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1.  Prenatal Exposure to Bereavement and Type-2 Diabetes: A Danish Longitudinal Population Based Study 
PLoS ONE  2012;7(8):e43508.
Background
The etiology of type-2 diabetes is only partly known, and a possible role of prenatal stress in programming offspring for insulin resistance has been suggested by animal models. Previously, we found an association between prenatal stress and type-1 diabetes. Here we examine the association between prenatal exposure to maternal bereavement during preconception and pregnancy and development of type-2 diabetes in the off-spring.
Methods
We utilized data from the Danish Civil Registration System to identify singleton births in Denmark born January 1st 1979 through December 31st 2008 (N = 1,878,246), and linked them to their parents, grandparents, and siblings. We categorized children as exposed to bereavement during prenatal life if their mothers lost an elder child, husband or parent during the period from one year before conception to the child’s birth. We identified 45,302 children exposed to maternal bereavement; the remaining children were included in the unexposed cohort. The outcome of interest was diagnosis of type-2 diabetes. We estimated incidence rate ratios (IRRs) from birth using log-linear poisson regression models and used person-years as the offset variable. All models were adjusted for maternal residence, income, education, marital status, sibling order, calendar year, sex, and parents’ history of diabetes at the time of pregnancy.
Results
We found children exposed to bereavement during their prenatal life were more likely to have a type-2 diabetes diagnosis later in life (aIRR: 1.31, 1.01–1.69). These findings were most pronounced when bereavement was caused by death of an elder child (aIRR: 1.51, 0.94–2.44). Results also indicated the second trimester of pregnancy to be the most sensitive period of bereavement exposure (aIRR:2.08, 1.15–3.76).
Conclusions
Our data suggests that fetal exposure to maternal bereavement during preconception and the prenatal period may increase the risk for developing type-2 diabetes in childhood and young adulthood.
doi:10.1371/journal.pone.0043508
PMCID: PMC3429491  PMID: 22952698
2.  Mortality after Parental Death in Childhood: A Nationwide Cohort Study from Three Nordic Countries 
PLoS Medicine  2014;11(7):e1001679.
Jiong Li and colleagues examine mortality rates in children who lost a parent before 18 years old compared with those who did not using population-based data from Denmark, Sweden, and Finland.
Please see later in the article for the Editors' Summary
Background
Bereavement by spousal death and child death in adulthood has been shown to lead to an increased risk of mortality. Maternal death in infancy or parental death in early childhood may have an impact on mortality but evidence has been limited to short-term or selected causes of death. Little is known about long-term or cause-specific mortality after parental death in childhood.
Methods and Findings
This cohort study included all persons born in Denmark from 1968 to 2008 (n = 2,789,807) and in Sweden from 1973 to 2006 (n = 3,380,301), and a random sample of 89.3% of all born in Finland from 1987 to 2007 (n = 1,131,905). A total of 189,094 persons were included in the exposed cohort when they lost a parent before 18 years old. Log-linear Poisson regression was used to estimate mortality rate ratio (MRR). Parental death was associated with a 50% increased all-cause mortality (MRR = 1.50, 95% CI 1.43–1.58). The risks were increased for most specific cause groups and the highest MRRs were observed when the cause of child death and the cause of parental death were in the same category. Parental unnatural death was associated with a higher mortality risk (MRR = 1.84, 95% CI 1.71–2.00) than parental natural death (MRR = 1.33, 95% CI 1.24–1.41). The magnitude of the associations varied according to type of death and age at bereavement over different follow-up periods. The main limitation of the study is the lack of data on post-bereavement information on the quality of the parent-child relationship, lifestyles, and common physical environment.
Conclusions
Parental death in childhood or adolescence is associated with increased all-cause mortality into early adulthood. Since an increased mortality reflects both genetic susceptibility and long-term impacts of parental death on health and social well-being, our findings have implications in clinical responses and public health strategies.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
When someone close dies, it is normal to grieve, to mourn the loss of that individual. Initially, people who have lost a loved one often feel numb and disorientated and find it hard to grasp what has happened. Later, people may feel angry or guilty, and may be overwhelmed by feelings of sadness and despair. They may become depressed or anxious and may even feel suicidal. People who are grieving can also have physical reactions to their loss such as sleep problems, changes in appetite, and illness. How long bereavement—the period of grief and mourning after a death—lasts and how badly it affects an individual depends on the relationship between the individual and the deceased person, on whether the death was expected, and on how much support the mourner receives from relatives, friends, and professionals.
Why Was This Study Done?
The loss of a life-partner or of a child is associated with an increased risk of death (mortality), and there is also some evidence that the death of a parent during childhood leads to an increased mortality risk in the short term. However, little is known about the long-term impact on mortality of early parental loss or whether the impact varies with the type of death—a natural death from illness or an unnatural death from external causes such as an accident—or with the specific cause of death. A better understanding of the impact of early bereavement on mortality is needed to ensure that bereaved children receive appropriate health and social support after a parent's death. Here, the researchers undertake a nationwide cohort study in three Nordic countries to investigate long-term and cause-specific mortality after parental death in childhood. A cohort study compares the occurrence of an event (here, death) in a group of individuals who have been exposed to a particular variable (here, early parental loss) with the occurrence of the same event in an unexposed cohort.
What Did the Researchers Do and Find?
The researchers obtained data on everyone born in Denmark from 1968 to 2008 and in Sweden from 1973 to 2006, and on most people born in Finland from 1987 to 2007 (more than 7 million individuals in total) from national registries. They identified 189,094 individuals who had lost a parent between the age of 6 months and 18 years. They then estimated the mortality rate ratio (MRR) associated with parental death during childhood or adolescence by comparing the number of deaths in this exposed cohort (after excluding children who died on the same day as a parent or shortly after from the same cause) and in the unexposed cohort. Compared with the unexposed cohort, the exposed cohort had 50% higher all-cause mortality (MRR = 1.50). The risk of mortality in the exposed cohort was increased for most major categories of cause of death but the highest MRRs were seen when the cause of death in children, adolescents, and young adults during follow-up and the cause of parental death were in the same category. Notably, parental unnatural death was associated with a higher mortality risk (MRR = 1.84) than parental natural death (MRR = 1.33). Finally, the exposed cohort had increased all-cause MRRs well into early adulthood irrespective of child age at parental death, and the magnitude of MRRs differed by child age at parental death and by type of death.
What Do These Findings Mean?
These findings show that in three high-income Nordic countries parental death during childhood and adolescence is associated with an increased risk of all-cause mortality into early adulthood, irrespective of sex and age at bereavement and after accounting for baseline characteristics such as socioeconomic status. Part of this association may be due to “confounding” factors—the people who lost a parent during childhood may have shared other unknown characteristics that increased their risk of death. Because the study was undertaken in high-income countries, these findings are unlikely to be the result of a lack of material or health care needs. Rather, the increased mortality among the exposed group reflects both genetic susceptibility and the long-term impacts of parental death on health and social well-being. Given that increased mortality probably only represents the tip of the iceberg of the adverse effects of early bereavement, these findings highlight the need to provide long-term health and social support to bereaved children.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001679.
The UK National Health Service Choices website provides information about bereavement, including personal stories; it also provides information about children and bereavement and about young people and bereavement, including links to not-for-profit organizations that support children through bereavement
The US National Cancer Institute has detailed information about dealing with bereavement for the public and for health professionals that includes a section on children and grief (in English and Spanish)
The US National Alliance for Grieving Children promotes awareness of the needs of children and teens grieving a death and provides education and resources for anyone who wants to support them
MedlinePlus provides links to other resources about bereavement (in English and Spanish)
doi:10.1371/journal.pmed.1001679
PMCID: PMC4106717  PMID: 25051501
3.  Prenatal Exposure to Maternal Bereavement and Childbirths in the Offspring: A Population-Based Cohort Study 
PLoS ONE  2014;9(7):e103353.
Introduction
The decline in birth rates is a concern in public health. Fertility is partly determined before birth by the intrauterine environment and prenatal exposure to maternal stress could, through hormonal disturbance, play a role. There has been such evidence from animal studies but not from humans. We aimed to examine the association between prenatal stress due to maternal bereavement following the death of a relative and childbirths in the offspring.
Materials and Methods
This population-based cohort study included all subjects born in Denmark after 1968 and in Sweden after 1973 and follow-up started at the age of 12 years. Subjects were categorized as exposed if their mothers lost a close relative during pregnancy or the year before and unexposed otherwise. The main outcomes were age at first child and age-specific mean numbers of childbirths. Data was analyzed using Cox Proportional Hazards models stratified by gender and adjusted for several covariates. Subanalyses were performed considering the type of relative deceased and timing of bereavement.
Results
A total of 4,121,596 subjects were followed-up until up to 41 years of age. Of these subjects, 93,635 (2.3%) were exposed and 981,989 (23.8%) had at least one child during follow-up time. Compared to unexposed, the hazard ratio (HR) [95% confidence interval] of having at least one child for exposed males and females were 0.98 [0.96–1.01] and 1.01 [0.98–1.03], respectively. We found a slightly reduced probability of having children in females born to mothers who lost a parent with HR = 0.97 [0.94–0.99] and increased probability in females born to mothers who lost another child (HR = 1.09 [1.04–1.14]), the spouse (HR = 1.29 [1.12–1.48]) or a sibling (HR = 1.13 [1.01–1.27]).
Conclusions
Our results suggested no overall association between prenatal exposure to maternal stress and having a child in early adulthood but a longer time of follow-up is necessary in order to reach a firmer conclusion.
doi:10.1371/journal.pone.0103353
PMCID: PMC4113360  PMID: 25068458
4.  Maternal Use of Antibiotics and the Risk of Childhood Febrile Seizures: A Danish Population-Based Cohort 
PLoS ONE  2013;8(4):e61148.
Objective
In a large population-based cohort in Denmark to examine if maternal use of antibiotics during pregnancy, as a marker of infection, increases the risk of febrile seizures in childhood in a large population-based cohort in Denmark.
Methods
All live-born singletons born in Denmark between January 1, 1996 and September 25, 2004 and who were alive on the 90th day of life were identified from the Danish National Birth Registry. Diagnoses of febrile seizures were obtained from the Danish National Hospital Register and maternal use of antibiotics was obtained from the National Register of Medicinal Product Statistics. Hazard ratios (HR) and 95% confidence intervals (95% CI) were estimated by Cox proportional hazard regression models.
Results
We followed 551,518 singletons for up to 5 years and identified a total of 21,779 children with a diagnosis of febrile seizures. Slightly increased hazard ratios were observed among most exposure groups when compared to the unexposed group, ex. HR 1.08 95% CI: 1.05–1.11 for use of any systemic antibiotic during pregnancy.
Conclusion
We found weak associations between the use of pharmacologically different antibiotics during pregnancy and febrile seizures in early childhood which may indicate that some infections, or causes or effects of infections, during pregnancy could affect the fetal brain and induce susceptibility to febrile seizures.
doi:10.1371/journal.pone.0061148
PMCID: PMC3627381  PMID: 23613800
5.  Prenatal Stress Exposure Related to Maternal Bereavement and Risk of Childhood Overweight 
PLoS ONE  2010;5(7):e11896.
Background
It has been suggested that prenatal stress contributes to the risk of obesity later in life. In a population–based cohort study, we examined whether prenatal stress related to maternal bereavement during pregnancy was associated with the risk of overweight in offspring during school age.
Methodology/Principal Findings
We followed 65,212 children born in Denmark from 1970–1989 who underwent health examinations from 7 to 13 years of age in public or private schools in Copenhagen. We identified 459 children as exposed to prenatal stress, defined by being born to mothers who were bereaved by death of a close family member from one year before pregnancy until birth of the child. We compared the prevalence of overweight between the exposed and the unexposed. Body mass index (BMI) values and prevalence of overweight were higher in the exposed children, but not significantly so until from 10 years of age and onwards, as compared with the unexposed children. For example, the adjusted odds ratio (OR) for overweight was 1.68 (95% confidence interval [CI] 1.08–2.61) at 12 years of age and 1.63 (95% CI 1.00–2.61) at 13 years of age. The highest ORs were observed when the death occurred in the period from 6 to 0 month before pregnancy (OR 3.31, 95% CI 1.71–6.42 at age 12, and OR 2.31, 95% CI 1.08–4.97 at age 13).
Conclusions/Significance
Our results suggest that severe pre-pregnancy stress is associated with an increased risk of overweight in the offspring in later childhood.
doi:10.1371/journal.pone.0011896
PMCID: PMC2912844  PMID: 20689593
6.  Psychological Stress and Hospitalization for Childhood Asthma-a Nationwide Cohort Study in Two Nordic Countries 
PLoS ONE  2013;8(10):e78816.
Objective
Exposures to psychological stress in early life may contribute to the development or exacerbation of asthma. We undertook a cohort study based on data from several population-based registers in Denmark and Sweden to examine whether bereavement in childhood led to increased asthma hospitalization.
Methods
All singleton children born in Denmark during 1977-2008 and in Sweden during 1973-2006 were included in the study (N=5,202,576). The children were followed from birth to the date of first asthma hospitalization, emigration, death, their 18th birthday, or the end of study (31 December 2007 in Sweden and 31 December 2008 in Denmark), whichever came first. All the children were assigned to the non-bereaved group until they lost a close relative (mother, father or a sibling), from when they were included in the bereaved group. We evaluated the hazard ratio (HR) of first hospitalization for asthma in bereaved children using Cox proportional hazards regression models, compared to those who were in the non-bereaved group. We also did a sub-analysis on the association between bereavement and first asthma medication.
Results
A total of 147,829 children were hospitalized for asthma. The overall adjusted HR of asthma hospitalization in bereaved children was 1.10 (95% confidence interval (CI): 1.04-1.16), compared to non-bereaved children. The risk of asthma hospitalization was increased in those who lost a close relative at age of 14-17 years (HR=1.54, 95% CI: 1.23-1.92), but not in younger age groups. The association between bereavement and asthma hospitalization did not change over time since bereavement. In the sub-analysis in singleton live births during 1996-2008 recorded in the DMBR, bereavement was associated with a lower use of asthma medication (HR=0.87, 95% CI: 0.80-0.95).
Conclusions
Our data suggests that psychological stress following bereavement in late adolescence is associated with an increased risk of asthma hospitalization or lowers the threshold for asthma hospitalization.
doi:10.1371/journal.pone.0078816
PMCID: PMC3808299  PMID: 24205324
7.  Antenatal maternal bereavement and childhood cancer in the offspring: a population-based cohort study in 6 million children 
British Journal of Cancer  2012;107(3):544-548.
Background:
Prenatal stress may increase the susceptibility to childhood cancer by affecting immune responses and hormonal balance. We examined whether antenatal stress following maternal bereavement increased the risk of childhood cancer.
Methods:
All children born in Denmark from 1968 to 2007 (N=2 743 560) and in Sweden from 1973 to 2006 (N=3 400 212) were included in this study. We compared cancer risks in children born to women who lost a first-degree relative (a child, spouse, a parent, or a sibling) the year before pregnancy or during pregnancy with cancer risks in children of women who did not experience such bereavement.
Results:
A total of 9795 childhood cancer cases were observed during follow-up of 68 360 707 person years. Children born to women who lost a child or a spouse, but not those who lost other relatives, had an average 30% increased risk of any cancer (hazard ratio (HR) 1.30, 95% confidence interval (CI) 0.96–1.77). The HRs were the highest for non-Hodgkin disease (512 cases in total, HR 3.40, 95% CI 1.51–7.65), hepatic cancer (125 cases in total, HR 5.51, 95% CI 1.34–22.64), and testicular cancer (86 cases in total, HR 8.52, 95% CI 2.03–37.73).
Conclusion:
Our data suggest that severe antenatal stress following maternal bereavement, especially due to loss of a child or a spouse, is associated with an increased risk of certain childhood cancers in the offspring, such as hepatic cancer and non-Hodgkin disease, but not with childhood cancer in general.
doi:10.1038/bjc.2012.288
PMCID: PMC3405225  PMID: 22759879
childhood cancer; bereavement; prenatal stress; mother; association
8.  Use of corticosteroids during pregnancy and risk of asthma in offspring: a nationwide Danish cohort study 
BMJ Open  2014;4(6):e005053.
Objective
To examine whether in utero exposure to local and systemic corticosteroids is associated with asthma development in offspring.
Design
Cohort study.
Setting
Denmark.
Participants
We included all singletons born alive in Denmark between 1996 and 2009. Data on maternal corticosteroid use, asthma in offspring and covariates were obtained from medical registries.
Main outcome measures
We compared asthma risks of children prenatally exposed to corticosteroids and of children of former corticosteroid users with that of unexposed children. We computed absolute risks and used proportional-hazards regression to compute adjusted HRs (aHRs). Using logistic regression we compared exposed children with unexposed siblings in a ‘within-mother-between-pregnancy’ analysis. Adjustment addressed varying length of follow-up.
Results
We identified 877 778 children, 3.6% of whom were prenatally exposed to systemic (n=5327) or local (n=24 436) corticosteroids. A total of 105 677 children developed asthma during follow-up with a 10-year risk of 18.4% among the exposed and 13.5% among the unexposed. The aHR was 1.54 (95% CI 1.45 to 1.65) for systemic use, 1.45 (95% CI 1.40 to 1.50) for local use and 1.32 (95% CI 1.30 to 1.34) for former use. The adjusted OR of the ‘within-mother-between-pregnancy’ analysis was 1.11 (95% CI 0.98 to 1.25).
Conclusions
These population-based data do not support a strong causal association between maternal corticosteroid use during pregnancy and increased asthma risk in offspring.
doi:10.1136/bmjopen-2014-005053
PMCID: PMC4054622  PMID: 24902733
CLINICAL PHARMACOLOGY; EPIDEMIOLOGY; PERINATOLOGY; RESPIRATORY MEDICINE (see Thoracic Medicine)
9.  Severe bereavement stress during the prenatal and childhood periods and risk of psychosis in later life: population based cohort study 
Objective To examine the risk of psychosis associated with severe bereavement stress during the antenatal and postnatal period, between conception to adolescence, and with different causes of death.
Design Population based cohort study.
Setting Swedish national registers including births between 1973 and 1985 and followed-up to 2006.
Participants In a cohort of 1 045 336 Swedish births (1973-85), offspring born to mothers exposed to severe maternal bereavement stress six months before conception or during pregnancy, or exposed to loss of a close family member subsequently from birth to 13 years of age were followed until 2006. Admissions were identified by linkage to national patient registers.
Main outcome measures Crude and adjusted odds ratios for all psychosis, non-affective psychosis, and affective psychosis.
Results Maternal bereavement stress occurring preconception or during the prenatal period was not associated with a significant excess risk of psychosis in offspring (adjusted odds ratio, preconception 1.24, 95% confidence interval 0.96 to 1.62; first trimester 0.95, 0.58 to1.56; second trimester 0.79, 0.46 to 1.33; third trimester 1.14, 0.78 to 1.66). Risks increased modestly after exposure to the loss of a close family member from birth to adolescence for all psychoses (adjusted odds ratio 1.17, 1.04 to 1.32). The pattern of risk was generally similar for non-affective and affective psychosis. Thus estimates were higher after death in the nuclear compared with extended family but remained non-significant for prenatal exposure; the earlier the exposure to death in the nuclear family occurred in childhood (all psychoses: adjusted odds ratio, birth to 2.9 years 1.84, 1.41 to 2.41; 3-6.9 years 1.47, 1.16 to 1.85; 7-12.9 years 1.32, 1.10 to 1.58) and after suicide. Following suicide, risks were especially higher for affective psychosis (birth to 2.9 years 3.33, 2.00 to 5.56; 6.9 years 1.84, 1.04 to 3.25; 7-12.9 years 2.68, 1.84 to 3.92). Adjustment for key confounders attenuated but did not explain associations with risk.
Conclusions Postnatal but not prenatal bereavement stress in mothers is associated with an increased risk of psychosis in offspring. Risks are especially high for affective psychosis after suicide in the nuclear family, an effect that is not explained by family psychiatric history. Future studies are needed to understand possible sources of risk and resilience so that structures can be put in place to support vulnerable children and their families.
doi:10.1136/bmj.f7679
PMCID: PMC3898661  PMID: 24449616
10.  Severe Maternal Stress Exposure Due to Bereavement before, during and after Pregnancy and Risk of Overweight and Obesity in Young Adult Men: A Danish National Cohort Study 
PLoS ONE  2014;9(5):e97490.
Background
Perinatal stress may programme overweight and obesity. We examined whether maternal pre- and post-natal bereavement was associated with overweight and obesity in young men.
Methods
A cohort study was conducted including 119,908 men born from 1976 to 1993 and examined for military service between 2006 and 2011. Among them, 4,813 conscripts were born to mothers bereaved by death of a close relative from 12 months preconception to birth of the child (exposed group). Median body mass index (BMI) and prevalence of overweight and obesity were estimated. Odds ratio of overweight (BMI≥25 kg/m2) and obesity (BMI≥30 kg/m2) were estimated by logistic regression analysis adjusted for maternal educational level.
Results
Median BMI was similar in the exposed and the unexposed group but the prevalence of overweight (33.3% versus 30.4%, p = 0.02) and obesity (9.8% versus 8.5%, p = 0.06) was higher in the exposed group. Conscripts exposed 6 to 0 months before conception and during pregnancy had a higher risk of overweight (odds ratio 1.15, 95% confidence interval (CI): 1.03; 1.27 and odds ratio 1.13, 95% CI: 1.03; 1.25, respectively). Conscripts born to mothers who experienced death of the child’s biological father before child birth had a two-fold risk of obesity (odds ratio 2.00, 95% CI: 0.93; 4.31). There was no elevated risk in those who experienced maternal bereavement postnatally.
Conclusion
Maternal bereavement during the prenatal period was associated with increased risk of overweight or obesity in a group of young male conscripts, and this may possibly be reflected to severe stress exposure early in life. However, not all associations were clear, and further studies are warranted.
doi:10.1371/journal.pone.0097490
PMCID: PMC4020839  PMID: 24828434
11.  Maternal Bereavement and Childhood Asthma—Analyses in Two Large Samples of Swedish Children 
PLoS ONE  2011;6(11):e27202.
Background
Prenatal factors such as prenatal psychological stress might influence the development of childhood asthma.
Methodology and Principal Findings
We assessed the association between maternal bereavement shortly before and during pregnancy, as a proxy for prenatal stress, and the risk of childhood asthma in the offspring, based on two samples of children 1–4 (n = 426 334) and 7–12 (n = 493 813) years assembled from the Swedish Medical Birth Register. Exposure was maternal bereavement of a close relative from one year before pregnancy to child birth. Asthma event was defined by a hospital contact for asthma or at least two dispenses of inhaled corticosteroids or montelukast. In the younger sample we calculated hazards ratios (HRs) of a first-ever asthma event using Cox models and in the older sample odds ratio (ORs) of an asthma attack during 12 months using logistic regression. Compared to unexposed boys, exposed boys seemed to have a weakly higher risk of first-ever asthma event at 1–4 years (HR: 1.09; 95% confidence interval [CI]: 0.98, 1.22) as well as an asthma attack during 12 months at 7–12 years (OR: 1.10; 95% CI: 0.96, 1.24). No association was suggested for girls. Boys exposed during the second trimester had a significantly higher risk of asthma event at 1–4 years (HR: 1.55; 95% CI: 1.19, 2.02) and asthma attack at 7–12 years if the bereavement was an older child (OR: 1.58; 95% CI: 1.11, 2.25). The associations tended to be stronger if the bereavement was due to a traumatic death compared to natural death, but the difference was not statistically significant.
Conclusions/Significance
Our results showed some evidence for a positive association between prenatal stress and childhood asthma among boys but not girls.
doi:10.1371/journal.pone.0027202
PMCID: PMC3210147  PMID: 22087265
12.  Febrile seizures 
BMJ Clinical Evidence  2010;2010:0324.
Introduction
Simple febrile seizures are generalised in onset, last <15 minutes, and do not occur more than once in 24 hours. Complex febrile seizures are longer lasting, have focal symptoms, and can recur within 24 hours. This review only deals with simple febrile seizures. About 2% to 5% of children in the USA and Western Europe, and 6% to 9% of infants and children in Japan will have experienced at least one febrile seizure by the age of 5 years. Simple febrile seizures may slightly increase the risk of developing epilepsy, but have no known adverse effects on behaviour, scholastic performance, or neurocognition.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments given during episodes of fever in children with one or more previous simple febrile seizures? What are the effects of long-term (daily, for >1 month) anticonvulsant treatment in children with a history of simple febrile seizures? What are the effects of treatments on reducing the risk of subsequent epilepsy in children with a history of simple febrile seizures? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 18 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: anticonvulsants (intermittent or continuous) and antipyretic treatments (physical antipyretic measures, paracetamol, ibuprofen).
Key Points
Febrile seizures are defined as events in infancy or childhood usually occurring between 3 months and 5 years of age associated with a fever, but without evidence of intracranial infection or defined cause for the seizure. Simple febrile seizures are generalised in onset, last <15 minutes, and do not occur more than once in 24 hours. Complex seizures are longer lasting, have focal symptoms, and can recur within 24 hours. This review only deals with simple febrile seizures.About 2% to 5% of children in the USA and Western Europe, and 6% to 9% of infants and children in Japan will have experienced at least one febrile seizure by age 5 years.Simple febrile seizures may slightly increase the risk of developing epilepsy, but have no known adverse effects on behaviour, scholastic performance, or neurocognition.
So far evidence showing whether antipyretic drug treatments or physical methods of temperature reduction are useful in treating episodes of fever to prevent seizure recurrence in children with one or more previous simple febrile seizures is lacking. Intermittent anticonvulsants used in treating episodes of fever to prevent seizure recurrence in children are associated with adverse effects, including hyperactivity, irritability, and difficulties with speech, activity level, or sleep.
Continuous anticonvulsant treatment may be effective for reducing recurrence in children with a history of simple febrile seizures, but is associated with adverse effects; for example, phenobarbital may be associated with cognitive impairments and behavioural adverse effects, including hyperactivity, irritability, and aggressiveness. Serious adverse events that may be associated with sodium valproate include hepatotoxicity and haematological toxicity, both of which may occasionally be fatal. Anticonvulsants do not seem to reduce the risk of epilepsy up to 12 years later in children with a history of simple febrile seizures.
PMCID: PMC3275324  PMID: 21406130
13.  Febrile seizures 
BMJ Clinical Evidence  2008;2008:0324.
Introduction
Simple febrile seizures are generalised in onset, last less than 15 minutes, and do not occur more than once in 24 hours. Complex seizures are longer lasting, have focal symptoms, and can recur within 24 hours. This review only deals with simple febrile seizures. About 2-5% of children in the USA and Western Europe, and 6-9% of infants and children in Japan, will have experienced at least one febrile seizure by the age of 5 years. Simple febrile seizures may slightly increase the risk of developing epilepsy, but have no known adverse effects on behaviour, scholastic performance, or neurocognition.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments given during episodes of fever in children with one or more previous simple febrile seizures? What are the effects of long-term (daily, for more than 1 month) anticonvulsant treatment in children with a history of simple febrile seizures? What are the effects of treatments on reducing the risk of subsequent epilepsy in children with a history of simple febrile seizures? We searched: Medline, Embase, The Cochrane Library and other important databases up to August 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 19 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: anticonvulsants (intermittent or continuous), and antipyretic treatments (physical antipyretic measures, paracetamol, ibuprofen).
Key Points
Febrile seizures are defined as events in infancy or childhood usually occurring between 3 months and 5 years of age associated with a fever, but without evidence of intracranial infection, or defined cause for the seizure. Simple febrile seizures are generalised in onset, last less than 15 minutes, and do not occur more than once in 24 hours. Complex seizures are longer lasting, have focal symptoms, and can recur within 24 hours. This review only deals with simple febrile seizures.About 2-5% of children in the USA and Western Europe, and 6-9% of infants and children in Japan will have experienced at least one febrile seizure by age 5 years.Simple febrile seizures may slightly increase the risk of developing epilepsy, but have no known adverse effects on behaviour, scholastic performance, or neurocognition.
We do not know whether antipyretics are useful in treating episodes of fever to prevent seizure recurrence in children with one or more previous simple febrile seizures. Intermittent anticonvulsants used in treating episodes of fever to prevent seizure recurrence in children are associated with adverse effects, including hyperactivity, irritability, and difficulties with speech, activity level, or sleep.
Continuous anticonvulsant treatment may be effective for reducing recurrence in children with a history of simple febrile seizures, but is associated with adverse effects: for example, phenobarbital is associated with cognitive impairments and behavioural adverse effects, including hyperactivity, irritability, and aggressiveness. Anticonvulsants do not appear to reduce the risk of epilepsy up to 12 years later in children with a history of simple febrile seizures.
PMCID: PMC2907951  PMID: 19450310
14.  Stable and Unstable Malaria Hotspots in Longitudinal Cohort Studies in Kenya 
PLoS Medicine  2010;7(7):e1000304.
Philip Bejon and colleagues document the clustering of malaria episodes and malarial parasite infection. These patterns may enable future prediction of hotspots of malaria infection and targeting of treatment or preventive interventions.
Background
Infectious diseases often demonstrate heterogeneity of transmission among host populations. This heterogeneity reduces the efficacy of control strategies, but also implies that focusing control strategies on “hotspots” of transmission could be highly effective.
Methods and Findings
In order to identify hotspots of malaria transmission, we analysed longitudinal data on febrile malaria episodes, asymptomatic parasitaemia, and antibody titres over 12 y from 256 homesteads in three study areas in Kilifi District on the Kenyan coast. We examined heterogeneity by homestead, and identified groups of homesteads that formed hotspots using a spatial scan statistic. Two types of statistically significant hotspots were detected; stable hotspots of asymptomatic parasitaemia and unstable hotspots of febrile malaria. The stable hotspots were associated with higher average AMA-1 antibody titres than the unstable clusters (optical density [OD] = 1.24, 95% confidence interval [CI] 1.02–1.47 versus OD = 1.1, 95% CI 0.88–1.33) and lower mean ages of febrile malaria episodes (5.8 y, 95% CI 5.6–6.0 versus 5.91 y, 95% CI 5.7–6.1). A falling gradient of febrile malaria incidence was identified in the penumbrae of both hotspots. Hotspots were associated with AMA-1 titres, but not seroconversion rates. In order to target control measures, homesteads at risk of febrile malaria could be predicted by identifying the 20% of homesteads that experienced an episode of febrile malaria during one month in the dry season. That 20% subsequently experienced 65% of all febrile malaria episodes during the following year. A definition based on remote sensing data was 81% sensitive and 63% specific for the stable hotspots of asymptomatic malaria.
Conclusions
Hotspots of asymptomatic parasitaemia are stable over time, but hotspots of febrile malaria are unstable. This finding may be because immunity offsets the high rate of febrile malaria that might otherwise result in stable hotspots, whereas unstable hotspots necessarily affect a population with less prior exposure to malaria.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Malaria, a mosquito-borne parasitic disease, is a major global public-health problem. About half the world's population is at risk of malaria and about one million people (mainly children living in sub-Saharan Africa) die each year from the disease. Malaria is transmitted to people through the bite of an infected mosquito. Initially, the parasite replicates inside human liver cells but, about a week after infection, these cells release “merozoites” (one of the life-stages of the parasite), which invade red blood cells. Here, the merozoites replicate rapidly before bursting out after 2–3 days and infecting more red blood cells. The cyclical and massive increase in parasitemia (parasites in the bloodstream) that results from this pattern of replication is responsible for malaria's recurring fevers and can cause life-threatening organ damage and anemia (a lack of red blood cells). Malaria can be prevented by controlling the mosquitoes that spread the parasite and by avoiding mosquito bites. Effective treatment with antimalarial drugs can also reduce malaria transmission.
Why Was This Study Done?
Like many other infectious diseases, the transmission of malaria is heterogeneous. That is, even in places where malaria is always present, there are “hotspots” of transmission, areas where the risk of catching malaria is particularly high. The existence of these hotspots, which are caused by a combination of genetic factors (for example, host susceptibility to infection) and environmental factors (for example, distance from mosquito breeding sites), reduces the efficacy of control strategies. However, mathematical models suggest that focusing control strategies on transmission hotspots might be an effective way to reduce overall malaria transmission. Efforts have been made to identify such hotspots using environmental data collected by satellites but with limited success. In this study, therefore, the researchers investigate the heterogeneity of malaria transmission in the Kilifi District of Kenya over time by analyzing data collected over up to 12 years (“longitudinal” data) on malaria episodes and parasitemia in three groups (cohorts) of children living in 256 homesteads.
What Did the Researchers Do and Find?
The researchers identified febrile malaria episodes in the homesteads by taking blood from children with fever (febrile children) to analyze for parasitemia. They took blood once a year from all the study participants just before the rainy season (when malaria peaks) to look for symptom-free parasitemia and they also looked for antibodies (proteins made by the immune system that fight disease) against malaria parasites in the blood of the participants. They then used a “spatial scan statistic” to look for heterogeneity of transmission and to identify transmission hotspots (groups of homesteads where the observed incidence of malaria or parasitemia was higher than would be expected if cases were evenly distributed). The researchers identified two types of hotspots—stable hotspots of symptom-free parasitemia that were still hotspots several years later and unstable hotspots of febrile malaria that rarely stayed in the same place for more than a year or two. Children living in the stable hotspots had slightly higher average amounts of antimalaria antibodies and developed malaria at a slightly lower average age than children living in the unstable hotspots.
What Do These Findings Mean?
These findings show that in Kilifi District, Kenya, hotspots of symptom-free parasitemia are stable over time but hotspots of febrile malaria are unstable. The researchers suggest that rapid acquisition of immunity in the stable hotspots reduces the occurrence of febrile malaria whereas in the unstable hotspots there is a high incidence of febrile malaria because lack of previous exposure to the parasite means there is a low level of immunity. Targeted strategies for malaria control should target both types of hotspots, suggest the researchers. Stable hotspots of symptom-free parasitemia (which can be identified by parasite or antibody surveys or by remote environmental sensing) should be targeted because mosquito dispersion probably increases malaria transmission rates near these hotspots. Unstable hotspots of febrile disease should be targeted to reduce both the burden of disease and transmission in the wider community. Unstable hotspots of febrile malaria, the researchers suggest, could be efficiently identified in Kilifi District (and maybe elsewhere) by determining which homesteads had malaria outbreaks during September (part of the dry season) one year and then focusing control interventions on these homesteads the next year.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000304.
Information is available from the World Health Organization on malaria (in several languages)
The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish)
MedlinePlus provides links to additional information on malaria (in English and Spanish)
Information is available from the Roll Back Malaria Partnership on the global control of malaria (in English and French) and on malaria in Kenya
doi:10.1371/journal.pmed.1000304
PMCID: PMC2897769  PMID: 20625549
15.  Antidepressant exposure in pregnancy and risk of autism spectrum disorders 
Clinical Epidemiology  2013;5:449-459.
Background
Both the use of antidepressant medication during pregnancy and the prevalence of autism spectrum disorder have increased during recent years. A causal link has recently been suggested, but the association may be confounded by the underlying indication for antidepressant use. We investigated the association between maternal use of antidepressant medication in pregnancy and autism, controlling for potential confounding factors.
Methods
We identified all children born alive in Denmark 1996–2006 (n=668,468) and their parents in the Danish Civil Registration System. We obtained information on the mother’s prescriptions filled during pregnancy from the Danish National Prescription Registry, and on diagnoses of autism spectrum disorders in the children and diagnoses of psychiatric disorders in the parents from the Danish Psychiatric Central Register. In a cohort analysis, we estimated hazard ratios of autism spectrum disorders in children exposed to antidepressant medication during pregnancy compared with children who were not exposed, using Cox proportional hazards regression analysis. Furthermore, we estimated the risk for autism spectrum disorder in a sibling design.
Results
Children exposed prenatally to antidepressants had an adjusted hazard ratio of 1.5 (95% confidence interval [CI] 1.2–1.9) for autism spectrum disorder compared with unexposed children. Restricting the analysis to children of women with a diagnosis of affective disorder, the adjusted hazard ratio was 1.2 (95% CI 0.7–2.1), and the risk was further reduced when exposed children were compared with their unexposed siblings (adjusted hazard ratio 1.1; 95% CI 0.5–2.3).
Conclusion
After controlling for important confounding factors, there was no significant association between prenatal exposure to antidepressant medication and autism spectrum disorders in the offspring.
doi:10.2147/CLEP.S53009
PMCID: PMC3832387  PMID: 24255601
antidepressants; depression; autism; autism spectrum disorder; childhood autism; pregnancy
16.  In-Utero Exposure to Bereavement and Offspring IQ: A Danish National Cohort Study 
PLoS ONE  2014;9(2):e88477.
Background
Intelligence is a life-long trait that has strong influences on lifestyle, adult morbidity and life expectancy. Hence, lower cognitive abilities are therefore of public health interest. Our primary aim was to examine if prenatal bereavement measured as exposure to death of a close family member is associated with the intelligence quotient (IQ) scores at 18-years of age of adult Danish males completing a military cognitive screening examination.
Methods
We extracted records for the Danish military screening test and found kinship links with biological parents, siblings, and maternal grandparents using the Danish Civil Registration System (N = 167,900). The prenatal exposure period was defined as 12 months before conception until birth of the child. We categorized children as exposed in utero to severe stress (bereavement) during prenatal life if their mothers lost an elder child, husband, parent or sibling during the prenatal period; the remaining children were included in the unexposed cohort. Mean score estimates were adjusted for maternal and paternal age at birth, residence, income, maternal education, gestational age at birth and birth weight.
Results
When exposure was due to death of a father the offsprings' mean IQ scores were lower among men completing the military recruitment exam compared to their unexposed counterparts, adjusted difference of 6.5 standard IQ points (p-value = 0.01). We did not observe a clinically significant association between exposure to prenatal maternal bereavement caused by death of a sibling, maternal uncle/aunt or maternal grandparent even after stratifying deaths only due to traumatic events.
Conclusion
We found maternal bereavement to be adversely associated with IQ in male offspring, which could be related to prenatal stress exposure though more likely is due to changes in family conditions after death of the father. This finding supports other literature on maternal adversity during fetal life and cognitive development in the offspring.
doi:10.1371/journal.pone.0088477
PMCID: PMC3928249  PMID: 24558394
17.  Early life bereavement and childhood cancer: a nationwide follow-up study in two countries 
BMJ Open  2013;3(5):e002864.
Objective
Childhood cancer is a leading cause of child deaths in affluent countries, but little is known about its aetiology. Psychological stress has been suggested to be associated with cancer in adults; whether this is also seen in childhood cancer is largely unknown. We investigated the association between bereavement as an indicator of severe childhood stress exposure and childhood cancer, using data from Danish and Swedish national registers.
Design
Population-based cohort study.
Setting
Denmark and Sweden.
Participants
All live-born children born in Denmark between 1968 and 2007 (n=2 729 308) and in Sweden between 1973 and 2006 (n=3 395 166) were included in this study. Exposure was bereavement by the death of a close relative before 15 years of age. Follow-up started from birth and ended at the first of the following: date of a cancer diagnosis, death, emigration, day before their 15th birthday or end of follow-up (2007 in Denmark, 2006 in Sweden).
Outcome measures
Rates and HRs for all childhood cancers and specific childhood cancers.
Results
A total of 1 505 938 (24.5%) children experienced bereavement at some point during their childhood and 9823 were diagnosed with cancer before the age of 15 years. The exposed children had a small (10%) increased risk of childhood cancer (HR 1.10; 95% CI 1.04 to 1.17). For specific cancers, a significant association was seen only for central nervous system tumours (HR 1.14; 95% CI 1.02 to 1.28).
Conclusions
Our data suggest that psychological stress in early life is associated with a small increased risk of childhood cancer.
doi:10.1136/bmjopen-2013-002864
PMCID: PMC3664350  PMID: 23793702
Childhood cancer; bereavement; psychological stress; risk factor; follow up
18.  Can Prenatal Malaria Exposure Produce an Immune Tolerant Phenotype?: A Prospective Birth Cohort Study in Kenya 
PLoS Medicine  2009;6(7):e1000116.
In a prospective cohort study of newborns residing in a malaria holoendemic area of Kenya, Christopher King and colleagues find a subset of children born to malaria-infected women who acquire a tolerant phenotype, which persists into childhood and is associated with increased susceptibility to malarial infection and anemia.
Background
Malaria in pregnancy can expose the fetus to malaria-infected erythrocytes or their soluble products, thereby stimulating T and B cell immune responses to malaria blood stage antigens. We hypothesized that fetal immune priming, or malaria exposure in the absence of priming (putative tolerance), affects the child's susceptibility to subsequent malaria infections.
Methods and Findings
We conducted a prospective birth cohort study of 586 newborns residing in a malaria-holoendemic area of Kenya who were examined biannually to age 3 years for malaria infection, and whose malaria-specific cellular and humoral immune responses were assessed. Newborns were classified as (i) sensitized (and thus exposed), as demonstrated by IFNγ, IL-2, IL-13, and/or IL-5 production by cord blood mononuclear cells (CBMCs) to malaria blood stage antigens, indicative of in utero priming (n = 246), (ii) exposed not sensitized (mother Plasmodium falciparum [Pf]+ and no CBMC production of IFNγ, IL-2, IL-13, and/or IL-5, n = 120), or (iii) not exposed (mother Pf−, no CBMC reactivity, n = 220). Exposed not sensitized children had evidence for prenatal immune experience demonstrated by increased IL-10 production and partial reversal of malaria antigen-specific hyporesponsiveness with IL-2+IL-15, indicative of immune tolerance. Relative risk data showed that the putatively tolerant children had a 1.61 (95% confidence interval [CI] 1.10–2.43; p = 0.024) and 1.34 (95% CI 0.95–1.87; p = 0.097) greater risk for malaria infection based on light microscopy (LM) or PCR diagnosis, respectively, compared to the not-exposed group, and a 1.41 (95%CI 0.97–2.07, p = 0.074) and 1.39 (95%CI 0.99–2.07, p = 0.053) greater risk of infection based on LM or PCR diagnosis, respectively, compared to the sensitized group. Putatively tolerant children had an average of 0.5 g/dl lower hemoglobin levels (p = 0.01) compared to the other two groups. Exposed not sensitized children also had 2- to 3-fold lower frequency of malaria antigen-driven IFNγ and/or IL-2 production (p<0.001) and higher IL-10 release (p<0.001) at 6-month follow-ups, when compared to sensitized and not-exposed children. Malaria blood stage–specific IgG antibody levels were similar among the three groups.
Conclusions
These results show that a subset of children exposed to malaria in utero acquire a tolerant phenotype to blood-stage antigens that persists into childhood and is associated with an increased susceptibility to malaria infection and anemia. This finding could have important implications for malaria vaccination of children residing in endemic areas.
Please see later in the article for Editors' Summary
Editors' Summary
Background
Each year, Plasmodium falciparum, a mosquito-borne parasite, causes about 500 million cases of malaria and about one million people die as a result. Most of these deaths occur in young children in sub-Saharan Africa. Indeed, malaria accounts for a fifth of all childhood deaths in Africa, which makes it one of the most important childhood infectious diseases in this region. Very young children—those up to 6 months old—are relatively resistant to high-density parasitaemia and to clinical malaria, but children between 6 and 36 months old have an increased susceptibility to parasitaemia and to clinical malaria. Parasitaemia is the presence of P. falciparum parasites in the blood; a high density of blood-stage parasites causes the symptoms of clinical malaria (including high fever) and life-threatening organ damage and anemia (a lack of red blood cells).
Why Was This Study Done?
The age-dependent pattern of susceptibility to malaria suggests that young babies are protected by antibodies provided by their mothers, but that by 6 months old, when these antibodies have largely disappeared, babies have not yet fully developed their own anti-malaria immunity. However, little is known about the acquisition of anti-malaria immunity in infants, a process that needs to be understood in order to design effective vaccines for this age group. In particular, it is unclear how maternal malaria infection affects the acquisition of anti-malaria immunity. Malaria in pregnancy may expose the unborn child to malaria-infected red blood cells and to soluble malaria antigens (molecules that the immune system recognizes as foreign). This exposure could increase or decrease the child's immune responses to blood-stage malaria antigens and thus affect his/her ability to fight off malaria. In this study, the researchers investigated how prenatal malaria exposure affects anti-malaria immunity in young children and their susceptibility to subsequent malaria infections.
What Did the Researchers Do and Find?
The researchers determined which of 586 newborn babies enrolled into their study in an area of Kenya where malaria is very common had been exposed to P. falciparum before birth by looking for parasites in their mother's blood at delivery. They looked for malaria-specific immune responses in T cells (a type of immune system cell) in the newborn babies' cord blood by measuring the production of cytokines (molecules that either activate or inhibit the immune system) by these cells after exposure to malaria antigens. Finally, they examined the infants twice yearly for 3 years for malaria infection, malaria-specific immune responses, and anemia. The researchers classified the babies into three groups; cord blood cells of “sensitized” babies made activating cytokines in response to malaria antigens; cord blood cells of “exposed, not-sensitized” babies did not make activating cytokines but made an inhibitory cytokine (IL-10); and “not-exposed” babies were born to mothers with no P. falciparum infection at delivery. In their first 3 years of life, the exposed, not-sensitized group had a 60% greater risk of malaria infection (measured by counting parasites in their blood) than the unexposed group and a slightly higher risk of malaria infection than the sensitized group. They also had lower hemoglobulin levels (a sign of anemia) than the other babies. At age 6 months, the T cells of exposed, not-sensitized children were less likely to make activating cytokines in response to malaria antigens but made more IL-10 than the T cells of the other children; malaria-specific antibody levels were similar in the three groups.
What Do These Findings Mean?
These findings suggest that some children who are exposed to malaria before birth become “tolerant” to blood-stage malaria antigens. Exposure to malaria antigens before birth “tricks” their T cells into recognizing these antigens as self antigens. This immune tolerance, which persists into childhood, reduces the ability of the immune system to attack and destroy parasites and increases the susceptibility of these tolerant children to malaria infection. Why some children who are exposed to malaria before birth become tolerant while exposure to malaria antigens “primes” the immune system of other children to respond efficiently to these antigens is not clear. However, these findings could have important implications for the design of malaria vaccines for use in areas where children are often exposed to malaria before birth and for the design of strategies for the prevention of malaria during pregnancy.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000116.
This study is further discussed in a PLoS Medicine Perspective by Lars Hviid
Information is available from the World Health Organization on malaria (in several languages)
The US Centers for Disease Control and Prevention provides information on malaria (in English and Spanish)
Information is available from the Roll Back Malaria Partnership on all aspects of global malaria control, including information on malaria in pregnancy and on children and malaria
MedlinePlus provides links to additional information on malaria (in English and Spanish)
doi:10.1371/journal.pmed.1000116
PMCID: PMC2707618  PMID: 19636353
19.  Prenatal Treatment for Serious Neurological Sequelae of Congenital Toxoplasmosis: An Observational Prospective Cohort Study 
PLoS Medicine  2010;7(10):e1000351.
An observational study by Ruth Gilbert and colleagues finds that prenatal treatment of congenital toxoplasmosis could substantially reduce the proportion of infected fetuses that develop serious neurological sequelae.
Background
The effectiveness of prenatal treatment to prevent serious neurological sequelae (SNSD) of congenital toxoplasmosis is not known.
Methods and Findings
Congenital toxoplasmosis was prospectively identified by universal prenatal or neonatal screening in 14 European centres and children were followed for a median of 4 years. We evaluated determinants of postnatal death or SNSD defined by one or more of functional neurological abnormalities, severe bilateral visual impairment, or pregnancy termination for confirmed congenital toxoplasmosis. Two-thirds of the cohort received prenatal treatment (189/293; 65%). 23/293 (8%) fetuses developed SNSD of which nine were pregnancy terminations. Prenatal treatment reduced the risk of SNSD. The odds ratio for prenatal treatment, adjusted for gestational age at maternal seroconversion, was 0.24 (95% Bayesian credible intervals 0.07–0.71). This effect was robust to most sensitivity analyses. The number of infected fetuses needed to be treated to prevent one case of SNSD was three (95% Bayesian credible intervals 2–15) after maternal seroconversion at 10 weeks, and 18 (9–75) at 30 weeks of gestation. Pyrimethamine-sulphonamide treatment did not reduce SNSD compared with spiramycin alone (adjusted odds ratio 0.78, 0.21–2.95). The proportion of live-born infants with intracranial lesions detected postnatally who developed SNSD was 31.0% (17.0%–38.1%).
Conclusion
The finding that prenatal treatment reduced the risk of SNSD in infected fetuses should be interpreted with caution because of the low number of SNSD cases and uncertainty about the timing of maternal seroconversion. As these are observational data, policy decisions about screening require further evidence from a randomized trial of prenatal screening and from cost-effectiveness analyses that take into account the incidence and prevalence of maternal infection.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Toxoplasmosis is a very common parasitic infection. People usually become infected with Toxoplasma gondii, the parasite that causes toxoplasmosis, by eating raw or undercooked meat that contains the parasite, but it can also be contracted by drinking unfiltered water or by handling cat litter. Most people with toxoplasmosis never know they have the disease. However, if a pregnant woman becomes infected with T. gondii, she can transmit the parasite to her unborn baby (fetus). Overall, about a quarter of women who catch toxoplasmosis during pregnancy transmit the parasite to their fetus. If transmission occurs early during pregnancy, the resultant “congenital toxoplasmosis” increases the risk of miscarriage and the risk of the baby being born with brain damage, epilepsy, deafness, blindness, or developmental problems (“serious neurological sequelae”). In the worst cases, babies may be born dead or die soon after birth. Congenital toxoplasmosis caught during the final third of pregnancy may not initially cause any health problems but eyesight problems often develop later in life.
Why Was This Study Done?
Clinicians can find out if a woman has been infected with T. gondii during pregnancy by looking for parasite-specific antibodies (proteins made by the immune system that fight infections) in her blood. If the pattern of antibodies suggests a recent infection, the woman can be given spiramycin or pyrimethamine-sulfonamide, antibiotics that are thought to reduce the risk of transmission to the fetus and the severity of toxoplasmosis in infected fetuses. In some countries where toxoplasmosis is particularly common (for example, France), pregnant women are routinely screened for toxoplasmosis and treated with antibiotics if there are signs of recent infection. But is prenatal treatment an effective way to prevent the serious neurological sequelae or postnatal death (SNSD) associated with congenital toxoplasmosis? In this observational study, the researchers examine this question by studying a group of children identified as having congenital toxoplasmosis by prenatal or neonatal screening in six European countries. An observational study measures outcomes in a group of patients without trying to influence those outcomes by providing a specific treatment.
What Did the Researchers Do and Find?
The researchers followed 293 children in whom congenital toxoplasmosis had been identified by prenatal screening (in France, Austria, and Italy) or by neonatal screening (in Denmark, Sweden, and Poland) for an average 4 years. Two-thirds of the children received prenatal treatment for toxoplasmosis and 23 fetuses (8% of the fetuses) developed SNSD; nine of these cases of SNSD were terminated during pregnancy. By comparing the number of cases of SNSD among children who received prenatal treatment with the number among children who did not receive prenatal treatment, the researchers estimate that prenatal treatment reduced the risk of SNSD by three-quarters. They also estimate that to prevent one case of SNSD after maternal infection at 10 weeks of pregnancy, it would be necessary to treat three fetuses with confirmed infection. To prevent one case of SNSD after maternal infection at 30 weeks of pregnancy, 18 fetuses would need to be treated. Finally, the researchers report that the effectiveness of pyrimethamine-sulfonamide and spiramycin (which is less toxic) was similar, and that a third of live-born infants with brain damage that was detected after birth subsequently developed SNSD.
What Do These Findings Mean?
These findings suggest that prenatal treatment of congenital toxoplasmosis could substantially reduce the proportion of infected fetuses that develop SNDS and would be particularly effective in fetuses whose mothers acquired T. gondii during the first third of pregnancy. These findings should be interpreted with caution, however, because of the small number of affected fetuses in the study and because of uncertainty about the timing of maternal infection. Furthermore, these findings only relate to the relatively benign strain of T. gondii that predominates in Europe and North America; further studies are needed to test whether prenatal treatment is effective against the more virulent strains of the parasite that occur in South America. Finally, because this study is an observational study, its findings might reflect differences between the study participants other than whether or not they received prenatal treatment. These findings need to be confirmed in randomized controlled trials of prenatal screening, therefore, before any policy decisions are made about routine prenatal screening and treatment for congenital toxoplasmosis.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000351.
The US Centers for Disease Control and Prevention provides detailed information about all aspects of toxoplasmosis, including toxoplasmosis in pregnant women (in English and Spanish)
The UK National Health Services Choices website has information for patients about toxoplasmosis and about the risks of toxoplasmosis during pregnancy
KidsHealth, a resource maintained by the Nemours Foundation (a not-for-profit organization for children's health), provides information for parents about toxoplasmosis (in English and Spanish)
Tommy's, a nonprofit organization that funds research on the health of babies, also has information on toxoplasmosis
MedlinePlus provides links to other information on toxoplasmosis (in English and Spanish)
EUROTOXO contains reports generated by a European consensus development project
Uptodate provides information about toxoplasmosis and pregnancy
doi:10.1371/journal.pmed.1000351
PMCID: PMC2953528  PMID: 20967235
20.  Offspring psychopathology following preconception, prenatal, and postnatal maternal bereavement stress 
Psychological medicine  2013;44(1):10.1017/S0033291713000780.
Background
Preconception, prenatal, and postnatal maternal stress are associated with increased offspring psychopathology, but findings are inconsistent and need replication. We estimated associations between maternal bereavement stress and offspring autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), bipolar disorder, schizophrenia, suicide attempt, and completed suicide.
Methods
Using Swedish registers, we conducted the largest population-based study to date examining associations between stress exposure in 738,144 offspring born 1992–2000 for childhood outcomes and 2,155,221 offspring born 1973–1997 for adult outcomes with follow-up through 2009. Maternal stress was defined as death of a first degree relative during 6 months before conception, across pregnancy, or the first two postnatal years. Cox proportional survival analyses were used to obtain hazard ratios (HR) in unadjusted and adjusted analyses.
Results
Marginal increased risk of bipolar disorder and schizophrenia following preconception bereavement stress was not significant. Third trimester prenatal stress increased risk of ASD (adjusted HR=1.58, 95% CI: 1.15–2.17) and ADHD (adjusted HR=1.31, 95% CI: 1.04–1.66). First postnatal year stress increased risk for offspring suicide attempt (adjusted HR=1.13, 95% CI: 1.02–1.25) and completed suicide (adjusted HR=1.51, 95% CI: 1.08–2.11). Bereavement stress during the second postnatal year increased risk of ASD (adjusted HR=1.30, 95% CI: 1.09–1.55).
Conclusions
Further research is needed on associations between preconception stress and psychopathological outcomes. Prenatal bereavement stress increases risk of offspring ASD and ADHD. Postnatal bereavement stress moderately increases risk of offspring suicide attempt, completed suicide, and ASD. Smaller previous studies may have overestimated associations between early stress and psychopathological outcomes.
doi:10.1017/S0033291713000780
PMCID: PMC3766407  PMID: 23591021
stress; preconception; prenatal; postnatal; psychiatric; psychopathology; autism; attention-deficit/hyperactivity disorder; schizophrenia; suicide
21.  In utero exposure to antidepressant drugs and risk of attention deficit hyperactivity disorder: a nationwide Danish cohort study 
BMJ Open  2013;3(9):e003507.
Objective
To investigate whether in utero exposure to antidepressants is associated with increased risk of attention deficit hyperactivity disorder (ADHD).
Design
Cohort study.
Setting
Denmark.
Participants
All Danish singletons born alive from 1996 to 2009 were included. Using national medical registries, we defined in utero exposure to antidepressants as redemption of an antidepressant prescription by the mother 30 days prior to or during pregnancy. We defined maternal former users of antidepressants as women, who had redeemed a prescription up to 30 days prior to pregnancy, and never users as women who had never redeemed a prescription.
Main outcome measures
ADHD was defined as redemption of a prescription for ADHD medication or an ADHD hospital diagnosis. Children were followed through 2010, and we used proportional-hazards regression to compute adjusted HRs comparing children exposed in utero and children born to former antidepressant users with children born to never users. To adjust for confounding from family-related factors, we conducted a within-mother between-pregnancy analysis comparing exposed children with unexposed siblings using conditional logistic regression.
Results
We identified a cohort of 877 778 children, of whom 1.7% were exposed in utero. The overall median follow-up time was 8 years; selective serotonin reuptake inhibitors were the most commonly used class of antidepressant during pregnancy (78% of users). The adjusted HR comparing children exposed to any antidepressant in utero with children born to never users was 1.2 (95% CI 1.1 to 1.4), and 1.6 (95% CI 1.5 to 1.8) comparing children born to former users to children born to never users of antidepressants. In the within-mother between-pregnancy analysis (n=867), the adjusted OR was 0.7 (95% CI 0.4 to 1.4).
Conclusions
This study provides no evidence to support a causal association between in utero exposure to antidepressants and risk of ADHD.
doi:10.1136/bmjopen-2013-003507
PMCID: PMC3780335  PMID: 24056487
22.  Parental anxiety and family disruption following a first febrile seizure in childhood 
Paediatrics & Child Health  2001;6(3):139-143.
OBJECTIVE:
To evaluate the degree of parental anxiety and family disruption following a child’s first febrile seizure.
PATIENTS AND METHODS:
The families of all children presenting with their first febrile seizure to any of the three emergency departments in the Saskatoon District, Saskatchewan, were invited to participate in a telephone interview to assess the degree of parental anxiety and family dysfunction that was experienced. Parameters measured included co-sleeping with the child, parental sleep disturbance, parental fatigue, monitor use, the number of night time checks on a child, child care use, parental outings, parental fear of missing a seizure, parental perception of a child’s increased vulnerability and the family’s stress level. The interview, which was conducted shortly after presentation at the emergency departments, compared anxiety and dysfunction experienced during the two weeks immediately preceding the visit with that experienced during the two weeks following a febrile seizure. Potential predictors of anxiety and dysfunction, including details of the presenting seizure, past medical illnesses, family history, the family’s socioeconomic status and parental perception of the risk of a febrile seizure were queried.
RESULTS:
Thirty-one (89%) of 35 families who were eligible for the study participated. Parental anxiety and family dysfunction were significantly greater for nearly all of the parameters assessed during the two weeks following a seizure. Socioeconomic factors correlated most closely with anxiety and dysfunction before a febrile seizure; however, socioeconomic factors were less predictive of anxiety and dysfunction during the two weeks following a seizure.
CONCLUSIONS:
Parental anxiety and family dysfunction are the rule following a child’s first febrile seizure. Neither higher socioeconomic status nor an understanding of the low risk of sequelae associated with febrile seizures was strongly predictive of improved coping during the two weeks following a seizure.
PMCID: PMC2804529  PMID: 20084226
Febrile seizures; Parental anxiety
23.  Maternal Use of Antibiotics, Hospitalisation for Infection during Pregnancy, and Risk of Childhood Epilepsy: A Population-Based Cohort Study 
PLoS ONE  2012;7(1):e30850.
Background
Maternal infection during pregnancy may be a risk factor for epilepsy in offspring. Use of antibiotics is a valid marker of infection.
Methodology/Principal Findings
To examine the relationship between maternal infection during pregnancy and risk of childhood epilepsy we conducted a historical cohort study of singletons born in northern Denmark from 1998 through 2008 who survived ≥29 days. We used population-based medical databases to ascertain maternal use of antibiotics or hospital contacts with infection during pregnancy, as well as first-time hospital contacts with a diagnosis of epilepsy among offspring. We compared incidence rates (IR) of epilepsy among children of mothers with and without infection during pregnancy. We examined the outcome according to trimester of exposure, type of antibiotic, and total number of prescriptions, using Poisson regression to estimate incidence rate ratios (IRRs) while adjusting for covariates. Among 191 383 children in the cohort, 948 (0.5%) were hospitalised or had an outpatient visit for epilepsy during follow-up, yielding an IR of 91 per 100 000 person-years (PY). The five-year cumulative incidence of epilepsy was 4.5 per 1000 children. Among children exposed prenatally to maternal infection, the IR was 117 per 100 000 PY, with an adjusted IRR of 1.40 (95% confidence interval (CI): 1.22–1.61), compared with unexposed children. The association was unaffected by trimester of exposure, antibiotic type, or prescription count.
Conclusions/Significance
Prenatal exposure to maternal infection is associated with an increased risk of epilepsy in childhood. The similarity of estimates across types of antibiotics suggests that processes common to all infections underlie this outcome, rather than specific pathogens or drugs.
doi:10.1371/journal.pone.0030850
PMCID: PMC3266299  PMID: 22295115
24.  Redefining Outcome of First Seizures by Acute Illness 
Pediatrics  2010;126(6):e1477-e1484.
BACKGROUND
Seizures are common in children, but the causes and recurrence risk for children with a nonfebrile first seizure remain poorly understood.
OBJECTIVE
In a prospective longitudinal study of children who presented with a first-time seizure, we investigated the viral etiology of associated infectious illnesses and sought to determine the risk of recurrent seizures stratified by fever and type of illness.
PATIENTS AND METHODS
Children (aged 6 months to 6 years) were enrolled at the time of evaluation for their first seizure and followed monthly for up to 5 years. Seizure and illness data were collected through parent interviews and medical-record reviews. Stool, serum, and cerebrospinal fluid collected within 48 hours of the first seizure were evaluated for viral gastrointestinal pathogens.
RESULTS
Of the 117 children enrolled, 78 (67%) had febrile seizures, 34 (29%) had nonfebrile-illness seizures, and 5 (4%) had unprovoked seizures. Children with nonfebrile-illness seizures were more likely than those with febrile seizures to have acute gastroenteritis (47% and 28%, respectively; P = .05). No significant differences in seizure recurrence were found between children with or without a fever at first seizure. Children with acute gastroenteritis at first seizure, regardless of fever, had a lower risk of seizure recurrence compared with children with other acute illnesses (hazard ratio: 0.28; 95% confidence interval: 0.09–0.80).
CONCLUSIONS
Our results confirm the role of gastrointestinal illness as a distinguishing feature in childhood seizures. Children with this distinct presentation have a low rate of seizure recurrence and few neurologic complications.
doi:10.1542/peds.2010-1138
PMCID: PMC3040576  PMID: 21098153
seizures; febrile; rotavirus; norovirus; child; gastroenteritis
25.  Early Life Disease Programming during the Preconception and Prenatal Period: Making the Link between Stressful Life Events and Type-1 Diabetes 
PLoS ONE  2010;5(7):e11523.
Background
To assess the risk of developing Type-1 diabetes among children who were exposed to maternal bereavement during the prenatal or 1-year preconception period.
Methods
We identified N = 1,548,746 singleton births born in Denmark between January 1st 1979 through December 31st 2004, and their next of kin. Altogether, 39,857 children were exposed to bereavement during their prenatal life. The main outcome of interest was hospitalization for type-1 diabetes (ICD 8: 249; ICD 10: E10).
Results
We found the strongest association for type-1 diabetes among children exposed to traumatic father or sibling deaths (aIRR: 2.03, 1.22–3.38); the association was mainly seen for girls (aIRR: 2.91, 1.61–5.26).
Conclusions
We found evidence to suggest that female fetuses exposed to severe prenatal stress are at increased risk for developing type-1 diabetes.
doi:10.1371/journal.pone.0011523
PMCID: PMC2901388  PMID: 20634978

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