Risk of childhood mortality associated with death of a mother in low-and-middle-income countries: a systematic review and meta-analysis.

BACKGROUND: Death of a mother at an early age of the child may result in an increased risk of childhood mortality, especially in low-and-middle-income countries. This study aims to synthesize estimates of the association between a mother's death and the risk of childhood mortality at different age ranges from birth to 18 years in these settings. METHODS: Various MEDLINE databases, EMBASE, and Global Health databases were searched for population-based cohort and case-control studies published from 1980 to 2017. Studies were included if they reported the risk of childhood mortality for children whose mother had died relative to those whose mothers were alive. Random-effects meta-analyses were used to pool effect estimates, stratified by various exposures (child's age when mother died, time since mother's death) and outcomes (child's age at risk of child death). RESULTS: A total of 62 stratified risk estimates were extracted from 12 original studies. Childhood mortality was associated with child's age at time of death of a mother and time since a mother's death. For children whose mother died when they were ≤ 42 days, the relative risk (RR) of dying within the first 1-6 months of the child's life was 35.5(95%CI:9.7-130.5, p [het] = 0.05) compared to children whose mother did not die; by 6-12 months this risk dropped to 2.8(95%CI:0.7-10.7). For children whose mother died when they were ≤ 1 year, the subsequent RR of dying in that year was 15.9(95%CI:2.2-116.1,p [het] = 0.02), compared to children whose mother lived. For children whose mother died when they were ≤ 5 years of age, the RR of dying before aged 12 was 4.1(95%CI:3.0-5.7),p [het] = 0.83. Mortality was also elevated in specific analysis  among children whose mother died when child was older than 42 days. Overall, for children whose mother died < 6 and 6+ months ago, RRs of dying before reaching adulthood (≤18 years) were 4.7(95%CI:2.6-8.7,p [het] = 0.2) and 2.1(95%CI:1.3-3.4,p [het] = 0.7), respectively, compared to children whose mother lived. CONCLUSIONS: There is evidence of an association between the death of a mother and childhood mortality in lower resource settings. These findings emphasize the critical importance of women in family outcomes and the importance of health care for women during the intrapartum and postpartum periods and throughout their child rearing years.

Viral coinfection analysis using a MinHash toolkit.

BACKGROUND: Human papillomavirus (HPV) is a common sexually transmitted infection associated with cervical cancer that frequently occurs as a coinfection of types and subtypes. Highly similar sublineages that show over 100-fold differences in cancer risk are not distinguishable in coinfections with current typing methods. RESULTS: We describe an efficient set of computational tools, rkmh, for analyzing complex mixed infections of related viruses based on sequence data. rkmh makes extensive use of MinHash similarity measures, and includes utilities for removing host DNA and classifying reads by type, lineage, and sublineage. We show that rkmh is capable of assigning reads to their HPV type as well as HPV16 lineage and sublineages. CONCLUSIONS: Accurate read classification enables estimates of percent composition when there are multiple infecting lineages or sublineages. While we demonstrate rkmh for HPV with multiple sequencing technologies, it is also applicable to other mixtures of related sequences.

Detection of human papillomavirus 16, 18, and 45 in women with ASC-US cytology and the risk of cervical precancer: results from the CLEAR HPV study.

OBJECTIVES: The Aptima human papillomavirus (HPV) 16 18/45 Genotype (GT) assay (AHPV-GT) is a qualitative E6/ E7 oncogene messenger RNA test that detects HPV 16 and a pool of HPV 18 and 45. The CLEAR (Clinical Evaluation of APTIMA mRNA) study was the pivotal, prospective, multicenter US clinical study to validate the Aptima HPV (AHPV) assays. METHODS: In this analysis, we evaluated the clinical performance of AHPV and AHPV-GT assays for detection of cervical intraepithelial neoplasia grade 2 or more severe (CIN2 +) and grade 3 (CIN3) or adenocarcinoma in situ in 912 women with atypical squamous cells of undetermined significance (ASC-US) Papanicolaou result. The AHPV-GT assay was performed on high-risk HPV (hrHPV) positives as determined by the AHPV assay. RESULTS: Overall, the percent positive for hrHPV was 38.8% (354/912), of which 34.2% (121/354) were GT positive. Among hrHPV-positive women, the risks of CIN2 + were 37.0% for HPV 16 positives, 15.9% for HPV 18/45 positives, 14.3% for other hrHPV positives, and 2.2% for AHPV negatives. The risks of CIN3 + were 20.5% for HPV 16 positives, 9.1% for HPV 18/45 positives, 4.3% for other hrHPV positives, and 0.7% for HPV negatives. CONCLUSIONS: We demonstrated that AHPV-GT is a reliable and effective test for cervical cancer risk stratification in women with an ASC-US cytology diagnosis.

Seroprevalence of 8 oncogenic human papillomavirus genotypes and acquired immunity against reinfection.

BACKGROUND: Natural human papillomavirus (HPV) antibody titers have shown protection against subsequent HPV infection, but previous studies were restricted to few HPV genotypes. We examined the association of naturally occurring antibodies against 8 carcinogenic HPV types with subsequent infections. METHODS: A total of 2302 women enrolled in the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study provided blood samples at baseline. Serum samples were tested for antibodies against 8 carcinogenic HPV genotypes (16, 18, 31, 33, 35, 45, 52, and 58) using a multiplex serology assay. We analyzed the relationship between HPV antibodies and HPV infection during 2 years of follow-up among women negative for the specific HPV type at baseline. RESULTS: Baseline seroprevalence for HPV16 L1 was associated with decreased risk of DNA positivity for HPV16 (odds ratio, 0.39 [95% confidence interval, .18-.86]) at ≥2 follow-up visits. We observed similar but nonsignificant decreased risks for HPV18 and 31. These findings were restricted to women reporting a new sex partner during follow-up. There was no association between baseline seroprevalence and detection of precancer during follow-up. CONCLUSIONS: Seroprevalence conferred protection against subsequent HPV infection for HPV16 and indicated possible protection for 2 other genotypes, suggesting that this effect is common to several HPV genotypes.

Natural immune responses against eight oncogenic human papillomaviruses in the ASCUS-LSIL Triage Study.

Only a subset of women with human papillomavirus (HPV) infections will become seropositive, and the factors influencing seroconversion are not well understood. We used a multiplex serology assay in women with mildly abnormal cytology results to examine seroreactivity to oncogenic HPV genotypes. An unbiased subset of women in the atypical squamous cell of undetermined significance /low-grade squamous intraepithelial lesion Triage Study provided blood samples at trial enrollment for serological testing. A Luminex assay based on glutathione s-transferase-L1 fusion proteins as antigens was used to test seroreactivity against eight carcinogenic HPV genotypes (16, 18, 31, 33, 35, 45, 52 and 58). We analyzed the relationship between seroprevalence in women free of precancer (N = 2,464) and HPV DNA status, age, sexual behavior and other HPV-related risk factors. The overall seroprevalence was 24.5% for HPV16 L1 and ∼20% for 18L1 and 31L1. Among women free of precancer, seroprevalence peaked in women less than 29 years and decreased with age. Type-specific seroprevalence was associated with baseline DNA detection for HPV16 (OR = 1.36, 95%CI: 1.04-1.79) and HPV18 (OR = 2.31, 95%CI: 1.61-3.32), as well as for HPV52 and HPV58. Correlates of sexual exposure were associated with increased seroprevalence across most genotypes. Women who were current or former smokers were less likely to be seropositive for all eight of the tested oncogenic genotypes. The multiplex assay showed associations between seroprevalence and known risk factors for HPV infection across nearly all tested HPV genotypes but associations between DNA- and serostatus were weak, suggesting possible misclassification of the participants' HPV serostatus.

Comparison of cervical cancer screening strategies incorporating different combinations of cytology, HPV testing, and genotyping for HPV 16/18: results from the ATHENA HPV study.

OBJECTIVE: The objective of the study was to compare 9 cervical cancer screening strategies to the current screening standard (cytology with human papillomavirus [HPV] triage of atypical squamous cells of undetermined significance) for the detection of high-grade cervical disease. STUDY DESIGN: Women (n = 34,254) aged 30 years or older from the Addressing the Need for Advanced HPV Diagnostics (ATHENA) study underwent screening with cytology and HPV testing with simultaneous HPV16/18 genotyping; those with atypical squamous cells of undetermined significance cytology or greater or HPV-positive status were referred for colposcopy. RESULTS: In general, screening strategies that offered greater sensitivity also required more referral to colposcopy. HPV testing was more sensitive than cytology for detection of cervical intraepithelial neoplasia grade 2 or greater, but strategies that depended on cytology for triage of HPV-positive women decreased this sensitivity. Various strategies of cotesting with cytology increased sensitivity but did so by increasing testing. Strategies that included integrated HPV16/18 testing provided more efficient referral to colposcopy. CONCLUSION: Strategies that maximize detection of women at greatest risk of cervical intraepithelial neoplasia grade 3 or greater by immediate referral to colposcopy, with follow-up testing of women at intermediate risk, maximize the benefits of cervical cancer screening while decreasing the potential harm. Incorporating screening with HPV and triage of HPV-positive women by a combination of genotyping for HPV16/18 and cytology provided a good balance between maximizing sensitivity (benefit) and specificity by limiting the number of colposcopies (potential harm).