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1.  Spatial and Temporal Clustering of Dengue Virus Transmission in Thai Villages 
PLoS Medicine  2008;5(11):e205.
Background
Transmission of dengue viruses (DENV), the leading cause of arboviral disease worldwide, is known to vary through time and space, likely owing to a combination of factors related to the human host, virus, mosquito vector, and environment. An improved understanding of variation in transmission patterns is fundamental to conducting surveillance and implementing disease prevention strategies. To test the hypothesis that DENV transmission is spatially and temporally focal, we compared geographic and temporal characteristics within Thai villages where DENV are and are not being actively transmitted.
Methods and Findings
Cluster investigations were conducted within 100 m of homes where febrile index children with (positive clusters) and without (negative clusters) acute dengue lived during two seasons of peak DENV transmission. Data on human infection and mosquito infection/density were examined to precisely (1) define the spatial and temporal dimensions of DENV transmission, (2) correlate these factors with variation in DENV transmission, and (3) determine the burden of inapparent and symptomatic infections. Among 556 village children enrolled as neighbors of 12 dengue-positive and 22 dengue-negative index cases, all 27 DENV infections (4.9% of enrollees) occurred in positive clusters (p < 0.01; attributable risk [AR] = 10.4 per 100; 95% confidence interval 1–19.8 per 100]. In positive clusters, 12.4% of enrollees became infected in a 15-d period and DENV infections were aggregated centrally near homes of index cases. As only 1 of 217 pairs of serologic specimens tested in positive clusters revealed a recent DENV infection that occurred prior to cluster initiation, we attribute the observed DENV transmission subsequent to cluster investigation to recent DENV transmission activity. Of the 1,022 female adult Ae. aegypti collected, all eight (0.8%) dengue-infected mosquitoes came from houses in positive clusters; none from control clusters or schools. Distinguishing features between positive and negative clusters were greater availability of piped water in negative clusters (p < 0.01) and greater number of Ae. aegypti pupae per person in positive clusters (p = 0.04). During primarily DENV-4 transmission seasons, the ratio of inapparent to symptomatic infections was nearly 1:1 among child enrollees. Study limitations included inability to sample all children and mosquitoes within each cluster and our reliance on serologic rather than virologic evidence of interval infections in enrollees given restrictions on the frequency of blood collections in children.
Conclusions
Our data reveal the remarkably focal nature of DENV transmission within a hyperendemic rural area of Thailand. These data suggest that active school-based dengue case detection prompting local spraying could contain recent virus introductions and reduce the longitudinal risk of virus spread within rural areas. Our results should prompt future cluster studies to explore how host immune and behavioral aspects may impact DENV transmission and prevention strategies. Cluster methodology could serve as a useful research tool for investigation of other temporally and spatially clustered infectious diseases.
Investigating dengue cases identified by testing febrile schoolchildren in rural Thai villages, Mammen P. Mammen and colleagues find a pattern of focal spread to houses neighboring those of case patients.
Editors' Summary
Background.
Every year, over 50 million people living in tropical and subtropical urban and semi-urban areas become infected with dengue (a mosquito-borne viral infection) and several hundred thousand develop a potentially lethal complication called dengue hemorrhagic fever. Dengue is caused by four closely related viruses that are transmitted to people through the bites of infected female Aedes aegypti mosquitoes. These day-biting insects, which breed in household water containers and in the water that collects in used tires and other discarded containers, acquire dengue virus through feeding on the blood of an infected person. Some people who become infected with dengue virus have no symptoms but others develop high fever, a rash, and severe headache that lasts two to seven days. In dengue hemorrhagic fever, small blood vessels become leaky, which causes nose and gum bleeds, bruising and, in the worst cases, failure of the circulatory system and death. There is no specific treatment for dengue fever or dengue hemorrhagic fever but standard medical care—in particular, replacement of lost blood fluids—helps most people survive the latter condition.
Why Was This Study Done?
There is no vaccine to prevent dengue. As a result the only way to minimize dengue outbreaks is to control mosquito numbers through environmental management—providing piped water, encouraging people not to store water in open containers, and removing other sources of standing water—and by applying insecticides to areas where mosquitoes breed. During outbreaks, because Ae. aegypti mosquitoes rest in houses, insecticides are also often sprayed in dwellings in the affected areas. However, to improve dengue prevention and surveillance, public-health officials need to know much more about the patterns of dengue virus transmission and about the factors that underlie these patterns. In this study, therefore, the researchers test the idea that dengue virus transmission occurs in localized neighborhood clusters over short periods of time.
What Did the Researchers Do and Find?
The researchers used “cluster investigations” to examine the pattern of dengue virus transmission among school children in several rural villages in Thailand, a country where dengue is very common (hyperendemic). Primary school children with fever were identified during two seasons of peak dengue virus transmission. Each child was characterized as a dengue-positive index case (by finding dengue virus in their blood) or as a dengue-negative index case. Data on human infection and mosquito infection and density were then collected within 100 meters of the homes of each index case—the “cluster area.” Not all the neighbors of the index cases participated in the study but among the 556 village children who did participate, there were 27 dengue infections, all of which occurred in clusters centered on the homes of the dengue-positive index cases. In the positive clusters, one in eight of the enrolled children became infected within 15 days of the index case becoming ill. Among 1,000 Ae. aegypti mosquitoes collected inside and around the houses in each cluster, only eight were infected with dengue and these were all collected from houses in positive clusters. Finally, there was a greater availability of piped water and fewer Ae. aegypti pupae in the negative clusters than in the positive clusters.
What Do These Findings Mean?
Although this study did not sample all the children or mosquitoes within each cluster area, these findings show that in an area where dengue is hyperendemic, dengue virus transmission among children occurs in localized areas and over short time periods. The findings also suggest that focal transmission is associated with recent dengue virus introductions and that one or a few mosquitoes are likely responsible for all the transmission in each cluster. Although it would be impractical to set up surveillance of all the school children in Thailand for dengue infections, these findings suggest that improved detection of cases within schools combined with local spraying inside the homes in the immediate vicinity of any affected children could help to halt dengue virus transmission. Future cluster studies could explore how human behavior and human immunity affect dengue virus transmission and could also be used to investigate other temporally and spatially clustered infectious diseases, including malaria.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050205.
Read the related PLoS Medicine Perspective by Steven Riley
The US Centers for Disease Control and Prevention provides detailed information about dengue fever, including a questions and answers section in English and Spanish
The World Health Organization provides information on dengue and dengue hemorrhagic fever around the world (in several languages)
Links to additional information about dengue are provided by MedlinePlus (in English and Spanish)
doi:10.1371/journal.pmed.0050205
PMCID: PMC2577695  PMID: 18986209
2.  Effectiveness of anonymised information sharing and use in health service, police, and local government partnership for preventing violence related injury: experimental study and time series analysis 
Objective To evaluate the effectiveness of anonymised information sharing to prevent injury related to violence.
Design Experimental study and time series analysis of a prototype community partnership between the health service, police, and local government partners designed to prevent violence.
Setting Cardiff, Wales, and 14 comparison cities designated “most similar” by the Home Office in England and Wales.
Intervention After a 33 month development period, anonymised data relevant to violence prevention (precise violence location, time, days, and weapons) from patients attending emergency departments in Cardiff and reporting injury from violence were shared over 51 months with police and local authority partners and used to target resources for violence prevention.
Main outcome measures Health service records of hospital admissions related to violence and police records of woundings and less serious assaults in Cardiff and other cities after adjustment for potential confounders.
Results Information sharing and use were associated with a substantial and significant reduction in hospital admissions related to violence. In the intervention city (Cardiff) rates fell from seven to five a month per 100 000 population compared with an increase from five to eight in comparison cities (adjusted incidence rate ratio 0.58, 95% confidence interval 0.49 to 0.69). Average rate of woundings recorded by the police changed from 54 to 82 a month per 100 000 population in Cardiff compared with an increase from 54 to 114 in comparison cities (adjusted incidence rate ratio 0.68, 0.61 to 0.75). There was a significant increase in less serious assaults recorded by the police, from 15 to 20 a month per 100 000 population in Cardiff compared with a decrease from 42 to 33 in comparison cities (adjusted incidence rate ratio 1.38, 1.13 to 1.70).
Conclusion An information sharing partnership between health services, police, and local government in Cardiff, Wales, altered policing and other strategies to prevent violence based on information collected from patients treated in emergency departments after injury sustained in violence. This intervention led to a significant reduction in violent injury and was associated with an increase in police recording of minor assaults in Cardiff compared with similar cities in England and Wales where this intervention was not implemented.
doi:10.1136/bmj.d3313
PMCID: PMC3116927  PMID: 21680632
3.  Involvement of deprivation and environmental lead in neural tube defects: a matched case-control study 
Archives of Disease in Childhood  1997;76(2):107-112.
Accepted 1 October 1996

OBJECTIVE—To analyse the prevalence of neural tube defects in small geographical areas and seek to explain any spatial variations with reference to environmental lead and deprivation.
SETTING—The Fylde of Lancashire in the north west of England.
DESIGN—Cases were ascertained as part of a prospective survey of major congenital malformations in babies born in the Fylde to residents there between 1957 and 1981. A matched case-control analysis used infants with cardiovascular system, alimentary tract, and urinary system malformations as controls. Conditional logistic regression was used to assess the effects of more than 10 µg/l lead in drinking water and the Townsend deprivation score.
RESULTS—The prevalence of neural tube defects in 1957-73 was higher in Blackpool, Fleetwood, and North Fylde, whereas the three control groups showed no significant spatial variation. In 1957-81 mothers living in electoral wards with either a higher proportion of houses with more than 10 µg/l lead in the water or a higher deprivation score had a greater risk of having a baby with a neural tube defect. For spina bifida and cranium bifidum alone, this was also true. For anencephaly, deprivation was less important although the effect of lead was still seen. In some neural tube defects, lead may act independently of other possible factors associated with deprivation. It seemed unlikely that lead levels changed significantly during the survey. The percentage of houses with 10 µg/l or more of lead in the water in 1984-5 was similar to that found in Great Britain 10 years previously.
CONCLUSION—There is evidence to suggest that lead is one cause of neural tube defects, especially anencephaly. This could link the known preventive actions of hard water and folic acid. Calcium is a toxicological antagonist of lead. One cause of a deficiency of folic acid is impaired absorption secondary to zinc deficiency, which may be produced or exacerbated by lead.


PMCID: PMC1717078  PMID: 9068297
4.  Comparison of complementary and alternative medicine use: reasons and motivations between two tertiary children's hospitals 
Archives of Disease in Childhood  2005;91(2):153-158.
Aims
To compare prevalence, reasons, motivations, initiation, perceived helpfulness, and communication of complementary and alternative medicine (CAM) use between two tertiary children's hospitals.
Methodology
A study, using a face‐to‐face questionnaire, of 500 children attending the University Hospital of Wales, Cardiff, UK was compared to an identical study of 503 children attending the Royal Children's Hospital, Melbourne, Australia.
Results
One year CAM use in Cardiff was lower than Melbourne (41% v 51%; OR = 0.67, 95% CI 0.52–0.85), reflected in non‐medicinal use (OR = 0.41, 95% CI 0.29–0.58) and general paediatric outpatients (OR = 0.38, 95% CI 0.21–0.67). Compared to Melbourne, factors associated with lower CAM use in Cardiff included families born locally (father: OR = 0.58, 95% CI 0.44–0.77) or non‐tertiary educated parents (mother: OR = 0.54, 95% CI 0.38–0.77). Cardiff participants used less vitamin C (OR = 0.31, 95% CI 0.18–0.51) and herbs (OR = 0.49, 95% CI 0.34–0.71), attended less chiropractors (OR = 0.25, 95% CI 0.06–0.37) and naturopaths (OR = 0.08, 95% CI 0.02–0.33), but saw more reflexologists (OR = 3.33, 95% CI 1.08–10.29). In Cardiff, CAM was more popular for relaxation (OR = 1.92, 95% CI 1.03–3.57) but less for colds/coughs (OR = 0.4, 95% CI 0.27–0.73). Most CAM was self‐initiated (by parent) in Cardiff and Melbourne (74% v 70%), but Cardiff CAM users perceived it less helpful (OR = 0.46, 95% CI 0.31–0.68). Non‐disclosure of CAM use was high in Cardiff and Melbourne (66% v 63%); likewise few doctors/nurses documented recent medicinal CAM use in inpatient notes (0/21 v 2/22).
Conclusions
The differences in CAM use may reflect variation in sociocultural factors influencing reasons, motivations, attitudes, and availability. The regional variation in use and poor communication highlights the importance of local policy development.
doi:10.1136/adc.2005.074872
PMCID: PMC2082694  PMID: 16166178
complementary and alternative medicine; comparison; reasons; motivations
5.  Exploratory spatial data analysis for the identification of risk factors to birth defects 
BMC Public Health  2004;4:23.
Background
Birth defects, which are the major cause of infant mortality and a leading cause of disability, refer to "Any anomaly, functional or structural, that presents in infancy or later in life and is caused by events preceding birth, whether inherited, or acquired (ICBDMS)". However, the risk factors associated with heredity and/or environment are very difficult to filter out accurately. This study selected an area with the highest ratio of neural-tube birth defect (NTBD) occurrences worldwide to identify the scale of environmental risk factors for birth defects using exploratory spatial data analysis methods.
Methods
By birth defect registers based on hospital records and investigation in villages, the number of birth defects cases within a four-year period was acquired and classified by organ system. The neural-tube birth defect ratio was calculated according to the number of births planned for each village in the study area, as the family planning policy is strictly adhered to in China. The Bayesian modeling method was used to estimate the ratio in order to remove the dependence of variance caused by different populations in each village. A recently developed statistical spatial method for detecting hotspots, Getis's [7], was used to detect the high-risk regions for neural-tube birth defects in the study area.
Results
After the Bayesian modeling method was used to calculate the ratio of neural-tube birth defects occurrences, Getis's statistics method was used in different distance scales. Two typical clustering phenomena were present in the study area. One was related to socioeconomic activities, and the other was related to soil type distributions.
Conclusion
The fact that there were two typical hotspot clustering phenomena provides evidence that the risk for neural-tube birth defect exists on two different scales (a socioeconomic scale at 6.84 km and a soil type scale at 22.8 km) for the area studied. Although our study has limited spatial exploratory data for the analysis of the neural-tube birth defect occurrence ratio and for finding clues to risk factors, this result provides effective clues for further physical, chemical and even more molecular laboratory testing according to these two spatial scales.
doi:10.1186/1471-2458-4-23
PMCID: PMC441386  PMID: 15202947
6.  Pregnancy and Infant Outcomes among HIV-Infected Women Taking Long-Term ART with and without Tenofovir in the DART Trial 
PLoS Medicine  2012;9(5):e1001217.
Diana Gibb and colleagues investigate the effect of in utero tenofovir exposure by analyzing the pregnancy and infant outcomes of HIV-infected women enrolled in the DART trial.
Background
Few data have described long-term outcomes for infants born to HIV-infected African women taking antiretroviral therapy (ART) in pregnancy. This is particularly true for World Health Organization (WHO)–recommended tenofovir-containing first-line regimens, which are increasingly used and known to cause renal and bone toxicities; concerns have been raised about potential toxicity in babies due to in utero tenofovir exposure.
Methods and Findings
Pregnancy outcome and maternal/infant ART were collected in Ugandan/Zimbabwean HIV-infected women initiating ART during The Development of AntiRetroviral Therapy in Africa (DART) trial, which compared routine laboratory monitoring (CD4; toxicity) versus clinically driven monitoring. Women were followed 15 January 2003 to 28 September 2009. Infant feeding, clinical status, and biochemistry/haematology results were collected in a separate infant study. Effect of in utero ART exposure on infant growth was analysed using random effects models.
382 pregnancies occurred in 302/1,867 (16%) women (4.4/100 woman-years [95% CI 4.0–4.9]). 226/390 (58%) outcomes were live-births, 27 (7%) stillbirths (≥22 wk), and 137 (35%) terminations/miscarriages (<22 wk). Of 226 live-births, seven (3%) infants died <2 wk from perinatal causes and there were seven (3%) congenital abnormalities, with no effect of in utero tenofovir exposure (p>0.4). Of 219 surviving infants, 182 (83%) enrolled in the follow-up study; median (interquartile range [IQR]) age at last visit was 25 (12–38) months. From mothers' ART, 62/9/111 infants had no/20%–89%/≥90% in utero tenofovir exposure; most were also zidovudine/lamivudine exposed. All 172 infants tested were HIV-negative (ten untested). Only 73/182(40%) infants were breast-fed for median 94 (IQR 75–212) days. Overall, 14 infants died at median (IQR) age 9 (3–23) months, giving 5% 12-month mortality; six of 14 were HIV-uninfected; eight untested infants died of respiratory infection (three), sepsis (two), burns (one), measles (one), unknown (one). During follow-up, no bone fractures were reported to have occurred; 12/368 creatinines and seven out of 305 phosphates were grade one (16) or two (three) in 14 children with no effect of in utero tenofovir (p>0.1). There was no evidence that in utero tenofovir affected growth after 2 years (p = 0.38). Attained height- and weight for age were similar to general (HIV-uninfected) Ugandan populations. Study limitations included relatively small size and lack of randomisation to maternal ART regimens.
Conclusions
Overall 1-year 5% infant mortality was similar to the 2%–4% post-neonatal mortality observed in this region. No increase in congenital, renal, or growth abnormalities was observed with in utero tenofovir exposure. Although some infants died untested, absence of recorded HIV infection with combination ART in pregnancy is encouraging. Detailed safety of tenofovir for pre-exposure prophylaxis will need confirmation from longer term follow-up of larger numbers of exposed children.
Trial registration
www.controlled-trials.com ISRCTN13968779
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Currently, about 34 million people (mostly in low- and middle-income countries) are infected with HIV, the virus that causes AIDS. At the beginning of the epidemic, more men than women were infected with HIV but now about half of all people living with HIV/AIDS are women, most of who became infected through unprotected sex with an infected partner. In sub-Saharan Africa alone, 12 million women are HIV-positive. Worldwide, HIV/AIDS is the leading cause of death among women of child-bearing age. Moreover, most of the 400,000 children who become infected with HIV every year acquire the virus from their mother during pregnancy or birth, or through breastfeeding, so-called mother-to-child transmission (MTCT). Combination antiretroviral therapy (ART)—treatment with cocktails of powerful antiretroviral drugs—reduces HIV-related illness and death among women, and ART given to HIV-positive mothers during pregnancy and delivery and to their newborn babies greatly reduces MTCT.
Why Was This Study Done?
Because of ongoing international efforts to increase ART coverage, more HIV-positive women in Africa have access to ART now than ever before. However, little is known about pregnancy outcomes among HIV-infected African women taking ART throughout pregnancy for their own health or about the long-term outcomes of their offspring. In particular, few studies have examined the effect of taking tenofovir (an antiretroviral drug that is now recommended as part of first-line ART) throughout pregnancy. Tenofovir readily crosses from mother to child during pregnancy and, in animal experiments, high doses of tenofovir given during pregnancy caused bone demineralization (which weakens bones), kidney problems, and impaired growth among offspring. In this study, the researchers analyze data collected on pregnancy and infant outcomes among Ugandan and Zimbabwean HIV-positive women who took ART throughout pregnancy in the Development of AntiRetroviral Therapy in Africa (DART) trial. This trial was designed to test whether ART could be safely and effectively delivered in Africa without access to the expensive laboratory tests that are routinely used to monitor ART toxicity and efficacy in developed countries.
What Did the Researchers Do and Find?
The pregnancy outcomes of 302 women who became pregnant during the DART trial and information on birth defects among their babies were collected as part of the DART protocol; information on the survival, growth, and development of the infants born to these women was collected in a separate infant study. Most of the women who became pregnant were taking tenofovir-containing ART before and throughout their pregnancies. 58% of the pregnancies resulted in a live birth, 7% resulted in a stillbirth (birth of a dead baby at any time from 22 weeks gestation to the end of pregnancy), and 35% resulted in a termination or miscarriage (before 22 weeks gestation). Of the 226 live births, seven infants died within 2 weeks and seven had birth defects. Similar proportions of the infants exposed and not exposed to tenofovir during pregnancy died soon after birth or had birth defects. Of the 182 surviving infants who were enrolled in the infant study, 14 subsequently died at an average age of 9 months, giving a 1-year mortality of 5%. None of the surviving children who were tested (172 infants) were HIV infected. No bone fractures or major kidney problems occurred during follow-up and prebirth exposure to tenofovir in utero had no effect on growth or weight gain at 2 years (in contrast to a previous US study).
What Do These Findings Mean?
By showing that prebirth tenofovir exposure does not affect pregnancy outcomes or increase birth defects, growth abnormalities, or kidney problems, these findings support the use of tenofovir-containing ART during pregnancy among HIV-positive African women, and suggest that it could also be used to prevent women of child-bearing age acquiring HIV-infection heterosexually. Notably, the observed 5% 1-year infant mortality is similar to the 2%–4% infant mortality normally seen in the region. The absence of HIV infection among the infants born to the DART participants is also encouraging. However, this is a small study (only 111 infants were exposed to tenofovir throughout pregnancy) and women were not randomly assigned to receive tenofovir-containing ART. Consequently, more studies are needed to confirm that tenofovir exposure during pregnancy does not affect pregnancy outcomes or have any long-term effects on infants. Such studies are essential because the use of tenofovir as a treatment for women who are HIV-positive is likely to increase and tenofovir may also be used in the future to prevent HIV acquisition in HIV-uninfected women.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001217.
Information is available from the US National Institute of Allergy and infectious diseases on all aspects of HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment (in several languages)
Information is available from Avert, an international AIDS nonprofit on many aspects of HIV/AIDS, including detailed information on HIV/AIDS treatment and care, women, HIV and AIDS, children, HIV and AIDS, and on HIV/AIDS and pregnancy (some information in English and Spanish); personal stories of women living with HIV are available
More information about the DART trial is available
Additional patient stories about living with HIV/AIDS are available through the nonprofit website Healthtalkonline
doi:10.1371/journal.pmed.1001217
PMCID: PMC3352861  PMID: 22615543
7.  Changing trend of neural tube defects in eastern Turkey. 
STUDY OBJECTIVE--The aim was to study the relationship between birth prevalence of neural tube defect (including anencephaly) in Eastern Turkey before and after the Chernobyl disaster. DESIGN--This was a prospective study of time trends in live births and stillbirths over the years 1985-1990. Medical and sociodemographic data were recorded for the mothers. SETTING--Elazig, Eastern Turkey. SUBJECTS--There were 5240 live births and stillbirths during the study period, 24 of whom had neural tube defect and of these 20 had anencephaly. MAIN RESULTS--Of the 5240 newborns, 24 had a neural tube defect, giving a birth prevalence of 4.5 per 1000 total births. Of these, 20 were anencephalic (3.8 per 1000). In all, of the 2355 conceptions estimated to have occurred prior to the Chernobyl disaster in May 1986, the birth prevalences of total neural tube defect and anencephaly were the same (1.7 per 1000). This contrasts with the years following after Chernobyl, when the birth prevalence of total neural tube defect was 6.9 per 1000 (5.5 per 1000 for anencephaly). The differences were statistically significant (p < 0.001). These two increased rates reached a peak of 12.4 (for total neural tube defects) and 8.9 (for anencephaly) in 1988. In 1989 the rate of total neural tube defects decreased to 10.0 and that of anencephaly to 8.6 per 1000. In 1990 the rate of total neural tube defects fell to 5.6 and that of anencephaly fell to 4.2. CONCLUSIONS--The changes in birth prevalence of neural tube defects might be due to the Chernobyl disaster. However, the increases observed occurred mainly in infants conceived well over a year after the Chernobyl disaster, suggesting that other factors may be responsible.
PMCID: PMC1059708  PMID: 8436892
8.  Impact of Scotland's Smoke-Free Legislation on Pregnancy Complications: Retrospective Cohort Study 
PLoS Medicine  2012;9(3):e1001175.
An analysis of pregnancy data for the whole of Scotland demonstrates a reduction in small-for-gestational-age births and preterm delivery since the introduction of legislation banning smoking in enclosed public spaces.
Background
Both active smoking and environmental tobacco smoke exposure are associated with pregnancy complications. In March 2006, Scotland implemented legislation prohibiting smoking in all wholly or partially enclosed public spaces. The aim of this study was to determine the impact of this legislation on preterm delivery and small for gestational age.
Methods and Findings
We conducted logistic regression analyses using national administrative pregnancy data covering the whole of Scotland. Of the two breakpoints tested, 1 January 2006 produced a better fit than the date when the legislation came into force (26 March 2006), suggesting an anticipatory effect. Among the 716,941 eligible women who conceived between August 1995 and February 2009 and subsequently delivered a live-born, singleton infant between 24 and 44 wk gestation, the prevalence of current smoking fell from 25.4% before legislation to 18.8% after legislation (p<0.001). Three months prior to the legislation, there were significant decreases in small for gestational age (−4.52%, 95% CI −8.28, −0.60, p = 0.024), overall preterm delivery (−11.72%, 95% CI −15.87, −7.35, p<0.001), and spontaneous preterm labour (−11.35%, 95% CI −17.20, −5.09, p = 0.001). In sub-group analyses, significant reductions were observed among both current and never smokers.
Conclusions
Reductions were observed in the risk of preterm delivery and small for gestational age 3 mo prior to the introduction of legislation, although the former reversed partially following the legislation. There is growing evidence of the potential for tobacco control legislation to have a positive impact on health.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The risks of smoking during pregnancy, both on mother and fetus, are well established: women who smoke during pregnancy are more likely to have a miscarriage. Smoking can cause placental problems, such as placental abruption, which can result in heavy bleeding during pregnancy, which is dangerous for both mother and baby. Other dangers of smoking during pregnancy include the baby being born too early (premature birth), the baby being below average weight (small for gestational age), birth defects, and infant death. Because of the serious damage to health caused by smoking, in 2005, under the auspices of the World Health Organization, countries adopted the Framework Convention on Tobacco Control to protect present and future generations from the devastating health, social, environmental, and economic consequences of tobacco consumption and exposure to tobacco smoke. Article 8 of the treaty obliges member states who have ratified the treaty—168 so far—to protect all people from exposure to tobacco smoke in indoor workplaces, public transport, and indoor public places. As a result, many countries around the world have banned smoking in public places.
Why Was This Study Done?
Scotland was the first country in the United Kingdom to ban smoking in public places, which was implemented as part of the Smoking, Health and Social Care (Scotland) Bill on 26 March 2006. Previous studies have shown that the introduction of the legislation led directly to a reduction in smoking and also a reduction in environmental tobacco smoke exposure in adults and children. Furthermore, the Scottish legislation has been accompanied by significant reductions in both cardiovascular and respiratory disease. Because of the known risks of smoking during pregnancy, the researchers wanted to investigate whether the change in policy on smoking in public places had positive benefits on the health of mothers and babies. They evaluated this by measuring the rates of preterm delivery and small for gestational age before and after the Scottish legislation went into effect.
What Did the Researchers Do and Find?
The researchers collected information on preterm delivery and small for gestational age in all single babies born live at 22–44 weeks gestation between 1 January 1996 and 31 December 2009 by using the Scottish Morbidity Record (SMR2), which collects relevant information on all women discharged from Scottish maternity hospitals, including maternal and infant characteristics and pregnancy complications. The researchers categorized preterm delivery into mild, moderate, and extreme depending on how much before 37 weeks the baby was born. They defined small for gestational age as the smallest 10% (below the 10th centile) for sex-specific birth weight at delivery, and very small for gestational age as the smallest 3% (below the 3rd centile), for all deliveries in Scotland over the study period. As some people may have stopped smoking in anticipation of the smoking ban, in their statistical model, the researchers included two possible breakpoints for the effect of the legislation—the actual date of implementation and 1 January 2006.
The researchers found that of the 716,968 pregnancies (the number eligible for inclusion in the study), 99.9% of women had their smoking status recorded, and among these 23.9% were current smokers, 57.6% never smokers, and 8.7% former smokers. However, following implementation of the legislation the researchers noted that there was a significant reduction in current smokers to 18.8%. In their statistical model, the researchers found that following 1 January 2006, there was a significant drop in overall preterm deliveries, which remained after adjustment for potential confounding factors. Likewise, there was a significant decrease in the number of infants born small, and very small, for gestational age after 1 January 2006. Furthermore, the researchers found that these significant reductions occurred in both mothers who smoked and those who had never smoked.
What Do These Findings Mean?
These findings suggest that the introduction of national, comprehensive smoke-free legislation in Scotland was associated with significant reductions in preterm delivery and babies being born small for gestational age. These findings are plausible and add to the growing evidence of the wide-ranging health benefits of smoke-free legislation, and support the adoption of such legislation in other countries that have yet to implement smoking bans.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001175.
More information is available on the World Health Organization's Framework Convention for Tobacco Control
More information on the Smoking, Health and Social Care (Scotland) Bill is available
The US Centers for Disease Control and Prevention has more information about the risks of smoking in pregnancy, as does the UK National Health Service's smokefree web page
NHS Health Scotland has a website that summarises all the studies to date evaluating the Scottish smoke-free legislation
doi:10.1371/journal.pmed.1001175
PMCID: PMC3295815  PMID: 22412353
9.  Seasonal prevalence of major congenital malformations in the Fylde of Lancashire 1957-1981. 
The seasonal prevalence of major congenital malformations was studied in a prospective survey of 88,449 children born in the circumscribed Fylde of Lancashire to residents there over 25 years. Ascertainment was thought to be as complete as was practically possible because cases were recorded daily by one, and for 17 years the only, paediatrician and a very high rate of necropsies was maintained. The number of malformations were classified by month of maternal last menstrual period and seasonal variation was assessed by three statistical models. Neural tube defects showed a significant seasonal variation in month of last menstrual period but not in month of birth. From May 1956 to April 1968, when the prevalence of neural tube defects was high (5.5 per 1000 total births), conceptions were significantly more common in December to May. For anencephaly alone the figures were not significant, but spina bifida and cranium bifidum were more common in March to May. From May 1968 to April 1981, when the prevalence of neural tube defects fell below the national average, the significant variations disappeared. Seasonality for spina bifida and cranium bifidum was seen only in "singles" (cases with no other major lesion), but for anencephaly it was seen only in "multiples" (cases with other lesions). The three types of cardiac septal defect and persistent ductus each showed a higher prevalence of conceptions at some time during May to October. In contrast the commonest group of cyanotic cases showed no such pattern but with greater numbers in winter. There was evidence of a seasonal variation for bilateral renal agenesis and for vesicoureteric reflux as ascertained. Seasonal prevalence in an aetiological factor for certain malformations of the central nervous system, cardiac and urinary systems.
PMCID: PMC1052870  PMID: 2614322
10.  The Effect of Intermittent Antenatal Iron Supplementation on Maternal and Infant Outcomes in Rural Viet Nam: A Cluster Randomised Trial 
PLoS Medicine  2013;10(6):e1001470.
Beverley-Anne Biggs and colleagues conduct a community-based cluster randomized trial in rural Viet Nam to compare the effect of antenatal iron-folic acid supplementation taken daily or twice weekly on maternal and infant outcomes.
Please see later in the article for the Editors' Summary
Background
Anemia affects over 500 million women, and in pregnancy is associated with impaired maternal and infant outcomes. Intermittent antenatal iron supplementation is an attractive alternative to daily dosing; however, the impact of this strategy on infant outcomes remains unclear. We compared the effect of intermittent antenatal iron supplementation with daily iron supplementation on maternal and infant outcomes in rural Viet Nam.
Methods and Findings
This cluster randomised trial was conducted in Ha Nam province, Viet Nam. 1,258 pregnant women (<16 wk gestation) in 104 communes were assigned to daily iron–folic acid (IFA), twice weekly IFA, or twice weekly multiple micronutrient (MMN) supplementation. Primary outcome was birth weight. Mean birth weight was 3,148 g (standard deviation 416). There was no difference in the birth weights of infants of women receiving twice weekly IFA compared to daily IFA (mean difference [MD] 28 g; 95% CI −22 to 78), or twice weekly MMN compared to daily IFA (MD −36.8 g; 95% CI −82 to 8.2). At 32 wk gestation, maternal ferritin was lower in women receiving twice weekly IFA compared to daily IFA (geometric mean ratio 0.73; 95% CI 0.67 to 0.80), and in women receiving twice weekly MMN compared to daily IFA (geometric mean ratio 0.62; 95% CI 0.57 to 0.68), but there was no difference in hemoglobin levels. Infants of mothers who received twice weekly IFA had higher cognitive scores at 6 mo of age compared to those who received daily IFA (MD 1.89; 95% CI 0.23 to 3.56).
Conclusions
Twice weekly antenatal IFA or MMN did not produce a clinically important difference in birth weight, when compared to daily IFA supplementation. The significant improvement in infant cognitive outcomes at 6 mo of age following twice weekly antenatal IFA requires further exploration, and provides additional support for the use of intermittent, rather than daily, antenatal IFA in populations with low rates of iron deficiency.
Trial registration
Australia New Zealand Clinical Trials Registry 12610000944033
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Anemia is a common condition in which the blood does not supply the body with enough oxygen because of a low number of red blood cells or low levels of hemoglobin—the iron-containing pigment that enables red blood cells to carry oxygen. Iron deficiency is the most common cause of anemia worldwide and, according to the World Health Organization, affects over 2 billion people: half of all pregnant women and 40% of preschool children in low- and middle-income countries are thought to be anemic. Anemia contributes to 20% of all maternal deaths and is also linked to increased maternal morbidity, higher rates of preterm birth and low birth weight, and reduced infant survival, with potential long-term consequences for child growth and development. Identifying and treating iron deficiency anemia is therefore a global health priority.
Why Was This Study Done?
Daily iron–folic acid supplementation given from early in pregnancy is the standard recommended approach to prevent and treat anemia in pregnant women, but recently the World Health Organization recommended intermittent use because of poor compliance with daily regimes (because of side effects) and poor bowel absorption. However, the evidence from many of the studies used to support this recommendation was of poor quality, and so it remains unclear whether intermittent supplementation is as, or more, effective than daily supplementation, especially in lower income settings where antenatal testing for anemia is not readily available. So in this study, the researchers conducted a community-based cluster randomized trial (where groups of people are randomized, rather than individuals) in rural Viet Nam to compare the effect of antenatal iron–folic acid supplementation taken twice weekly (either alone, or in combination with other micronutrients) with daily iron–folic acid supplementation, on maternal and infant outcomes during the first six months of life.
What Did the Researchers Do and Find?
The researchers randomized 104 communes in Ha Nam Province, Viet Nam, and enrolled 1,258 women who were less than 16 weeks pregnant into the study between September and November 2010. Although the researchers intended to register the trial before the study started, registration was delayed by a month because the supplements arrived earlier than the researchers anticipated, and they thought it best to start recruiting at that time to avoid the Vietnamese New Year, when women might be travelling. Each woman was interviewed and had blood taken for hemoglobin and iron indices (ferritin) before receiving daily iron–folic acid supplementation (426 women), twice weekly iron–folic acid supplementation (425 women), or twice weekly iron–folic acid supplementation plus micronutrients (407 women). The women had follow-up assessments at 32 weeks gestation, delivery, and at six months postpartum: their infants were assessed at birth and at six months old.
The researchers found that at enrollment, the women's average hemoglobin concentration was 123 g/l, and 12.6% of the women were anemic. At 32 weeks gestation, 10.8% of the women were anemic, but there was no difference in hemoglobin levels between the three supplement groups. The average ferritin level was 75.6 µg/l at enrollment, with 2.2% of women iron deficient. Ferritin levels decreased from enrollment to 32 weeks gestation in all supplement groups but were lower in women who took twice weekly supplements. The researchers also found that birth weight (the primary outcome) was similar in all supplement groups, and there were also no differences in gestational age or in the risk of prematurity, stillbirth, or early neonatal death. At six months, there were also no differences in the levels of infant hemoglobin, prevalence of anemia, or growth rates. However, infants born to mothers in the twice weekly iron–folic acid group had improved cognitive development compared to infants born to mothers in the daily supplement group. Finally, the researchers found that adherence rates were significantly higher in the twice weekly iron–folic acid supplement group compared to the once daily regime.
What Do These Findings Mean?
These findings suggest that in an area of Southeast Asia with low anemia prevalence, once daily antenatal supplementation with iron–folic acid did not provide any benefits in birth weight or improved infant growth over twice weekly supplementation. Furthermore, twice weekly supplementation with iron–folic acid was associated with improved maternal adherence rates and also improved cognitive development in infants aged six months—a finding that requires further study and provides added support for the use of intermittent iron–folic acid supplementation over daily supplementation.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001470.
The World Health Organization website has comprehensive information on anemia, including a report of global estimates and the guideline Intermittent Iron and Folic Acid Supplementation in Non-Anaemic Pregnant Women
Wikipedia provides information on iron supplementation (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001470
PMCID: PMC3708703  PMID: 23853552
11.  Spina Bifida and Anencephalus in Greater London 
Journal of Medical Genetics  1973;10(3):209-234.
In order to make comparisons with the findings in a high frequency area, South Wales, with those in a low frequency area, south-east England, a birth frequency and family study was made of all births with neural tube malformations (spina bifida cystica, encephalocele, anencephaly, and iniencephaly) in 32 of the 33 London Boroughs over a 3-year period from 1 April 1965 to 31 March 1968. The births were ascertained through local authority registers, stillbirth and infant death certificates, and hospital records. The frequencies found were 1·54 for spina bifida (including encephalocele) and 1·41 for anencephaly (including iniencephaly). This was less than four tenths of the South Wales frequency. Evidence of an excess of winter births was found for both types of malformation, with a peak for conceptions in February, March, and April.
The parents of 870 of the original 1209 index patients were traced and visited for the family survey. The usual social class effect was seen, a deficit of fathers in social class I and II. The birth order distribution of legitimately born patients standardized for maternal age showed only a small excess of firstborn and a deficit rather than an excess of lateborn. For maternal age, however, standardized for birth order, there was an excess of patients born to mothers under 20 and over 35 years of age. The whole family study sample showed a striking excess of patients born to parents from India and Pakistan compared to parents born in the West Indies in relation to households of immigrant parents in the 1966 sample Census. A small sample of 164 patients with matched controls had more parents born in Ireland and India and Pakistan and fewer born in south-east England and the West Indies than the controls.
The proportions of sibs affected with spina bifida and anencephaly were 3·42% for spina bifida index patients and 5·44% for anencephaly. For patients born after the index patient the proportions were 5·17 and 4·17%, respectively. The overall risk to sibs was lower than that shown in the South Wales survey, but substantially higher relative to the population birth frequency. The risk to sibs was not apparently influenced by father's social class but there was an indication of an effect of mother's father's social class, with a lower risk where mother had grown up in a class I, II, or IIIa home. There was no apparent influence of grandparental birth place. There was no apparent effect of a relative affected other than a sib. Among cousins a significant increase over the population birth frequency was seen only in mother's sisters' children.
The findings, like those of earlier surveys, suggest a multifactorial aetiology of the neural tube malformations, depending both on genetic predisposition and environmental triggers.
PMCID: PMC1013025  PMID: 4590246
12.  Global Burden of Sickle Cell Anaemia in Children under Five, 2010–2050: Modelling Based on Demographics, Excess Mortality, and Interventions 
PLoS Medicine  2013;10(7):e1001484.
Frédéric Piel and colleagues combine national sickle cell anemia (SCA) frequencies with projected demographic data to estimate the number of SCA births in children under five globally from 2010 to 2050, and then estimate the number of lives that could be be saved following implementation of specific health interventions starting in 2015.
Please see later in the article for the Editors' Summary
Background
The global burden of sickle cell anaemia (SCA) is set to rise as a consequence of improved survival in high-prevalence low- and middle-income countries and population migration to higher-income countries. The host of quantitative evidence documenting these changes has not been assembled at the global level. The purpose of this study is to estimate trends in the future number of newborns with SCA and the number of lives that could be saved in under-five children with SCA by the implementation of different levels of health interventions.
Methods and Findings
First, we calculated projected numbers of newborns with SCA for each 5-y interval between 2010 and 2050 by combining estimates of national SCA frequencies with projected demographic data. We then accounted for under-five mortality (U5m) projections and tested different levels of excess mortality for children with SCA, reflecting the benefits of implementing specific health interventions for under-five patients in 2015, to assess the number of lives that could be saved with appropriate health care services. The estimated number of newborns with SCA globally will increase from 305,800 (confidence interval [CI]: 238,400–398,800) in 2010 to 404,200 (CI: 242,500–657,600) in 2050. It is likely that Nigeria (2010: 91,000 newborns with SCA [CI: 77,900–106,100]; 2050: 140,800 [CI: 95,500–200,600]) and the Democratic Republic of the Congo (2010: 39,700 [CI: 32,600–48,800]; 2050: 44,700 [CI: 27,100–70,500]) will remain the countries most in need of policies for the prevention and management of SCA. We predict a decrease in the annual number of newborns with SCA in India (2010: 44,400 [CI: 33,700–59,100]; 2050: 33,900 [CI: 15,900–64,700]). The implementation of basic health interventions (e.g., prenatal diagnosis, penicillin prophylaxis, and vaccination) for SCA in 2015, leading to significant reductions in excess mortality among under-five children with SCA, could, by 2050, prolong the lives of 5,302,900 [CI: 3,174,800–6,699,100] newborns with SCA. Similarly, large-scale universal screening could save the lives of up to 9,806,000 (CI: 6,745,800–14,232,700) newborns with SCA globally, 85% (CI: 81%–88%) of whom will be born in sub-Saharan Africa. The study findings are limited by the uncertainty in the estimates and the assumptions around mortality reductions associated with interventions.
Conclusions
Our quantitative approach confirms that the global burden of SCA is increasing, and highlights the need to develop specific national policies for appropriate public health planning, particularly in low- and middle-income countries. Further empirical collaborative epidemiological studies are vital to assess current and future health care needs, especially in Nigeria, the Democratic Republic of the Congo, and India.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
More than seven million babies are born each year with a structural or functional abnormality. Although some birth defects are caused by environmental factors, many are caused by the inheritance of a defective gene. One common inherited birth defect is sickle cell anemia (SCA). SCA arises when a baby inherits the gene for sickle hemoglobin (HbS), a structural variant of normal adult hemoglobin (HbA, the protein in the disc-shaped red blood cells that carry oxygen round the body), from both its parents. Every cell in the human body contains two full sets of genes, and babies inherit one set of genes from each parent. The parents usually each have one HbS gene and one HbA gene, and are unaffected. However, the red blood cells of their offspring who inherit two copies of HbS develop a sickle (crescent) shape. Sickle cells can block blood vessels in the limbs and organs and have a shorter lifespan than normal red blood cells, which causes anemia. Together, these changes can cause acute pain and organ damage, and can increase the risk of severe infections. SCA can be prevented by prenatal diagnosis and managed by interventions such as the provision of antibiotics and vaccination to prevent infections.
Why Was This Study Done?
Without early diagnosis and treatment, children with SCA often die within the first few years of life. Having one copy of the HbS gene provides people with protection from malaria, therefore SCA occurs mainly in low- and middle-income countries in tropical regions, where early diagnosis and treatment is often unavailable. Recent improvements in overall infant and childhood survival in these countries and population migration to higher-income countries mean that the global burden of SCA is likely to increase over the coming decades. To date, no one has tried to quantify this increase, although this information is needed to guide decisions on public health spending. In this modeling study, the researchers assess the size of the expected global burden of SCA between 2010 and 2050 in children under five years old and estimate the number of newborn lives that might be saved by implementation of various health interventions.
What Did the Researchers Do and Find?
The researchers used estimates of national SCA frequencies and data on projected birth rates to calculate that the number of newborns with SCA will increase from about 305,800 in 2010 to about 404,200 in 2050. They estimated that Nigeria, the Democratic Republic of Congo (DRC), and India accounted for 57% of newborns with SCA in 2010, and that Nigeria and the DRC will probably still be the countries most in need of policies for the prevention and management of SCA in 2050. The researchers then assessed how many newborns might be saved by the implementation of various health measures in 2015 that affect excess mortality (the difference between the frequency of SCA in newborns and in five-year-olds divided by the frequency of SCA in newborns) among children born with SCA. Implementation of prenatal diagnosis and newborn screening programs, and provision of antibiotics and vaccinations (interventions assumed by the researchers to reduce excess mortality from 90% to 50% in low- and middle-income countries and from 10% to 5% in high-income countries) could prolong the life of more than five million newborns with SCA by 2050. Implementation of universal screening and provision of other specific measures predicted to reduce excess mortality to 5% and 0% in low-to-middle-income countries and high-income countries, respectively, could save nearly ten million lives by 2050.
What Do These Findings Mean?
In estimating the global burden of SCA in children under five years old between 2010 and 2050 and the number of newborn lives that could be saved by implementation of health interventions, the researchers made numerous assumptions reflected in the uncertainty associated with the projections. For example, they assumed that implementation of specific interventions would lead to an immediate reduction of excess mortality in newborns with SCA. The study's findings confirm, however, that the global burden of SCA is increasing and indicate that the implementation of specific interventions could extend the lives of millions of newborns with SCA. Although further studies are needed to assess the current and future health care needs of children with SCA, these findings highlight the need to develop and implement national public health planning and funding policies for SCA, particularly in low- and middle-income countries.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001484.
This study is further discussed in a PLOS Medicine Perspective by Edward Fottrell and David Osrin
The US National Heart, Lung, and Blood Institute provides detailed information (including personal stories) about sickle cell anemia (in English and Spanish)
The UK National Health Service Choices website also provides detailed information and a personal story about sickle cell anemia
The Sickle Cell Society, a UK-based not-for-profit organization, provides information for patients and carers and includes a children's website
The World Health Organization has a factsheet on sickle cell anemia and other inherited hemoglobin diseases (in several languages)
MedlinePlus provides links to further resources about sickle cell anemia (in English and Spanish)
The Malaria Atlas Project provides epidemiological information on the inherited blood disorders (including sickle cell anemia) that affect our response to malaria infection
The Global Sickle Cell Disease Network is a portal bringing together leading sickle cell disease researchers and clinicians from high-, middle-, and low-income countries to form a network
doi:10.1371/journal.pmed.1001484
PMCID: PMC3712914  PMID: 23874164
13.  Association between Prenatal Exposure to Antiretroviral Therapy and Birth Defects: An Analysis of the French Perinatal Cohort Study (ANRS CO1/CO11) 
PLoS Medicine  2014;11(4):e1001635.
Jeanne Sibiude and colleagues use the French Perinatal Cohort to estimate the prevalence of birth defects in children born to HIV-infected women receiving antiretroviral therapy during pregnancy.
Please see later in the article for the Editors' Summary
Background
Antiretroviral therapy (ART) has major benefits during pregnancy, both for maternal health and to prevent mother-to-child transmission of HIV. Safety issues, including teratogenic risk, need to be evaluated. We estimated the prevalence of birth defects in children born to HIV-infected women receiving ART during pregnancy, and assessed the independent association of birth defects with each antiretroviral (ARV) drug used.
Methods and Findings
The French Perinatal Cohort prospectively enrolls HIV-infected women delivering in 90 centers throughout France. Children are followed by pediatricians until 2 y of age according to national guidelines.
We included 13,124 live births between 1994 and 2010, among which, 42% (n = 5,388) were exposed to ART in the first trimester of pregnancy. Birth defects were studied using both European Surveillance of Congenital Anomalies (EUROCAT) and Metropolitan Atlanta Congenital Defects Program (MACDP) classifications; associations with ART were evaluated using univariate and multivariate logistic regressions. Correction for multiple comparisons was not performed because the analyses were based on hypotheses emanating from previous findings in the literature and the robustness of the findings of the current study. The prevalence of birth defects was 4.4% (95% CI 4.0%–4.7%), according to the EUROCAT classification. In multivariate analysis adjusting for other ARV drugs, maternal age, geographical origin, intravenous drug use, and type of maternity center, a significant association was found between exposure to zidovudine in the first trimester and congenital heart defects: 2.3% (74/3,267), adjusted odds ratio (AOR) = 2.2 (95% CI 1.3–3.7), p = 0.003, absolute risk difference attributed to zidovudine +1.2% (95% CI +0.5; +1.9%). Didanosine and indinavir were associated with head and neck defects, respectively: 0.5%, AOR = 3.4 (95% CI 1.1–10.4), p = 0.04; 0.9%, AOR = 3.8 (95% CI 1.1–13.8), p = 0.04. We found a significant association between efavirenz and neurological defects (n = 4) using the MACDP classification: AOR = 3.0 (95% CI 1.1–8.5), p = 0.04, absolute risk +0.7% (95% CI +0.07%; +1.3%). But the association was not significant using the less inclusive EUROCAT classification: AOR = 2.1 (95% CI 0.7–5.9), p = 0.16. No association was found between birth defects and lopinavir or ritonavir with a power >85% for an odds ratio of 1.5, nor for nevirapine, tenofovir, stavudine, or abacavir with a power >70%. Limitations of the present study were the absence of data on termination of pregnancy, stillbirths, tobacco and alcohol intake, and concomitant medication.
Conclusions
We found a specific association between in utero exposure to zidovudine and heart defects; the mechanisms need to be elucidated. The association between efavirenz and neurological defects must be interpreted with caution. For the other drugs not associated with birth defects, the results were reassuring. Finally, whatever the impact that some ARV drugs may have on birth defects, it is surpassed by the major role of ART in the successful prevention of mother-to-child transmission of HIV.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
AIDS and HIV infection are commonly treated with antiretroviral therapy (ART), a combination of individual drugs that work together to prevent the replication of the virus and further spread of the infection. Starting in the 1990s, studies have shown that ART of HIV-infected women can substantially reduce transmission of the virus to the child during pregnancy and birth. Based on these results, ART was subsequently recommended for pregnant women. Since 2004, ART has been standard therapy for pregnant women with HIV/AIDS in high-income countries, and it is now recommended for all HIV-infected women worldwide. Several different antiviral drug combinations have been shown to be effective and are used to prevent mother-to-infant transmission. However, as with any other drugs taken during pregnancy, there is concern that ART can harm the developing fetus.
Why Was This Study Done?
Several previous studies have assessed the risk that ART taken by a pregnant woman might pose to her developing fetus, but the results have been inconsistent. Animal studies suggested an elevated risk for some drugs but not others. While some clinical studies have reported increases in birth defects in children born to mothers on ART, others have shown no such increase.
The discrepancy may be due to differences between the populations included in the studies and the different methods used to diagnose birth defects. Additional large studies are therefore necessary to obtain more and better evidence on the potential harm of individual anti-HIV drugs to children exposed during pregnancy. So in this study, the authors conducted a large cohort study in France to assess the relationship between different antiretroviral drugs and specific birth defects.
What Did the Researchers Do and Find?
The researchers used a large national health database known as the French Perinatal Cohort that contains information on HIV-infected mothers who delivered infants in 90 centers throughout France. Pediatricians follow all children, whatever their HIV status, to two years of age, and health statistics are collected according to national health-care guidelines. Analyzing the records, the researchers estimated the rate at which birth defects occurred in children exposed to antiretroviral drugs during pregnancy.
The researchers included 13,124 children who were born alive between 1994 and 2010 and had been exposed to ART during pregnancy. Children exposed in the first trimester of pregnancy, and those exposed during the second or third trimester, were compared to a control group (children not exposed to the drug during the whole pregnancy). Using two birth defect classification systems (EUROCAT and MACDP—MACDP collects more details on disease classification than EUROCAT), the researchers sought to detect a link between the occurrence of birth defects and exposure to individual antiretroviral drugs.
They found a small increase in the risk for heart defects in children with exposure to zidovudine. They also found an association between efavirenz exposure and a small increase in neurological defects, but only when using the MACDP classification system. The authors found no association between other antiretroviral drugs, including nevirapine (acting similar to efavirenz); tenofovir, stavudine, and abacavir (all three acting similar to zidovudine); and lopinavir and ritonavir (proteinase inhibitors) and any type of birth defect.
What Do These Findings Mean?
These findings show that, overall, the risks of birth defects in children exposed to antiretroviral drugs in utero are small when considering the clear benefit of preventing mother-to-child transmission of HIV. However, where there are safe and effective alternatives, it might be appropriate to avoid use by pregnant women of those drugs that are associated with elevated risks of birth defects.
Worldwide, a large number of children are exposed to zidovudine in utero, and these results suggest (though cannot prove) that these children may be at a slightly higher risk of heart defects. Current World Health Organization (WHO) guidelines for the prevention of mother-to-child transmission no longer recommend zidovudine for first-line therapy.
The implications of the higher rate of neurological birth defects observed in infants exposed to efavirenz in the first trimester are less clear. The EUROCAT classification excludes minor neurological abnormalities without serious medical consequences, and so the WHO guidelines that stress the importance of careful clinical follow-up of children with exposure to efavirenz seem adequate, based on the findings of this study. The study is limited by the lack of data on the use of additional medication and alcohol and tobacco use, which could have a direct impact on fetal development, and by the absence of data on birth defects and antiretroviral drug exposure from low-income countries. However, the findings of this study overall are reassuring and suggest that apart from zidovudine and possibly efavirenz, other antiretroviral drugs are not associated with birth defects, and their use during pregnancy does not pose a risk to the infant.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001635.
This study is further discussed in a PLOS Medicine Perspective by Mofenson and Watts
The World Health Organization has a webpage on mother-to-child transmission of HIV
The US National Institutes of Health provides links to additional information on mother-to-child transmission of HIV
The Elizabeth Glaser Pediatric AIDS Foundation also has a webpage on mother-to-child transmission
The French Perinatal Cohort has a webpage describing the cohort and its main publications (in French, with a summary in English)
doi:10.1371/journal.pmed.1001635
PMCID: PMC4004551  PMID: 24781315
14.  Drug prescribing by GPs in Wales and in England. 
There is a large excess in prescribing costs by GPs in Wales compared with England. This excess amounts to about 30%, equivalent at present to over pounds 11 m a year. The pattern of drug prescribing by GPs and of patient consultation was studied in random samples of electors in Cardiff and Bristol. Overall, more subjects in Cardiff had received prescriptions, and the average number of scripts for each person was higher than in England in the same period. The pattern for consultations was similar. For both prescriptions and consultations the rates were higher in Wales and the difference from those in England seemed to be greater for women than for men. There was no consistent difference between the two cities in the proportions of those who had consulted who received a script, nor was there any evidence that subjects in Cardiff received more prescriptions without a consultation. In both cities similar proportions of subjects bought drugs from chemists without a prescription.
PMCID: PMC1052055  PMID: 7400723
15.  Myocilin polymorphisms and high myopia in subjects of European origin 
Molecular Vision  2009;15:213-222.
Purpose
Three previous studies have tested for an association between high myopia and polymorphisms in the open angle glaucoma gene, myocilin (MYOC), all in subjects of Chinese ethnicity. In two of the studies, a significant association was found while in the third, there was no association. We sought to investigate the association between high myopia and polymorphisms in MYOC in subjects of European ethnicity.
Methods
Subjects were recruited from two sites, Cardiff University in the UK and Duke University in the United States. The Cardiff University cohort was comprised of 164 families with high myopia (604 subjects) plus 112 unrelated, highly myopic cases and 114 emmetropic controls. The Duke University cohort was comprised of 87 families with high myopia (362 subjects) plus 59 unrelated, highly myopic cases. Subject DNA was genotyped with a panel of MYOC single nucleotide polymorphisms (SNPs) including those found previously associated with high myopia. The Cardiff cohort was also genotyped for two flanking microsatellite markers analyzed in prior studies. Association between high myopia and MYOC polymorphisms was assessed using the Unphased program.
Results
Since there was no evidence of heterogeneity in genotype frequencies between families and singleton samples or between cohorts, both subject groups (families and unrelated subjects) from both recruitment sites were analyzed jointly for those SNPs genotyped in common. Two variants showed significant association before correction for multiple testing. These two variants were rs16864720 (p=0.043) and NGA17 (p=0.026). However, there was no significant association after Bonferroni correction. The estimated relative risk (RR) conferred by each of the MYOC variants was low (RR<1.5).
Conclusions
Our results suggest that MYOC polymorphisms have a very low, or possibly negligible, influence on high myopia susceptibility in subjects of European ethnicity.
PMCID: PMC2632735  PMID: 19180258
16.  Spatiotemporal Patterns of Japanese Encephalitis in China, 2002–2010 
Objective
The aim of the study is to examine the spatiotemporal pattern of Japanese Encephalitis (JE) in mainland China during 2002–2010. Specific objectives of the study were to quantify the temporal variation in incidence of JE cases, to determine if clustering of JE cases exists, to detect high risk spatiotemporal clusters of JE cases and to provide evidence-based preventive suggestions to relevant stakeholders.
Methods
Monthly JE cases at the county level in mainland China during 2002–2010 were obtained from the China Information System for Diseases Control and Prevention (CISDCP). For the purpose of the analysis, JE case counts for nine years were aggregated into four temporal periods (2002; 2003–2005; 2006; and 2007–2010). Local Indicators of Spatial Association and spatial scan statistics were performed to detect and evaluate local high risk space-time clusters.
Results
JE incidence showed a decreasing trend from 2002 to 2005 but peaked in 2006, then fluctuated over the study period. Spatial cluster analysis detected high value clusters, mainly located in Southwestern China. Similarly, we identified a primary spatiotemporal cluster of JE in Southwestern China between July and August, with the geographical range of JE transmission increasing over the past years.
Conclusion
JE in China is geographically clustered and its spatial extent dynamically changed during the last nine years in mainland China. This indicates that risk factors for JE infection are likely to be spatially heterogeneous. The results may assist national and local health authorities in the development/refinement of a better preventive strategy and increase the effectiveness of public health interventions against JE transmission.
Author Summary
Japanese encephalitis (JE) is a mosquito-borne disease, which primarily occurs in rural and suburban areas of Southeast Asia and the Western Pacific region. JE still remains a significant public health problem in mainland China, with approximately 50% of global cases annually. Few studies have explored the spatiotemporal patterns of JE cases in China. Here we reported the results of Local Indicators of Spatial Association and spatial scan statistics of JE cases in mainland China at the county level during the four periods: 2002; 2003–2005; 2006; 2007–2010. The primary spatiotemporal cluster of JE was detected in Southwestern China between July and August, with the geographical range of JE transmission increasing over the past years. The results of LISA and spatial scan statistics were consistent which indicates that these methods are reliable and could have wider applications in the fields of disease surveillance and management in China, particularly in the surveillance and monitoring of other vector-borne diseases. These findings may assist in informing prevention and control strategies and increase the effectiveness of public health interventions against JE transmission.
doi:10.1371/journal.pntd.0002285
PMCID: PMC3688550  PMID: 23819000
17.  HIV-1 Drug Resistance Emergence among Breastfeeding Infants Born to HIV-Infected Mothers during a Single-Arm Trial of Triple-Antiretroviral Prophylaxis for Prevention of Mother-To-Child Transmission: A Secondary Analysis 
PLoS Medicine  2011;8(3):e1000430.
Analysis of a substudy of the Kisumu breastfeeding trial by Clement Zeh and colleagues reveals the emergence of HIV drug resistance in HIV-positive infants born to HIV-infected mothers treated with antiretroviral drugs.
Background
Nevirapine and lamivudine given to mothers are transmitted to infants via breastfeeding in quantities sufficient to have biologic effects on the virus; this may lead to an increased risk of a breastfed infant's development of resistance to maternal antiretrovirals. The Kisumu Breastfeeding Study (KiBS), a single-arm open-label prevention of mother-to-child HIV transmission (PMTCT) trial, assessed the safety and efficacy of zidovudine, lamivudine, and either nevirapine or nelfinavir given to HIV-infected women from 34 wk gestation through 6 mo of breastfeeding. Here, we present findings from a KiBS trial secondary analysis that evaluated the emergence of maternal ARV-associated resistance among 32 HIV-infected breastfed infants.
Methods and Findings
All infants in the cohort were tested for HIV infection using DNA PCR at multiple study visits during the 24 mo of the study, and plasma RNA viral load for all HIV-PCR–positive infants was evaluated retrospectively. Specimens from mothers and infants with viral load >1,000 copies/ml were tested for HIV drug resistance mutations. Overall, 32 infants were HIV infected by 24 mo of age, and of this group, 24 (75%) infants were HIV infected by 6 mo of age. Of the 24 infants infected by 6 mo, nine were born to mothers on a nelfinavir-based regimen, whereas the remaining 15 were born to mothers on a nevirapine-based regimen. All infants were also given single-dose nevirapine within 48 hours of birth. We detected genotypic resistance mutations in none of eight infants who were HIV-PCR positive by 2 wk of age (specimens from six infants were not amplifiable), for 30% (6/20) at 6 wk, 63% (14/22) positive at 14 wk, and 67% (16/24) at 6 mo post partum. Among the 16 infants with resistance mutations by 6 mo post partum, the common mutations were M184V and K103N, conferring resistance to lamivudine and nevirapine, respectively. Genotypic resistance was detected among 9/9 (100%) and 7/15 (47%) infected infants whose mothers were on nelfinavir and nevirapine, respectively. No mutations were detected among the eight infants infected after the breastfeeding period (age 6 mo).
Conclusions
Emergence of HIV drug resistance mutations in HIV-infected infants occurred between 2 wk and 6 mo post partum, most likely because of exposure to maternal ARV drugs through breast milk. Our findings may impact the choice of regimen for ARV treatment of HIV-infected breastfeeding mothers and their infected infants.
Trial Registration
ClinicalTrials.gov NCT00146380
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Globally, more than 2 million children are infected with the human immunodeficiency virus (HIV) that causes acquired immunodeficiency syndrome (AIDS), and half a million children are newly infected every year. These infections are mainly the result of mother-to-child transmission (MTCT) of HIV during pregnancy, labor and delivery, or through breastfeeding. MTCT can be greatly reduced by treating HIV-positive mothers and their babies with antiretroviral drugs (ARVs). Without ARVs, up to half of babies born to HIV-positive mothers become infected with HIV. This rate of transmission falls to below 5% if a combination of three ARVs is given to the mother throughout pregnancy. Unfortunately, this triple-ARV therapy is too expensive for use in the resource-limited countries where most MTCT occurs. Instead, many such countries have introduced simpler, shorter ARV regimens such as a daily dose of zidovudine (a nucleoside reverse transcriptase inhibitor or NRTI) given to HIV-positive women during late pregnancy coupled with single-dose nevirapine (a non-nucleoside reverse transcriptase inhibitor or NNRTI) at the onset of labor, zidovudine and lamivudine (another NRTI) during labor and delivery, and single-dose nevirapine given to the baby at birth.
Why Was This Study Done?
More than 95% of HIV-exposed children are born in resource-limited settings where breastfeeding is the norm and is crucial for child survival even though it poses a risk of HIV transmission. Consequently, several recent studies have investigated whether MTCT can be further reduced by giving the mother ARVs while she is breastfeeding. In the Kisumu Breastfeeding Study (KiBS), for example, researchers assessed the effects of giving zidovudine, lamivudine, and either nevirapine or nelfinavir (a protease inhibitor) to HIV-infected women from 34 weeks of pregnancy through 6 months of breastfeeding. The results of KiBS indicate that this approach might be a safe, feasible way to reduce MTCT (see the accompanying paper by Thomas and colleagues). However, low amounts of nevirapine and lamivudine are transferred from mother to infant in breast milk and this exposure to ARVs could induce the development of resistance to ARVs among HIV-infected infants. In this KiBS substudy, the researchers investigate whether HIV drug resistance emerged in any of the HIV-positive infants in the parent study.
What Did the Researchers Do and Find?
In KiBS, 32 infants were HIV-positive at 24 months old; 24 were HIV-positive at 6 months old when their mothers stopped taking ARVs and when breastfeeding was supposed to stop. The researchers analyzed blood samples taken from these infants at various ages and from their mothers for the presence of HIV drug resistance mutations (DNA changes that make HIV resistant to killing by ARVs). They detected no resistance mutations in samples taken from 2-week old HIV-positive infants or from the infants who became infected after the age of 6 months. However, they found resistance mutations in a third and two-thirds of samples taken from 6-week and 6-month old HIV-positive infants, respectively. The commonest mutations conferred resistance to lamivudine and nevirapine. Moreover, resistance mutations were present in samples taken from all the HIV-positive infants whose mothers who had received nelfinavir but in only half those taken from infants whose mothers who had received nevirapine. Finally, most of the mothers of HIV-positive infants had no HIV drug resistance mutations, and only one mother-infant pair had an overlapping pattern of HIV drug resistance mutations.
What Do These Findings Mean?
These findings indicate that, in this KiBS substudy, the emergence of HIV drug resistance mutations in HIV-infected infants whose mothers were receiving ARVs occurred between 2 weeks and 6 months after birth. The pattern of mutations suggests that drug resistance most likely arose through exposure of the infants to low levels of ARVs in breast milk rather than through MTCT of drug-resistant virus. These findings need confirming but suggest that infants exposed to ARVs through breast milk—a situation that may become increasingly common given the reduction in MTCT seen in KiBS and other similar trials—should be carefully monitored for HIV infection. Providers should consider the mothers' regimen when choosing treatment for infants who are found to be HIV-infected despite maternal triple drug prophylaxis. Infants exposed to a maternal regimen with NNRTI drugs should receive first-line therapy with lopinavir/ritonavir, a protease inhibitor. The significance of the NRTI mutations such as M184V with regard to response to therapy needs further evaluation. The M184V mutation may result in hypersensitization to other NRTI drugs and delay or reverse zidovudine resistance. Given the limited availability of alternative drugs for infants in resource-limited settings, provision of the standard WHO-recommended first-line NRTI backbone, which includes 3TC, with enhanced monitoring of the infant to ensure virologic suppression, could be considered. Such an approach should reduce both illness and morbidity among infants who become HIV positive through breastfeeding.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/ 10.1371/journal.pmed.1000430.
The accompanying PLoS Medicine Research article by Thomas and colleagues describes the primary findings of the Kisumu Breastfeeding Study
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIV InSite has comprehensive information on HIV/AIDS
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on children, HIV, and AIDS and on preventing mother-to-child transmission of HIV (in English and Spanish)
UNICEF also has information about children and HIV and AIDS (in several languages)
The World Health organization has information on mother-to-child transmission of HIV (in several languages), and guidance on the use of ARVs for preventing MTCT
doi:10.1371/journal.pmed.1000430
PMCID: PMC3066134  PMID: 21468304
18.  Efficacy and effectiveness of infant vaccination against chronic hepatitis B in the Gambia Hepatitis Intervention Study (1986–90) and in the nationwide immunisation program 
Background
Gambian infants were not routinely vaccinated against hepatitis B virus (HBV) before 1986. During 1986–90 the Gambia Hepatitis Intervention Study (GHIS) allocated 125,000 infants, by area, to vaccination or not and thereafter all infants were offered the vaccine through the nationwide immunisation programme. We report HBV serology from samples of GHIS vaccinees and unvaccinated controls, and from children born later.
Methods
During 2007–08, 2670 young adults born during the GHIS (1986-90) were recruited from 80 randomly selected villages and four townships. Only 28% (753/2670) could be definitively linked to their infant HBV vaccination records (255 fully vaccinated, 23 partially vaccinated [1–2 doses], 475 not vaccinated). All were tested for current HBV infection (HBV surface antigen [HBsAg]) and, if HBsAg-negative, evidence of past infection (HBV core-protein antibody [anti-HBc]). HBsAg-positive samples (each with two age- and sex-matched HBsAg-negative samples) underwent liver function tests. In addition, 4613 children born since nationwide vaccination (in 1990-2007) were tested for HBsAg. Statistical analyses ignore clustering.
Results
Comparing fully vaccinated vs unvaccinated GHIS participants, current HBV infection was 0.8% (2/255) vs 12.4% (59/475), p < 0.0001, suggesting 94% (95% CI 77-99%) vaccine efficacy. Among unvaccinated individuals, the prevalence was higher in males (p = 0.015) and in rural areas (p = 0.009), but adjustment for this did not affect estimated vaccine efficacy. Comparing fully vaccinated vs unvaccinated participants, anti-HBc was 27.4% (70/255) vs 56.0% (267/475), p < 0.00001. Chronic active hepatitis was not common: the proportion of HBsAg-positive subjects with abnormal liver function tests (ALT > 2 ULN) was 4.1%, compared with 0.2% in those HBsAg-negative. The prevalence of antibodies to hepatitis C virus was low (0.5%, 13/2592). In children born after the end of GHIS, HBsAg prevalence has remained low; 1.4% (15/1103) in those born between 1990–97, and 0.3% (9/35150) in those born between 1998–2007.
Conclusions
Infant HBV vaccination achieves substantial protection against chronic carriage in early adulthood, even though approximately a quarter of vaccinated young adults have been infected. This protection persists past the potential onset of sexual activity, reinforcing previous GHIS findings of protection during childhood and suggesting no need for a booster dose. Nationwide infant HBV vaccination is controlling chronic infection remarkably effectively.
doi:10.1186/1471-2334-14-7
PMCID: PMC3898092  PMID: 24397793
19.  Ethnic differences in selective neonatal BCG immunisation: white British children miss out 
Thorax  2005;61(3):247-249.
Background
Tuberculosis (TB) is a re‐emerging problem, especially in the larger cities of Western Europe. Selective neonatal BCG vaccination is recommended for infants at risk of TB in the UK. Neonatal BCG is safe and effective, with an overall protective value of 75%. This study aimed to assess BCG rates among at risk infants in Cardiff and the Vale of Glamorgan, South Wales in the year 2003.
Methods
A cohort of infants at risk for TB was identified from demographic data stored on a computerised maternity activity database. A manual search of immunisation records determined overall rates and the rates for infants belonging to various ethnic groups.
Results: Of 5308 infants born in 2003, 514 (9.6%) were at risk of TB; 423 (82.2%) of these infants were referred postnatally for BCG vaccination and 391 received it. Twenty six of the 41 at risk white British infants missed having a BCG vaccination compared with 47 of 288 Asian infants and seven of 39 black African babies. The rate of BCG vaccination among white British infants was 36.5% compared with 83.6% for Asian infants from the Indian subcontinent (χ2 = 7.25, p<0.01) and 82% for black African infants (χ2 = 4.48, p<0.05).
Conclusions: The overall BCG rate among at risk infants in Cardiff was 76% during the study period. The vaccination rate was poor among white British infants compared with other ethnic groups. Enhanced awareness of health professionals to recognise the need for vaccinating certain white children at risk of TB is essential to improve BCG coverage in an increasingly multiethnic population.
doi:10.1136/thx.2004.036269
PMCID: PMC2080732  PMID: 16384882
tuberculosis; infants; BCG vaccination; ethnicity
20.  Green space, social inequalities and neonatal mortality in France 
Background
Few studies have considered using environmental amenities to explain social health inequalities.
Nevertheless, Green spaces that promote good health may have an effect on socioeconomic health inequalities. In developed countries, there is considerable evidence that green spaces have a beneficial effect on the health of urban populations and recent studies suggest they can have a positive effect on pregnancy outcomes. To investigate the relationship between green spaces and the spatial distribution of infant mortality taking account neighborhood deprivation levels.
Methods
The study took place in Lyon metropolitan area, France. All infant deaths that occurred between 2000 and 2009 were geocoded at census block level. Each census block was assigned greenness and socioeconomic deprivation levels. The spatial–scan statistic was used to identify high risk cluster of infant mortality according to these neighborhood characteristics.
Results
The spatial distribution of infant mortality was not random with a high risk cluster in the south east of the Lyon metropolitan area (p<0.003). This cluster disappeared (p=0.12) after adjustment for greenness level and socioeconomic deprivation, suggesting that these factors explain part of the spatial distribution of infant mortality. These results are discussed using a conceptual framework with 3 hypothetical pathways by which green spaces may have a beneficial effect on adverse pregnancy outcomes: (i) a psychological pathway, (ii) a physiological disruption process and (iii) an environmental pathway.
Conclusions
These results add some evidence to the hypothesis that there is a relationship between access to green spaces and pregnancy outcomes but further research is required to confirm this.
doi:10.1186/1471-2393-13-191
PMCID: PMC4015785  PMID: 24139283
Greenness level; Neighborhood deprivation; Infant mortality; Spatial analysis
21.  Periconceptional vitamin supplementation and neural tube defects; evidence from a case-control study in Western Australia and a review of recent publications. 
STUDY OBJECTIVE--The aim was to assess the association of neural tube defects with periconceptional vitamin supplementation. DESIGN--This was a matched, population based case-control study. SETTING--Western Australia, 1982-1984. PARTICIPANTS--Mothers of 77 cases (93% of those eligible) with isolated neural tube defects, mothers of 77 matched control infants with defects other than neural tube defects (control group I), and mothers of 154 liveborn, matched, control infants with no birth defects (control group II) participated in the study. MEASUREMENTS AND MAIN RESULTS--Information was collected by interview and self administered questionnaire. Crude and adjusted odds ratios (and their 95% confidence intervals) showed a small but non-significant protective effect of folate supplementation in comparisons with both control groups. The adjusted ratios for the three months before pregnancy were 0.69 (0.06, 8.53) with control group I, and 0.11 (0.01, 1.33) with control group II. In the first six weeks of pregnancy, the adjusted odds ratios were 0.70 (0.32, 1.52) with control group I and 0.74 (0.29, 1.88) with control group II. The odds ratios for vitamin supplementation of any kind were all very close to or greater than one, and all confidence intervals embraced unity. CONCLUSIONS--These data do not provide evidence of an association between periconceptional vitamin supplementation and neural tube defects, although a protective effect of folate supplementation cannot be excluded with confidence, due to the low power of the study. Of three other observational studies of vitamins and neural tube defects, two have shown an association. While further studies of this kind may be of value, evidence must now be sought from randomised controlled trials.
PMCID: PMC1059526  PMID: 1583432
22.  Dysconnectivity of neurocognitive networks at rest in very-preterm born adults☆ 
NeuroImage : Clinical  2014;4:352-365.
Advances in neonatal medicine have resulted in a larger proportion of preterm-born individuals reaching adulthood. Their increased liability to psychiatric illness and impairments of cognition and behaviour intimate lasting cerebral consequences; however, the central physiological disturbances remain unclear. Of fundamental importance to efficient brain function is the coordination and contextually-relevant recruitment of neural networks. Large-scale distributed networks emerge perinatally and increase in hierarchical complexity through development. Preterm-born individuals exhibit systematic reductions in correlation strength within these networks during infancy. Here, we investigate resting-state functional connectivity in functional magnetic resonance imaging data from 29 very-preterm (VPT)-born adults and 23 term-born controls. Neurocognitive networks were identified with spatial independent component analysis conducted using the Infomax algorithm and employing Icasso procedures to enhance component robustness. Network spatial focus and spectral power were not generally significantly affected by preterm birth. By contrast, Granger-causality analysis of the time courses of network activity revealed widespread reductions in between-network connectivity in the preterm group, particularly along paths including salience-network features. The potential clinical relevance of these Granger-causal measurements was suggested by linear discriminant analysis of topological representations of connection strength, which classified individuals by group with a maximal accuracy of 86%. Functional connections from the striatal salience network to the posterior default mode network informed this classification most powerfully. In the VPT-born group it was additionally found that perinatal factors significantly moderated the relationship between executive function (which was reduced in the VPT-born as compared with the term-born group) and generalised partial directed coherence. Together these findings show that resting-state functional connectivity of preterm-born individuals remains compromised in adulthood; and present consistent evidence that the striatal salience network is preferentially affected. Therapeutic practices directed at strengthening within-network cohesion and fine-tuning between-network inter-relations may have the potential to mitigate the cognitive, behavioural and psychiatric repercussions of preterm birth.
Highlights
•Functional connectivity was investigated using fMRI in preterm-born adults at rest.•Generalised partial directed coherence was assessed between neurocognitive networks.•Preterm-born adults exhibited widespread reductions in connection strength.•Coherence-derived graph topology permitted identification of preterm-born adults.
doi:10.1016/j.nicl.2014.01.005
PMCID: PMC3930099  PMID: 24567907
Preterm birth; Resting-state; Functional connectivity; Neurocognitive networks; Executive function
23.  Neural tube defects in a country town 
Eighteen infants with neural tube defects occurring in 979 births over five years in a small Wiltshire town were investigated for evidence of spatial epidemicity. Applying a method not used previously in the study of these defects, clustering was confirmed, a critical distance between cases of up to 100 metres giving a highly significant result (P = 0·001), and with one exception the observed number of pairs significantly exceeds the expected number (P < 0·01) even up to 1,000 metres.
PMCID: PMC478858  PMID: 4606840
24.  The spatial-temporal clustering of Plasmodium falciparum infection over eleven years in Gezira State, The Sudan 
Malaria Journal  2010;9:172.
Background
Malaria infection and disease exhibit microgeographic heterogeneity which if predictable could have implications for designing small-area intervention. Here, the space-time clustering of Plasmodium falciparum infections using data from repeat cross-sectional surveys in Gezira State, a low transmission area in northern Sudan, is investigated.
Methods
Data from cross-sectional surveys undertaken in January each year from 1999-2009 in 88 villages in the Gezira state were assembled. During each survey, about a 100 children between the ages two to ten years were sampled to examine the presence of P. falciparum parasites. In 2009, all the villages were mapped using global positioning systems. Cluster level data were analysed for spatial-only and space-time clustering using the Bernoulli model and the significance of clusters were tested using the Kulldorff scan statistic.
Results
Over the study period, 96,022 malaria slide examinations were undertaken and the P. falciparum prevalence was 8.6% in 1999 and by 2009 this had reduced to 1.6%. The cluster analysis showed the presence of one significant spatial-only cluster in each survey year and one significant space-time cluster over the whole study period. The primary spatial-only clusters in 10/11 years were either contained within or overlapped with the primary space-time cluster.
Conclusion
The results of the study confirm the generally low malaria transmission in the state of Gezira and the presence of spatial and space-time clusters concentrated around a specific area in the south of the state. Improved surveillance data that allows for the analysis of seasonality, age and other risk factors need to be collected to design effective small area interventions as Gezira state targets malaria elimination.
doi:10.1186/1475-2875-9-172
PMCID: PMC2903606  PMID: 20565854
25.  Spatial patterns of fetal loss and infant death in an arsenic-affected area in Bangladesh 
Background
Arsenic exposure in pregnancy is associated with adverse pregnancy outcome and infant mortality. Knowledge of the spatial characteristics of the outcomes and their possible link to arsenic exposure are important for planning effective mitigation activities. The aim of this study was to identify spatial and spatiotemporal clustering of fetal loss and infant death, and spatial relationships between high and low clusters of fetal loss and infant death rates and high and low clusters of arsenic concentrations in tube-well water used for drinking.
Methods
Pregnant women from Matlab, Bangladesh, who used tube-well water for drinking while pregnant between 1991 and 2000, were included in this study. In total 29,134 pregnancies were identified. A spatial scan test was used to identify unique non-random spatial and spatiotemporal clusters of fetal loss and infant death using a retrospective spatial and spatiotemporal permutation and Poisson probability models.
Results
Two significant clusters of fetal loss and infant death were identified and these clusters remained stable after adjustment for covariates. One cluster of higher rates of fetal loss and infant death was in the vicinity of the Meghna River, and the other cluster of lower rates was in the center of Matlab. The average concentration of arsenic in the water differed between these clusters (319 μg/L for the high cluster and 174 μg/L for the low cluster). The spatial patterns of arsenic concentrations in tube-well water were found to be linked with the adverse pregnancy outcome clusters. In the spatiotemporal analysis, only one high fetal loss and infant death cluster was identified in the same high cluster area obtained from purely spatial analysis. However, the cluster was no longer significant after adjustment for the covariates.
Conclusion
The finding of this study suggests that given the geographical variation in tube-well water contamination, higher fetal loss and infant deaths were observed in the areas of higher arsenic concentrations in groundwater. This illustrates a possible link between arsenic contamination in tube-well water and adverse pregnancy outcome. Thus, these areas should be considered a priority in arsenic mitigation programs.
doi:10.1186/1476-072X-9-53
PMCID: PMC2987785  PMID: 20977746

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