Vertical transmission of Zika virus and its outcomes: a Bayesian synthesis of prospective studies.

BACKGROUND: Prospective studies of Zika virus in pregnancy have reported rates of congenital Zika syndrome and other adverse outcomes by trimester. However, Zika virus can infect and damage the fetus early in utero, but clear before delivery. The true vertical transmission rate is therefore unknown. We aimed to provide the first estimates of underlying vertical transmission rates and adverse outcomes due to congenital infection with Zika virus by trimester of exposure. METHODS: This was a Bayesian latent class analysis of data from seven prospective studies of Zika virus in pregnancy. We estimated vertical transmission rates, rates of Zika-virus-related and non-Zika-virus-related adverse outcomes, and the diagnostic sensitivity of markers of congenital infection. We allowed for variation between studies in these parameters and used information from women in comparison groups with no PCR-confirmed infection, where available. FINDINGS: The estimated mean risk of vertical transmission was 47% (95% credible interval 26 to 76) following maternal infection in the first trimester, 28% (15 to 46) in the second, and 25% (13 to 47) in the third. 9% (4 to 17) of deliveries following infections in the first trimester had symptoms consistent with congenital Zika syndrome, 3% (1 to 7) in the second, and 1% (0 to 3) in the third. We estimated that in infections during the first, second, and third trimester, respectively, 13% (2 to 27), 3% (-5 to 14), and 0% (-7 to 11) of pregnancies had adverse outcomes attributable to Zika virus infection. Diagnostic sensitivity of markers of congenital infection was lowest in the first trimester (42% [18 to 72]), but increased to 85% (51 to 99) in trimester two, and 80% (42 to 99) in trimester three. There was substantial between-study variation in the risks of vertical transmission and congenital Zika syndrome. INTERPRETATION: This preliminary analysis recovers the causal effects of Zika virus from disparate study designs. Higher transmission in the first trimester is unusual with congenital infections but accords with laboratory evidence of decreasing susceptibility of placental cells to infection during pregnancy. FUNDING: European Union Horizon 2020 programme.

Researching Zika in pregnancy: lessons for global preparedness.

Our understanding of congenital infections is based on prospective studies of women infected during pregnancy. The EU has funded three consortia to study Zika virus, each including a prospective study of pregnant women. Another multi-centre study has been funded by the US National Institutes of Health. This Personal View describes the study designs required to research Zika virus, and questions whether funding academics in the EU and USA to work with collaborators in outbreak areas is an effective strategy. 3 years after the 2015-16 Zika virus outbreaks, these collaborations have taught us little about vertical transmission of the virus. In the time taken to approve funding, agree contracts, secure ethics approval, and equip laboratories, Zika virus had largely disappeared. By contrast, prospective studies based on local surveillance and standard-of-care protocols have already provided valuable data. Threats to fetal and child health pose new challenges for global preparedness requiring support for the design and implementation of locally appropriate protocols. These protocols can answer the key questions earlier than externally designed studies and at lower cost. Local protocols can also provide a framework for recruitment of unexposed controls that are required to study less specific outcomes. Other priorities include accelerated development of non-invasive tests, and longer-term storage of neonatal and antenatal samples to facilitate retrospective reconstruction of cohort studies.

Earlier initiation of ART and further decline in mother-to-child HIV transmission rates, 2000-2011.

OBJECTIVES: To analyze mother-to-child HIV transmission (MTCT) rates over time in light of changes in management, demographic, and pregnancy characteristics. DESIGN: Population-based surveillance data on diagnosed HIV-positive women and their infants are routinely collected in the UK and Ireland. METHODS: A total of 12486 singleton pregnancies delivered in 2000-2011 were analyzed. HIV infection status was available for 11515 infants (92.2%). RESULTS: The rate of MTCT declined from 2.1% (17/816) in 2000-2001 to 0.46% (nine of 1975, 95% confidence interval: 0.21-0.86%) in 2010-2011 (trend, P=0.01), because of a combination of factors including earlier initiation of antenatal combination antiretroviral therapy (cART). Excluding 63 infants who were breastfed or acquired HIV postnatally, MTCT risk was significantly higher for all modes of delivery in women with viral load of 50-399  copies/ml (1.0%, 14/1349), compared with viral load of less than 50 copies/ml (0.09%, six of 6347, P<0.001). Among the former (viral load 50-399 copies/ml), the risk of MTCT was 0.26% (two of 777) following elective cesarean section and 1.1% (two of 188) following planned vaginal delivery (P=0.17), excluding in-utero transmissions. MTCT probability declined rapidly with each additional week of treatment initially, followed by a slower decline up to about 15 weeks of cART, with substantial differences by baseline viral load. CONCLUSION: MTCT rates in the UK and Ireland have continued to decline since 2006, reaching an all-time low of 5 per 1000 in 2010-2011. This was primarily because of a reduction in transmissions associated with late initiation or nonreceipt of antenatal cART, and an increase in the proportion of women on cART at conception.

Long-term outcomes of congenital cytomegalovirus infection in Sweden and the United Kingdom.

BACKGROUND: Congenital cytomegalovirus (CMV) is an important cause of neurological problems, particularly sensorineural hearing loss, but data on long-term sequelae and the impact of nonprimary maternal infection are limited. We report updated findings on childhood outcomes from 2 large prospective studies. METHODS: Pregnant women in Malmö, Sweden, and London, United Kingdom, were included between 1977 and 1986, and newborns were screened for CMV (virus culture of urine or saliva). Cases and matched controls underwent regular, detailed developmental assessments up to at least age 5 years. RESULTS: One hundred seventy-six congenitally infected infants were identified among >50 000 screened (Malmö: 76 [4.6/1000 births]; London: 100 [3.2/1000 births]); 214 controls were selected. Symptoms were recorded in 11% of CMV-infected neonates (19/176) and were mostly mild; only 1 neonate had neurological symptoms. At follow-up, 7% of infants (11/154) were classified as having mild, 5% (7/154) moderate, and 6% (9/154) severe neurological sequelae. Four of 161 controls (2%) had mild impairment. Among children symptomatic at birth, 42% (8/19) had sequelae, versus 14% (19/135) of the asymptomatic infants (P = .006). All moderate/severe outcomes were identified by age 1; mild sequelae were first identified at age 2-5 years in 6 children, and age 6-7 years in 3. Among the 16 children with moderate/severe outcomes, 2 had mothers with confirmed and 7 with presumed nonprimary infection. CONCLUSIONS: Moderate or severe outcomes were reported in 11% of children with congenital CMV identified through population screening, all by 1 year; all impairment detected after this age was mild. Nonprimary infections contributed substantially to the burden of childhood congenital CMV disease.

Surveillance of congenital cytomegalovirus in the UK and Ireland.

OBJECTIVE: To explore the presentation and management of congenital cytomegalovirus (CMV) identified through routine clinical investigations, and ascertain outcome in early childhood. DESIGN: Active population-based surveillance. SETTING: UK and Ireland. METHODS: Infants born in 2001-2002 with confirmed or suspected congenital CMV infection were reported through the British Paediatric Surveillance Unit, and clinicians completed questionnaires on presentation, diagnosis, management and subsequent outcome. RESULTS: 86 confirmed and 70 possible cases of congenital CMV infection were reported. Over a third (27/72) of singleton infants with confirmed and 44% (27/61) with possible congenital infection were preterm (<37 weeks gestation). Among confirmed cases, 75% (64/85) presented with neonatal manifestations compatible with congenital CMV, over half (34/64) of whom had neurological signs; 17 infants were treated with gancyclovir. Among confirmed cases with information on outcome, 31% (24/78) were developing normally, 18% (14/78) had mild, 24% (19/78) moderate and 14% (11/78) severe sequelae, and 13% (10/78) had died. Median age at follow-up among survivors was 18 months (IQR 15-22 months). Children with neonatal CMV manifestations were significantly more likely than those without to have moderate or severe outcomes (including death) (60%, 36/60, vs 22%, 4/18, p=0.001). 27% of survivors (17/63) had bilateral hearing loss. CONCLUSIONS: The number of confirmed cases of diagnosed congenital CMV reported in this study was lower than expected, highlighting the need for early and appropriate investigations when congenital infection is suspected. Due to the unexpectedly high proportion of preterm infants, resulting from differential case ascertainment, it was difficult to distinguish prematurity and CMV-related symptoms.

Myopia over the lifecourse: prevalence and early life influences in the 1958 British birth cohort.

PURPOSE: To investigate the hypothesis that the excessive growth of the eye in myopia is associated with general growth and thus influenced by early life biological and social factors, and that these associations underlie recent secular trends of increasing prevalence and severity of myopia. DESIGN: Cohort study. PARTICIPANTS: A total of 2487 randomly selected 44-year-old members of the 1958 British birth cohort (27% subsample). METHODS: Diverse and detailed biological, social, and lifestyle data have been collected by following members since birth through a series of clinical examinations or face-to-face interviews carried out by trained examiners. At 44 years, cohort members underwent autorefraction using the Nikon Retinomax 2 (Nikon Corp., Tokyo, Japan) under non-cycloplegic conditions. A lifecourse epidemiologic approach, based on 4 sequential multivariable "life stage" models (preconceptional; prenatal, perinatal, and postnatal; childhood; and adult), was used to examine the influence of early life biological, social and lifestyle factors, growth patterns, and "eye-specific" factors on myopia. MAIN OUTCOME MEASURES: Myopia severity (all, mild/moderate: spherical equivalent -0.75 to -5.99 diopters [D]; severe: ≥-6.00 D extreme vs. emmetropia -0.74 to +0.99 D) and myopia onset (early [<16 years] vs. later). RESULTS: A total of 1214 individuals (49%; 95% confidence interval, 48.8-50.8) were myopic (late onset in 979 [80.6%]). Myopia was positively associated with low birthweight for gestational age, gender, greater maternal age, higher paternal occupational social class, and maternal smoking in early pregnancy. Myopia was independently associated with proxy markers of near work and educational performance, with some differences by onset and severity. In adults, greater height and higher educational attainment and socioeconomic status were associated with myopia. CONCLUSIONS: Trends in the key influences on child health and growth identified as novel putative risk factors in this study are consistent with global trends of increasing myopia: increasing births to older mothers, increasing rates of intrauterine growth retardation and survival of affected children, increasing persistence of smoking in pregnancy, and changing socioeconomic status. Prospects for prevention of myopia would be improved by a paradigm shift in myopia research, with lifecourse and genetic epidemiologic approaches applied in tandem in large unselected populations.

Improving detection of blindness in childhood: the British Childhood Vision Impairment study.

OBJECTIVES: In industrialized countries, there are established programs of childhood vision screening and surveillance, but little is known about their performance. We investigated the patterns of presentation/detection and early treatment of a nationally representative cohort of children with severe visual impairment or blindness (SVI/BL) in 1 year (2000) in the United Kingdom. METHODS: All children who were younger than 16 years and had a new diagnosis of SVI/BL were identified by active surveillance through the British Ophthalmological and Pediatric Surveillance Units. Data that were collected up to 1 year after diagnosis included sociodemographic characteristics, detection of SVI/BL, nonophthalmic disorders/impairments, ophthalmic findings, and early management. RESULTS: Of 439 identified children, 65% were younger than 1 year at diagnosis, 28% were of nonwhite ethnicity, and 40% in the worst quintile of deprivation score. A total of 77% had associated nonophthalmic disorders/impairments. Although 70% had established symptoms or signs at diagnosis by a health professional, parents had suspected blindness in only 47%. A quarter of isolated SVI/BL was detected through routine vision screening; however, 46% of children's SVI/BL and associated nonophthalmic disorders/impairments were diagnosed through a clinical surveillance examination undertaken because of high risk for a specific eye disease. CONCLUSIONS: The "patient journey" of children with visual impairment is markedly influenced by the presence of additional impairments/chronic diseases. Parents' understanding of normal visual development needs to be improved. Increasingly, new evidence-based formal programs of clinical (ophthalmic) surveillance are needed in response to the changing population of children who are at risk for blinding eye disease.

Visual function in working-age adults: early life influences and associations with health and social outcomes.

PURPOSE: To investigate how visual function in mid-adult life is associated with health and social outcomes and, using life-course epidemiology, whether it is influenced by early life biological and social factors. DESIGN: Population-based cohort study. PARTICIPANTS: Nine thousand three hundred thirty members of the 1958 British birth cohort at age 44 or 45 years. METHODS: Distance, near, and stereo vision were assessed as part of a broader biomedical examination. Logistic, multinomial, and proportional odds ordinal logistic regression were used, as appropriate, to assess the association between these vision functions and both key early life influences and health and social outcomes in mid-adult life. MAIN OUTCOME MEASURES: Distance, near, and stereo acuities and health and social outcomes. RESULTS: In mid-adult life, vision function (across the full spectrum of both type and level of function) is associated with unemployment resulting from permanent sickness, lower socioeconomic status, and poorer general health (for example, for blindness; odds ratios were 2.5, 2.6, and 1.2, respectively). Also, impaired visual functions in mid-adult life are associated with a low birthweight, being small for gestational age, maternal smoking in pregnancy, and markers of socioeconomic deprivation in childhood (for example, for impaired distance acuity; odds ratios were 1.4, 1.3, 1.02, and 1.1, respectively). CONCLUSIONS: Although relatively uncommon in working-age adults, impaired vision can have important adverse consequences, which highlights the value of investigating visual function in the broader context of health and social functioning. In addition, visual function in adult life may be influenced directly by key prenatal and childhood biological and social determinants of general health. Thus, application of life-course epidemiology to complex chronic ophthalmic diseases of adult life such as glaucoma or macular degeneration is likely to prove valuable in elucidating whether and how biological, social, and lifestyle factors contribute to the cause.

Antiretroviral therapy and congenital abnormalities in infants born to HIV-infected women in the UK and Ireland, 1990-2007.

OBJECTIVE: To explore the rate of reported congenital abnormalities in infants exposed to antiretroviral therapy in utero. DESIGN: Comprehensive national surveillance study in the UK and Ireland. METHODS: Births to diagnosed HIV-infected women are reported to the National Study of HIV in Pregnancy and Childhood. Infants born between 1990 and 2007 were included. RESULTS: The rate of reported major and minor congenital abnormality was 2.8% (232/8242) overall, and there was no significant difference by timing of ART exposure: 2.8% (14/498) in unexposed infants, 2.7% (147/5427) following second or third trimester exposure, and 3.1% (53/1708) following first trimester exposure (P = 0.690). There was no difference in abnormality rates by class of ART exposure in the first trimester (P = 0.363), and no category of abnormality was significantly associated with timing of ART, although numbers in these groups were small. There was no increased risk of abnormalities in infants exposed to efavirenz (P = 0.672) or didanosine (P = 0.816) in the first trimester. CONCLUSION: These findings, based on a large, national, unselected population provide further reassurance that ART in utero does not pose a major risk of fetal anomaly.

Visual impairment and vision-related quality of life in working-age adults: findings in the 1958 British birth cohort.

PURPOSE: To describe the prevalence of impaired vision and its relative burden, together with the prevalence of impaired vision-related quality of life (VRQOL), and investigate associations with social outcomes in a contemporary and nationally representative population of working age adults. DESIGN: Population-based cross-sectional study. PARTICIPANTS: We included 9330 members of the 1958 British birth cohort at age 44 and 45 years. METHODS: "Habitual" and "best achieved" distance visual acuity in each eye, binocular near vision acuity and stereoacuity (three dimensional/depth perception) were tested during a broader biomedical examination. VRQOL was assessed using the Vision-related Quality of Life Core Measure 1 (VCM1), a validated, 10-item, self-complete instrument. Logistic and proportional odds ordinal logistic regression were used to calculate odds ratios (ORs) of the association of VRQOL with visual acuities and social outcomes. MAIN OUTCOME MEASURES: Distance, near, and stereo acuities and VRQOL and social outcomes. RESULTS: Of the 1.3% (124) of those with visual loss that precluded driving, a further 0.75% (70) were visually impaired or severely visually impaired and 0.15% (14) blind, the latter accounting for 19% total population (all ages) burden of blindness. Impairment of VRQOL is strongly associated with impaired distance, near, and stereo vision, as well as with adverse occupational and other social outcomes. However, VRQOL impairment is also sometimes reported with unilateral or mild bilateral visual loss. CONCLUSIONS: Although impaired vision in working age adults is relatively uncommon, it confers important adverse consequences for the "health and wealth" of the public. This may be captured best by assessment of VRQOL in addition to objective visual function. Ophthalmic disorders occurring or impacting in middle life should be given a higher priority than currently in national and international strategies against avoidable visual disability. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Low rates of mother-to-child transmission of HIV following effective pregnancy interventions in the United Kingdom and Ireland, 2000-2006.

AIM: In the United Kingdom (UK) and Ireland, avoidance of breastfeeding and alternative combinations of antiretroviral therapy regimen and mode of delivery are recommended according to maternal clinical status. The aim of this analysis was to explore the impact of different strategies to prevent mother-to-child transmission at a population level. DESIGN: Comprehensive national surveillance study. METHODS: Pregnancies in diagnosed HIV-infected women in the UK and Ireland are notified to the National Study of HIV in Pregnancy and Childhood; infant infection status is subsequently reported. Factors associated with transmission in this observational study were explored for singleton births between 2000 and 2006. RESULTS: The overall mother-to-child transmission rate was 1.2% (61/5151, 95% confidence interval: 0.9-1.5%), and 0.8% (40/4864) for women who received at least 14 days of antiretroviral therapy. Transmission rates following combinations recommended in British guidelines were 0.7% (17/2286) for highly active antiretroviral therapy with planned Caesarean section, 0.7% (4/559) for highly active antiretroviral therapy with planned vaginal delivery, and 0% (0/464) for zidovudine monotherapy with planned Caesarean section (P = 0.150). Longer duration of highly active antiretroviral therapy was associated with reduced transmission after adjusting for viral load, mode of delivery and sex (adjusted odds ratio = 0.90 per week of highly active antiretroviral therapy, P = 0.007). Among 2117 infants born to women on highly active antiretroviral therapy with viral load less than 50 copies/ml, only three (0.1%) were infected, two with evidence of in-utero transmission. CONCLUSION: Sustained low HIV transmission rates following different combinations of interventions in this large unselected population are encouraging. Current options for treatment and delivery offered to pregnant women according to British guidelines appear to be effective.

The Roles of PAX6 and SOX2 in Myopia: lessons from the 1958 British Birth Cohort.

PURPOSE: Myopia is a common complex trait that affects up to 60% of some populations. Its development is influenced by multiple genes and environmental factors. PAX6 and SOX2 are genes with fundamental roles in ocular growth and development, and they have been linked with myopia in a recent linkage study. The authors investigated the roles of PAX6 and SOX2 in common myopia as part of a broader association study of refractive error. METHODS: Five hundred ninety-six persons from the 1958 British Birth Cohort, a nationally representative population, were randomly selected from the outer tertiles of the refractive error (RE) distribution and were genotyped using 25 tagSNPs across PAX6 and 3 tagSNPs across SOX2 and their putative control regions. This experiment had 80% power to exclude either gene contributing more than 10% of the variance of refractive error. RESULTS: All SNPs were in Hardy-Weinberg equilibrium, and the genotyping failure rate was less than 5%. Accounting for multiple testing, no significant association (P < 0.05) was found between any of the SNPs or haplotypes and refractive error. CONCLUSIONS: PAX6 and SOX2 are obvious candidates in RE genetic studies because of their biological roles and prior linkage studies. The present findings strongly suggest refractive error is not directly affected in this population by variants in either gene or by their known promoters/enhancers. The authors suggest that neither PAX6 nor SOX2 should be prioritized in the international search for genetic modifiers of refractive error. Their findings contribute to broader understanding of the pathophysiology of refractive error and highlight the critical role of replication in genetic research on complex disorders.

Antiretroviral therapy and premature delivery in diagnosed HIV-infected women in the United Kingdom and Ireland.

OBJECTIVE: To explore the association between antiretroviral therapy in pregnancy and premature delivery, birthweight, stillbirth and neonatal mortality, in pregnancies in HIV-infected women delivering between 1990 and 2005. DESIGN: Pregnancies in women with diagnosed HIV infection in the UK and Ireland are notified to the National Study of HIV in Pregnancy and Childhood (NSHPC) through a well-established surveillance scheme. RESULTS: The prematurity rate (< 37 weeks gestation) was higher in women on highly active antiretroviral therapy (HAART) (14.1%, 476/3384) than in women on mono/dual therapy (10.1%, 107/1061), even after adjusting for ethnicity, maternal age, clinical status and injecting drug use as the source of HIV acquisition [adjusted odds ratio (AOR) = 1.51, 95% confidence interval (CI), 1.19-1.93; P = 0.001]. Delivery at < 35 weeks was even more strongly associated with HAART (AOR = 2.34; 95% CI, 1.64-3.37; P < 0.001). The effect was the same whether or not HAART included a protease inhibitor. In comparison with exposure to mono/dual therapy, exposure to HAART was associated with lower birthweight standardized for gestational age (P < 0.001), and an increased risk of stillbirth (AOR = 2.27; 95% CI, 0.96-5.41; P = 0.063). CONCLUSIONS: These findings, based on comprehensive population surveillance, demonstrate an increased risk of prematurity associated with HAART, and a possible association with other perinatal outcomes, including stillbirth and birthweight. Although the beneficial effects of antiretroviral therapy on mother-to-child transmission are indisputable, monitoring antiretroviral therapy in pregnancy remains a priority.

Inferring myopia over the lifecourse from uncorrected distance visual acuity in childhood.

AIM: To report the usefulness of uncorrected distance visual acuity (DVA) at 16 years to "screen" for myopia status and to assess the lifetime risk of myopia, based on a national birth cohort. METHODS: 1867 members of the 1958 British birth cohort for whom there were data on acuity at 16 years had autorefraction, as part of a biomedical survey, at 45 years. Reduced uncorrected DVA at age 16 years (6/12 or worse in both eyes) was compared with adult refraction (spherical equivalent). RESULTS: Only a quarter of individuals in the population studied who had developed myopia by 45 years of age had reduced acuity at 16 years of age. Notably, half of all adults with moderate myopia (-2.99 to -5.99) and 31% (11/35) with severe myopia (> or =-6) had good uncorrected DVA in both eyes at 16 years of age. Thus, sensitivities were low, ranging from 16% for all myopia (cut-off point spherical equivalent -0.5) to 69% for severe myopia (cut-off point spherical equivalent -6). However, a high (91%) lifetime probability of primary myopia (spherical equivalent > or =-0.5) given a reduced uncorrected DVA at 16 years was found. CONCLUSION: In this population, reduced uncorrected DVA in childhood is an inaccurate and inappropriate intermediate "phenotype" for capturing adult myopia status. However, our findings support assessment of DVA in secondary school children as an effective method of identifying refractive error (both myopia and hypermetropia).

Antiretroviral therapy and congenital abnormalities in infants born to HIV-1-infected women in the United Kingdom and Ireland, 1990 to 2003.

Antiretroviral therapy (ART) in pregnancy substantially reduces the risk of mother-to-child transmission of HIV, but concerns exist about the potential for teratogenic effects. This analysis was undertaken to explore the relation between ART in pregnancy and birth defects in infants born to HIV-infected women in the United Kingdom and Ireland between 1990 and 2003. Comprehensive obstetric and pediatric HIV surveillance is carried out through the National Study of HIV in Pregnancy and Childhood. Congenital abnormalities were reported in 101 of 3172 infants (100 of 3120 pregnancies). There was no statistically significant association between the prevalence of congenital abnormalities and exposure to ART overall: 3.4% (90 of 2657 pregnancies) in exposed pregnancies and 2.2% (10 of 463 pregnancies) in nonexposed pregnancies (P = 0.166); prevalence was similar whether or not exposure occurred in the first trimester: 3.7% (20 of 541 pregnancies) after early exposure and 3.1% (80 of 2579 pregnancies) without early exposure (P = 0.476). There was also no significant association with type of ART in early pregnancy (ie, highly active antiretroviral therapy [HAART] vs. mono- or dual therapy, HAART with protease inhibitor and/or nonnucleoside reverse transcriptase inhibitor). The lack of association was maintained after adjustment for potential confounding factors. These findings are reassuring, but continued monitoring is essential in view of the increasing number of women on therapy at conception and the likely continuing diversity of drug regimens.