational diabetes expression.^3–5 However, these studies have been performed among women at risk of gestational diabetes and should be replicated in samples of women with various risk levels. Regardless of pregnancy, a person with normal fasting glucose can still meet the criteria for glucose intolerance or diabetes during an oral glucose tolerance test. Several studies have also shown that maternal pre-pregnancy obesity is directly associated with an increased risk of gestational diabetes. However, results vary widely across studies, possibly because of lack of specificity of tools for measurement of adiposity.⁶ A recent study has suggested that abdominal visceral adiposity, specifically, is associated with risk of gestational diabetes expression.⁷The hypertriglyceridemic-waist phenotype has been identified as a simple, easily available clinical marker of visceral obesity and related metabolic abnormalities.^8,9 It is defined as the simultaneous presence of abdominal obesity (i.e., a waist girth greater than 85 cm in women or greater than 90 cm in men) and hypertriglyceridemia (i.e., a triglyceride concentration ≥ 2 mmol/L). The aim of our study was to document the association between the presence of the hypertriglyceridemic-waist phenotype in early pregnancy and impaired glucose tolerance in later pregnancy.     

Effective Coverage for Antiretroviral Therapy in a Ugandan District with a Decentralized Model of Care

Introduction

While increasing access to antiretroviral therapy (ART) is reported from many African countries, data on effective coverage particular from settings without external support or research remains scarce. We examined and report effective coverage data from a public ART program in rural Uganda.

Methods

We conducted a retrospective cohort study at all ART-providing governmental health facilities in Iganga District, Eastern Uganda. Based on all HIV patients registered between April 2004 and September 2009 (n = 4775), we assessed indicators of program performance and determined rates of retention and Cox proportional hazards for attrition. Effective ART coverage was calculated using projections (SPECTRUM software) adapted to the district demographic structure and number of people receiving ART.

Results

By September 2009, district public sector effective ART coverage was 10.3% for adults and 1.9% for children. After a median follow-up of 26.9 months, overall ART retention was 54.7%. The probability of retention was 0.72 (95% confidence interval (CI) 0.69–0.75) at 12 and 0.58 (CI 0.54–0.62) at 36 months after ART initiation. Individual health facilities differed considerably regarding performance indicators and retention. Overall, 198 (16.9%) individual files of 1171 registered ART patients were lost. Young adult age (15–24 years) had a higher risk of attrition (HR 2.1, CI 1.4–3.2) as well as WHO stage I (HR 4.8, CI 1.9–11.8) and WHO stage IV (HR 2.5, CI 1.3–4.7). An interval ≥6 weeks between HIV testing and ART initiation was associated with a reduced risk (HR 0.6, CI 0.47–0.78).

Conclusion

Compared to reported national data effective ART coverage in Iganga District was low. Intensified efforts to improve access, retention in care, and quality of documentation are urgently needed. Children and young adults require special attention in the program.     

Determinants of Mortality and Loss to Follow-Up among Adults Enrolled in HIV Care Services in Rwanda

Background

Antiretroviral therapy (ART) improves morbidity and mortality in patients with HIV, however high rates of loss to follow-up (LTF) and mortality have been documented in HIV care and treatment programs.

Methods

We analyzed routinely-collected data on HIV-infected patients ≥15 years enrolled at 41 healthcare facilities in Rwanda from 2005 to 2010. LTF was defined as not attending clinic in the last 12 months for pre-ART patients and 6 months for ART patients. For the pre-ART period, sub-distribution hazards models were constructed to estimate LTF and death to account for competing risks. Kaplan-Meier (KM) and Cox proportional hazards models were used for patients on ART.

Results

31,033 ART-naïve adults were included, 64% were female and 75% were WHO stage I or II at enrollment. 17,569 (56%) patients initiated ART. Pre-ART competing risk estimates of LTF at 2 years was 11.2% (95%CI, 10.9–11.6%) and 2.9% for death (95%CI 2.7–3.1%). Among pre-ART patients, male gender was associated with higher LTF (adjusted sub-hazard ratio (aSHR) 1.3, 95%CI 1.1–1.5) and death (aSHR 1.7, 95%CI 1.4–2.1). Low CD4 count (CD4<100 vs. ≥350 aSHR 0.2, 95%CI 0.1–0.3) and higher WHO stage (WHO stage IV vs. stage I aSHR 0.4, 95%CI 0.2–0.6) were protective against pre-ART LTF. KM estimates for LTF and death in ART patients at 2 years were 4.4% (95%CI 4.4–4.5%) and 6.3% (95%CI 6.2–6.4%). In patients on ART, male gender was associated with LTF (adjusted hazard ratio (AHR) 1.4, 95%CI 1.2–1.7) and death (AHR1.3, 95%CI 1.2–1.5). Mortality was higher for ART patients ≥40 years and in those with lower CD4 count at ART initiation.

Conclusions

Low rates of LTF and death were founds among pre-ART and ART patients in Rwanda but greater efforts are needed to retain patients in care prior to ART initiation, particularly among those who are healthy at enrollment.     

A Systematic Review of Health System Barriers and Enablers for Antiretroviral Therapy (ART) for HIV-Infected Pregnant and Postpartum Women

Background

Despite global progress in the fight to reduce maternal mortality, HIV-related maternal deaths remain persistently high, particularly in much of Africa. Lifelong antiretroviral therapy (ART) appears to be the most effective way to prevent these deaths, but the rates of three key outcomes—ART initiation, retention in care, and long-term ART adherence—remain low. This systematic review synthesized evidence on health systems factors affecting these outcomes in pregnant and postpartum women living with HIV.

Methods

Searches were conducted for studies addressing the population of interest (HIV-infected pregnant and postpartum women), the intervention of interest (ART), and the outcomes of interest (initiation, adherence, and retention). Quantitative and qualitative studies published in English since January 2008 were included. A four-stage narrative synthesis design was used to analyze findings. Review findings from 42 included studies were categorized according to five themes: 1) models of care, 2) service delivery, 3) resource constraints and governance challenges, 4) patient-health system engagement, and 5) maternal ART interventions.

Results

Low prioritization of maternal ART and persistent dropout along the maternal ART cascade were key findings. Service delivery barriers included poor communication and coordination among health system actors, poor clinical practices, and gaps in provider training. The few studies that assessed maternal ART interventions demonstrated the importance of multi-pronged, multi-leveled interventions.

Conclusions

There has been a lack of emphasis on the experiences, needs and vulnerabilities particular to HIV-infected pregnant and postpartum women. Supporting these women to successfully traverse the maternal ART cascade requires carefully designed and targeted interventions throughout the steps. Careful design of integrated service delivery models is of critical importance in this effort. Key knowledge gaps and research priorities were also identified, including definitions and indicators of adherence rates, and the importance of cumulative measures of dropout along the maternal ART cascade.     

Attitudes of People in the UK with HIV Who Are Antiretroviral (ART) Na?ve to Starting ART at High CD4 Counts for Potential Health Benefit or to Prevent HIV Transmission

Objective

To assess if a strategy of early ART to prevent HIV transmission is acceptable to ART naïve people with HIV with high CD4 counts.

Design

ASTRA is a UK multicentre, cross sectional study of 3258 HIV outpatients in 2011/12. A self-completed questionnaire collected sociodemographic, behavioral and health data, and attitudes to ART; CD4 count was recorded from clinical records.

Methods

ART naïve participants with CD4 ≥350 cells/µL (n = 281) were asked to agree/disagree/undecided with the statements (i) I would want to start treatment now if this would slightly reduce my risk of getting a serious illness, and (ii) I would want to start treatment now if this would make me less infectious to a sexual partner, even if there was no benefit to my own health.

Results

Participants were 85% MSM, 76% white, 11% women. Of 281 participants, 49.5% and 45.2% agreed they would start ART for reasons (i) and (ii) respectively; 62.6% agreed with either (i) or (ii); 12.5% agreed with neither; 24.9% were uncertain. Factors independently associated (p<0.1) with agreement to (i) were: lower CD4, more recent HIV diagnosis, physical symptoms, not being depressed, greater financial hardship, and with agreement to (ii) were: being heterosexual, more recent HIV diagnosis, being sexually active.

Conclusions

A strategy of starting ART at high CD4 counts is likely to be acceptable to the majority of HIV-diagnosed individuals. Almost half with CD4 >350 would start ART to reduce infectiousness, even if treatment did not benefit their own health. However a significant minority would not like to start ART either for modest health benefit or to reduce infectivity. Any change in approach to ART initiation must take account of individual preferences. Transmission models of potential benefit of early ART should consider that ART uptake may be lower than that seen with low CD4 counts.     

Antenatal Screening for Down Syndrome Using Serum Placental Growth Factor with the Combined,Quadruple, Serum Integrated and Integrated Tests

Objective

To estimate the value of first or second trimester placental growth factor (PlGF) as an additional antenatal screening marker for Down syndrome.

Design

Nested case-control study.

Setting

Antenatal screening service.

Population or Sample

532 Down syndrome pregnancies and 1,155 matched unaffected pregnancies.

Methods

Stored maternal serum samples (−40°C) were assayed for PlGF. Monte Carlo simulation was used to estimate the screening performance of PlGF with the Combined, Quadruple, serum Integrated and Integrated tests.

Main Outcome Measures

Median PlGF levels in affected and unaffected pregnancies and screening performance (detection rates [DR] for specified false-positive rates [FPR] and vice versa).

Results

First trimester median PlGF was 15%, 28% and 39% lower in Down syndrome than unaffected pregnancies at 11, 12 and 13 completed weeks’ gestation respectively (all p<0.001). Second trimester median PlGF was 31% lower at 14 weeks (p<0.001), and the difference decreased (6% lower at 17 weeks). At a 90% DR with first trimester markers measured at 13 weeks, adding PlGF decreased the FPR from 11.1 to 5.1% using the Combined test, 9.3% to 4.5% using the serum Integrated test, and 3.4% to 1.5% using the Integrated test (or 1.5 to 1.4% with first trimester markers measured at 11 weeks). Adding PlGF to the Quadruple test (measured at 15 weeks) decreased the FPR from 10.0% to 9.6% at a 90% DR.

Conclusions

First trimester PlGF measurements improve the performance of antenatal screening for Down syndrome using the Combined, serum Integrated and Integrated tests. Second trimester PlGF measurements are of limited value.     

Impact of Maternal Obesity on Inhaled Corticosteroid Use in Childhood: A Registry Based Analysis of First Born Children and a Sibling Pair Analysis

Background

It has been proposed that maternal obesity during pregnancy may increase the risk that the child develops allergic disease and asthma, although the mechanisms underpinning this relationship are currently unclear. We sought to assess if this association may be due to confounding by genetic or environmental risk factors that are common to maternal obesity and childhood asthma, using a sibling pair analysis.

Methods

The study population comprised a Swedish national cohort of term children born between 1992 and 2008 to native Swedish parents. Maternal body mass index (BMI) was measured at 8–10 weeks gestation. Unconditional logistic regression models were used to determine if maternal obesity was associated with increased risk of inhaled corticosteroid (ICS) in 431,718 first-born children, while adjusting for potential confounders. An age-matched discordant sib-pair analysis was performed, taking into account shared genetic and environmental risk factors.

Results

Maternal over-weight and obesity were associated with increased risk that the child would require ICS (for BMI≥35 kg/m², aOR = 1.30, 95%CI = 1.10–1.52 compared with normal weight mothers) in children aged 6–12 years. Similar effects were seen in younger children, but in children aged 13–16 years, maternal obesity (BMI≥30) was related to increased risk of ICS use in girls (aOR = 1.28, 95%CI = 1.07–1.53) but not boys (OR = 1.05, 95%CI = 0.87–1.26). The sib-pair analysis, which included 2,034 sib-pairs older than six years who were discordant for both ICS use and maternal BMI category, failed to find any evidence that increasing maternal weight was related to increased risk of ICS use.

Conclusion

Maternal obesity is associated with increased risk of childhood ICS use up to approximately 12 years of age, but only in girls after this age. These effects could not be confirmed in a sib pair analysis, suggesting either limited statistical power, or the effects of maternal BMI may be due to shared genetic or environmental risk factors.     

Predictive Factors of Plasma HIV Suppression during Pregnancy: A Prospective Cohort Study in Benin

Objective

To investigate the factors associated with HIV₁ RNA plasma viral load (pVL) below 40 copies/mL at the third trimester of pregnancy, as part of prevention of mother-to-child transmission (PMTCT) in Benin.

Design

Sub study of the PACOME clinical trial of malaria prophylaxis in HIV-infected pregnant women, conducted before and after the implementation of the WHO 2009 revised guidelines for PMTCT.

Methods

HIV-infected women were enrolled in the second trimester of pregnancy. Socio-economic characteristics, HIV history, clinical and biological characteristics were recorded. Malaria prevention and PMTCT involving antiretroviral therapy (ART) for mothers and infants were provided. Logistic regression helped identifying factors associated with virologic suppression at the end of pregnancy.

Results

Overall 217 third trimester pVLs were available, and 71% showed undetectability. Virologic suppression was more frequent in women enrolled after the change in PMTCT recommendations, advising to start ART at 14 weeks instead of 28 weeks of pregnancy. In multivariate analysis, Fon ethnic group (the predominant ethnic group in the study area), regular job, first and second pregnancy, higher baseline pVL and impaired adherence to ART were negative factors whereas higher weight, higher antenatal care attendance and longer ART duration were favorable factors to achieve virologic suppression.

Conclusions

This study provides more evidence that ART has to be initiated before the last trimester of pregnancy to achieve an undetectable pVL before delivery. In Benin, new recommendations supporting early initiation were well implemented and, together with a high antenatal care attendance, led to high rate of virologic control.     

The Degree of Segmental Aneuploidy Measured by Total Copy Number Abnormalities Predicts Survival and Recurrence in Superficial Gastroesophageal Adenocarcinoma

Background

Prognostic biomarkers are needed for superficial gastroesophageal adenocarcinoma (EAC) to predict clinical outcomes and select therapy. Although recurrent mutations have been characterized in EAC, little is known about their clinical and prognostic significance. Aneuploidy is predictive of clinical outcome in many malignancies but has not been evaluated in superficial EAC.

Methods

We quantified copy number changes in 41 superficial EAC using Affymetrix SNP 6.0 arrays. We identified recurrent chromosomal gains and losses and calculated the total copy number abnormality (CNA) count for each tumor as a measure of aneuploidy. We correlated CNA count with overall survival and time to first recurrence in univariate and multivariate analyses.

Results

Recurrent segmental gains and losses involved multiple genes, including: HER2, EGFR, MET, CDK6, KRAS (recurrent gains); and FHIT, WWOX, CDKN2A/B, SMAD4, RUNX1 (recurrent losses). There was a 40-fold variation in CNA count across all cases. Tumors with the lowest and highest quartile CNA count had significantly better overall survival (p = 0.032) and time to first recurrence (p = 0.010) compared to those with intermediate CNA counts. These associations persisted when controlling for other prognostic variables.

Significance

SNP arrays facilitate the assessment of recurrent chromosomal gain and loss and allow high resolution, quantitative assessment of segmental aneuploidy (total CNA count). The non-monotonic association of segmental aneuploidy with survival has been described in other tumors. The degree of aneuploidy is a promising prognostic biomarker in a potentially curable form of EAC.     

Temporal Trends in Treatment Outcomes for HIV-1 and HIV-2-Infected Adults Enrolled in C?te d'Ivoire's National Antiretroviral Therapy Program

Background

In Côte d''Ivoire during 2004–2007, numbers of ART enrollees increased from <5,000 to 36,943. Trends in nationally representative ART program outcomes have not yet been reported.

Methodology/Principal Findings

We conducted a retrospective chart review to assess trends in patient characteristics and attrition [death or loss to follow-up (LTFU)] over time, among a nationally representative sample of 3,682 adults (≥15 years) initiating ART during 2004–2007 at 34 health facilities. Among ART enrollees during 2004–2007, median age was 36, the proportion female was 67%, the proportion HIV-2-infected or dually HIV-1&2 reactive was 5%, and median baseline CD4⁺ T-cell (CD4) count was 135 cells/µL. Comparing cohorts initiating ART in 2004 with cohorts initiating ART in 2007, median baseline weight declined from 55 kg to 52 kg (p = 0.008) and the proportion weighing <45 kg increased from 17% to 22% (p = 0.014). During 2004–2007, pharmacy-based estimates of the percentage of new ART enrollees ≥95% adherent to ART declined from 74% to 60% (p = 0.026), and twelve-month retention declined from 86% to 69%, due to increases in 12-month mortality from 2%–4% and LTFU from 12%–28%. In univariate analysis, year of ART initiation was associated with increasing rates of both LTFU and mortality. Controlling for baseline CD4, weight, adherence, and other risk factors, year of ART initiation was still strongly associated with LTFU but not mortality. In multivariate analysis, weight <45 kg and adherence <95% remained strong predictors of LTFU and mortality.

Conclusions

During 2004–2007, increasing prevalence among ART enrollees of measured mortality risk factors, including weight <45 kg and ART adherence <95%, might explain increases in mortality over time. However, the association between later calendar year and increasing LTFU is not explained by risk factors evaluated in this analysis. Undocumented transfers, political instability, and patient dissatisfaction with crowded facilities might explain increasing LTFU.