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1.  Five-minute Apgar score as a marker for developmental vulnerability at 5 years of age 
Objective
To assess the relationship between the 5 min Apgar score and developmental vulnerability at 5 years of age.
Design
Population-based retrospective cohort study.
Setting
Manitoba, Canada.
Participants
All children born between 1999 and 2006 at term gestation, with a documented 5 min Apgar score.
Exposure
5 min Apgar score.
Main outcome measures
Childhood development at 5 years of age, expressed as vulnerability (absent vs present) on five domains of the Early Development Instrument: physical health, social competence, emotional maturity, language and cognitive development, and communication skills.
Results
Of the 33 883 children in the study, most (82%) had an Apgar score of 9; 1% of children had a score <7 and 5.6% had a score of 10. Children with Apgar scores <10 had higher odds of vulnerability on the physical domain at age 5 years compared with children with a score of 10 (eg, adjusted OR (aOR) for Apgar 9=1.23, 95% CI 1.05 to 1.44). Similarly, children with Apgar scores of <10 were more vulnerable on the emotional domain (eg, aOR for Apgar 9=1.20, 95% CI 1.03 to 1.41). Nevertheless, the Apgar-based prognostic model had a poor sensitivity for physical vulnerability (19%, 95% CI 18% to 20%). Although the Apgar score-based prognostic model had reasonable calibration ability and risk-stratification accuracy for identifying developmentally vulnerable children, classification accuracy was poor.
Conclusions
The risk of developmental vulnerability at 5 years of age is inversely associated with the 5 min Apgar score across its entire range, and the score can serve as a population-level indicator of developmental risk.
doi:10.1136/archdischild-2015-308458
PMCID: PMC4789716  PMID: 26187935
Child Psychology; Comm Child Health; Epidemiology
2.  Maternal Overweight and Obesity and Risks of Severe Birth-Asphyxia-Related Complications in Term Infants: A Population-Based Cohort Study in Sweden 
PLoS Medicine  2014;11(5):e1001648.
Martina Persson and colleagues use a Swedish national database to investigate the association between maternal body mass index in early pregnancy and severe asphyxia-related outcomes in infants delivered at term.
Please see later in the article for the Editors' Summary
Background
Maternal overweight and obesity increase risks of pregnancy and delivery complications and neonatal mortality, but the mechanisms are unclear. The objective of the study was to investigate associations between maternal body mass index (BMI) in early pregnancy and severe asphyxia-related outcomes in infants delivered at term (≥37 weeks).
Methods and Findings
A nation-wide Swedish cohort study based on data from the Medical Birth Register included all live singleton term births in Sweden between 1992 and 2010. Logistic regression analyses were used to obtain odds ratios (ORs) with 95% CIs for Apgar scores between 0 and 3 at 5 and 10 minutes, meconium aspiration syndrome, and neonatal seizures, adjusted for maternal height, maternal age, parity, mother's smoking habits, education, country of birth, and year of infant birth. Among 1,764,403 term births, 86% had data on early pregnancy BMI and Apgar scores. There were 1,380 infants who had Apgar score 0–3 at 5 minutes (absolute risk  = 0.8 per 1,000) and 894 had Apgar score 0–3 at 10 minutes (absolute risk  = 0.5 per 1,000). Compared with infants of mothers with normal BMI (18.5–24.9), the adjusted ORs (95% CI) for Apgar scores 0–3 at 10 minutes were as follows: BMI 25–29.9: 1.32 (1.10–1.58); BMI 30–34.9: 1.57 (1.20–2.07); BMI 35–39.9: 1.80 (1.15–2.82); and BMI ≥40: 3.41 (1.91–6.09). The ORs for Apgar scores 0–3 at 5 minutes, meconium aspiration, and neonatal seizures increased similarly with maternal BMI. A study limitation was lack of data on effects of obstetric interventions and neonatal resuscitation efforts.
Conclusion
Risks of severe asphyxia-related outcomes in term infants increase with maternal overweight and obesity. Given the high prevalence of the exposure and the severity of the outcomes studied, the results are of potential public health relevance and should be confirmed in other populations. Prevention of overweight and obesity in women of reproductive age is important to improve perinatal health.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Economic, technologic, and lifestyle changes over the past 30 years have created an abundance of cheap, accessible, high-calorie food. Combined with fewer demands for physical activity, this situation has lead to increasing body mass throughout most of the world. Consequently, being overweight or obese is much more common in many high-income and low-and middle-income countries compared to 1980. Worldwide estimates put the percentage of overweight or obese adults as increasing by over 10%, between 1980 and 2008.
As being overweight becomes a global epidemic, its prevalence in women of reproductive age has also increased. Pregnant women who are overweight or obese are a cause for concern because of the possible associated health risks to both the infant and mother. Research is necessary to more clearly define these risks.
Why Was This Study Done?
In this study, the researchers investigated the complications associated with excess maternal weight that could hinder an infant from obtaining enough oxygen during delivery (neonatal asphyxia). All fetuses experience a loss of oxygen during contractions, however, a prolonged loss of oxygen can impact an infant's long-term development. To explore this risk, the researchers relied on a universal scoring system known as the Apgar score. An Apgar score is routinely recorded at one, five, and ten minutes after birth and is calculated from an assessment of heart rate, respiratory effort, and color, along with reflexes and muscle tone. An oxygen deficit during delivery will have an impact on the score. A normal score is in the range of 7–10. Body mass index (BMI) a calculation that uses height and weight, was used to assess the weight status (i.e., normal, overweight, obese) of the mother during pregnancy.
What Did the Researchers Do and Find?
Using the Swedish medical birth registry (a database including nearly all the births occurring in Sweden since 1973) the researchers selected records for single births that took place between 1992 to 2010. The registry also incorporates prenatal care data and researchers further selected for records that included weight and height measurement taken during the first prenatal visit. BMI was calculated using the weight and height measurement. Based on BMI ranges that define weight groups as normal, overweight, and obesity grades I, II, and III, the researchers analyzed and compared the number of low Apgar scoring infants (Apgar 0–3) in each group. Mothers with normal weight gave birth to the majority of infants with Apgar 0–3. In comparison the proportion of low Apgar scores were greater in babies of overweight and obese mothers. The researchers found that the rates of low Apgar scores increased with maternal BMI: the authors found that rates of low Apgar score at 5 minutes increased from 0.4 per 1,000 among infants of underweight women (BMI <18.5) to 2.4 per 1,000 among infants of women with obesity class III (BMI ≥40). Furthermore, overweight (BMI 25.0–29.9) was associated with a 55% increased risk of low Apgar scores at 5 minutes; obesity grade I (BMI 30–34.9) and grade II (BMI 35.0–39.9) with an almost 2-fold and a more than 2-fold increased risk, respectively; and obesity grade ΙΙΙ (BMI ≥40.0) with a more than 3-fold increase in risk. Finally, maternal overweight and obesity also increase the risks for seizures and meconium aspiration in the neonate.
What Do These Findings Mean?
These findings suggest that the risk of experiencing an oxygen deficit increases for the babies of women who are overweight or obese. Given the high prevalence of overweight and obesity in many countries worldwide, these findings are important and suggest that preventing women of reproductive age from becoming overweight or obese is therefore important to the health of their children.
A limitation of this study is the lack of data on the effects of clinical interventions and neonatal resuscitation efforts that may have been performed at the time of birth. Also Apgar scoring is based on five variables and a low score is not the most direct way to determine if the infant has experienced an oxygen deficit. However, these findings suggest that early detection of perinatal asphyxia is particularly relevant among infants of overweight and obese women although more studies are necessary to confirm the results in other populations.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001648.
The US National Institutes of Health explains and calculates body mass index
The NIH also defines the Apgar scoring system
The United Kingdom's National Health Service has information for pregnant woman who are overweight
The UK-based Overseas Development Institute discusses how changes in diet have led to a worldwide health crisis in its “Future Diets” publication
Information about the Swedish health care system is available
Information in English is available from the National Board of Health and Welfare in Sweden
doi:10.1371/journal.pmed.1001648
PMCID: PMC4028185  PMID: 24845218
3.  Apgar score and hospitalization for epilepsy in childhood: a registry-based cohort study 
BMC Public Health  2006;6:23.
Background
A depressed Apgar score at 5 minutes is a marker for perinatal insults, including neurologic damage. We examined the association between 5-minute Apgar score and the risk of epilepsy hospitalization in childhood.
Methods
Using records linked from population registries, we conducted a cohort study among singleton children born alive in the period 1978–2001 in North Jutland County, Denmark. The first hospital discharge diagnosis of epilepsy during the follow-up time was the main outcome. We followed each child for up to 12 years, calculated absolute risks and risk differences, and used a Poisson regression model to estimate risk ratios for epilepsy hospitalization. We adjusted risk ratio estimates for birth weight, gestational age, mode of delivery, birth presentation, mother's age at delivery, and birth defects.
Results
One percent of the 131,853 eligible newborns had a 5-minute Apgar score <7. These children were more likely to be hospitalized with epilepsy during the follow-up than were children with an Apgar score of 7 or greater. The crude risk difference for epilepsy hospitalization was 2.5 cases per 100 (95% confidence interval [CI] 1.3 to 3.8). The risk difference estimates were greater in the presence of other perinatal risk factors. The adjusted risk ratio was 2.4 (95% CI 1.5 to 3.8). Half of the 12-year risk for epilepsy hospitalization in those with a depressed Apgar score occurred during the first year of life. The risk ratio during the first year of life was 4.9 (95% CI 2.0 to 12.3).
Conclusion
An Apgar score <7 at five minutes predicts an increase in the subsequent risk of epilepsy hospitalization. This association is amplified by other perinatal risk factors.
doi:10.1186/1471-2458-6-23
PMCID: PMC1409783  PMID: 16451724
4.  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
5.  Inter-pregnancy Weight Change and Risks of Severe Birth-Asphyxia-Related Outcomes in Singleton Infants Born at Term: A Nationwide Swedish Cohort Study 
PLoS Medicine  2016;13(6):e1002033.
Background
Maternal overweight and obesity are associated with increased risks of birth-asphyxia-related outcomes, but the mechanisms are unclear. If a change of exposure (i.e., maternal body mass index [BMI]) over time influences risks, this would be consistent with a causal relationship between maternal BMI and offspring risks. Our objective was to investigate associations between changes in maternal BMI between consecutive pregnancies and risks of birth-asphyxia-related outcomes in the second offspring born at term.
Methods and Findings
This study was a prospective population-based cohort study that included 526,435 second-born term (≥37 wk) infants of mothers with two consecutive live singleton term births in Sweden between January 1992 and December 2012.
We estimated associations between the difference in maternal BMI between the first and second pregnancy and risks of low Apgar score (0–6) at 5 min, neonatal seizures, and meconium aspiration in the second-born offspring. Odds ratios (ORs) were adjusted for BMI at first pregnancy, maternal height, maternal age at second delivery, smoking, education, mother´s country of birth, inter-pregnancy interval, and year of second delivery. Analyses were also stratified by BMI (<25 versus ≥25 kg/m2) in the first pregnancy.
Risks of low Apgar score, neonatal seizures, and meconium aspiration increased with inter-pregnancy weight gain. Compared with offspring of mothers with stable weight (BMI change of −1 to <1 kg/m2), the adjusted OR for a low Apgar score in the offspring of mothers with a BMI change of 4 kg/m2 or more was 1.33 (95% CI 1.12–1.58). The corresponding risks for neonatal seizures and meconium aspiration were 1.42 (95% CI 1.00–2.02) and 1.78 (95% CI 1.19–2.68), respectively. The increased risk of neonatal seizures related to weight gain appeared to be restricted to mothers with BMI < 25 kg/m2 in the first pregnancy. A study limitation was the lack of data on the effects of obstetric interventions and neonatal resuscitation efforts.
Conclusions
Risks of birth-asphyxia-related outcomes increased with maternal weight gain between pregnancies. Preventing weight gain before and in between pregnancies may improve neonatal health.
Using data from the Swedish Medical Birth Register, Martina Persson and colleagues examine the associations between inter-pregnancy weight change and risks of severe birth asphyxia-related outcomes in singleton infants born at term.
Author Summary
Why Was This Study Done?
The increasing prevalence of overweight and obesity has epidemic proportions, also among pregnant women.
Maternal overweight and obesity increase the risks of pregnancy complications and adverse neonatal outcomes, including severe birth asphyxia disorders.
An independent association between maternal body mass index (BMI) and birth asphyxia would be further supported if maternal weight gain between pregnancies increases the risks of birth asphyxia in the following pregnancy.
What Did the Researchers Do and Find?
Data from the nationwide Swedish Medical Birth Register were used, which included 532,858 second-born infants born at term (≥37 weeks gestation) to mothers having their first and second infants between 1992 and 2012.
We estimated the associations between inter-pregnancy weight change and the risks of a low Apgar score (0–6) at 5 min (rate 5.4/1,000), neonatal seizures (rate 1.2/1,000), and meconium aspiration (rate 0.7/1,000).
The risks of a low Apgar score consistently increased with maternal weight gain. Compared with mothers with stable weight (−1 to <1 kg/m2 change in BMI between pregnancies), infants born to mothers who gained 4 kg/m2 or more between pregnancies had a 33% to 78% increased risk of low Apgar score, neonatal seizures, and meconium aspiration.
A study limitation is that we could not investigate the potential impact of obstetric and neonatal interventions.
What Do These Findings Mean?
The risk of birth asphyxia increases with maternal weight gain between pregnancies. Consequently, preventing weight gain between pregnancies could reduce the risk of birth asphyxia and improve infant health.
doi:10.1371/journal.pmed.1002033
PMCID: PMC4896455  PMID: 27270217
6.  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
7.  Association of cerebral palsy with Apgar score in low and normal birthweight infants: population based cohort study  
Objectives To assess the association of Apgar score 5 minutes after birth with cerebral palsy in both normal weight and low birthweight children, and also the association with the cerebral palsy subdiagnoses of quadriplegia, diplegia, and hemiplegia.
Design Population based cohort study.
Setting The Medical Birth Registry of Norway was used to identify all babies born between 1986 and 1995. These data were linked to the Norwegian Registry of Cerebral Palsy in Children born 1986-95, which was established on the basis of discharge diagnoses at all paediatric departments in Norway.
Population All singletons without malformations born in Norway during 1986-95 and who survived the first year of life (n=543 064).
Main outcome measure Cerebral palsy diagnosed before the age of 5 years.
Results 988 children (1.8 in 1000) were diagnosed with cerebral palsy before the age of 5 years. In total, 11% (39/369) of the children with Apgar score of less than 3 at birth were diagnosed with cerebral palsy, compared with only 0.1% (162/179 515) of the children with Apgar score of 10 (odds ratio (OR) 53, 95% CI 35 to 80 after adjustment for birth weight). In children with a birth weight of 2500 g or more, those with an Apgar score of less than 4 were much more likely to have cerebral palsy than those who had an Apgar score of more than 8 (OR 125, 95% confidence interval 91 to 170). The corresponding OR in children weighing less than 1500 g was 5 (95% CI 2 to 9). Among children with Apgar score of less than 4, 10-17% in all birthweight groups developed cerebral palsy. Low Apgar score was strongly associated with each of the three subgroups of spastic cerebral palsy, although the association was strongest for quadriplegia (adjusted OR 137 for Apgar score <4 v Apgar score >8, 95% CI 77 to 244).
Conclusions Low Apgar score was strongly associated with cerebral palsy. This association was high in children with normal birth weight and modest in children with low birth weight. The strength of the association differed between subgroups of spastic cerebral palsy. Given that Apgar score is a measure of vitality shortly after birth, our findings suggest that the causes of cerebral palsy are closely linked to factors that reduce infant vitality.
doi:10.1136/bmj.c4990
PMCID: PMC2952090  PMID: 20929920
8.  Association of cerebral palsy with Apgar score in low and normal birthweight infants: population based cohort study  
The BMJ  2010;341:c4990.
Objectives To assess the association of Apgar score 5 minutes after birth with cerebral palsy in both normal weight and low birthweight children, and also the association with the cerebral palsy subdiagnoses of quadriplegia, diplegia, and hemiplegia.
Design Population based cohort study.
Setting The Medical Birth Registry of Norway was used to identify all babies born between 1986 and 1995. These data were linked to the Norwegian Registry of Cerebral Palsy in Children born 1986-95, which was established on the basis of discharge diagnoses at all paediatric departments in Norway.
Population All singletons without malformations born in Norway during 1986-95 and who survived the first year of life (n=543 064).
Main outcome measure Cerebral palsy diagnosed before the age of 5 years.
Results 988 children (1.8 in 1000) were diagnosed with cerebral palsy before the age of 5 years. In total, 11% (39/369) of the children with Apgar score of less than 3 at birth were diagnosed with cerebral palsy, compared with only 0.1% (162/179 515) of the children with Apgar score of 10 (odds ratio (OR) 53, 95% CI 35 to 80 after adjustment for birth weight). In children with a birth weight of 2500 g or more, those with an Apgar score of less than 4 were much more likely to have cerebral palsy than those who had an Apgar score of more than 8 (OR 125, 95% confidence interval 91 to 170). The corresponding OR in children weighing less than 1500 g was 5 (95% CI 2 to 9). Among children with Apgar score of less than 4, 10-17% in all birthweight groups developed cerebral palsy. Low Apgar score was strongly associated with each of the three subgroups of spastic cerebral palsy, although the association was strongest for quadriplegia (adjusted OR 137 for Apgar score <4 v Apgar score >8, 95% CI 77 to 244).
Conclusions Low Apgar score was strongly associated with cerebral palsy. This association was high in children with normal birth weight and modest in children with low birth weight. The strength of the association differed between subgroups of spastic cerebral palsy. Given that Apgar score is a measure of vitality shortly after birth, our findings suggest that the causes of cerebral palsy are closely linked to factors that reduce infant vitality.
doi:10.1136/bmj.c4990
PMCID: PMC2952090  PMID: 20929920
9.  Apgar-score in children prenatally exposed to antiepileptic drugs: a population-based cohort study 
BMJ Open  2015;5(9):e007425.
Objectives
It is unknown if prenatal exposure to antiepileptic drugs (AEDs) increases the risk of low Apgar score in offspring.
Setting
Population-based study using health registers in Denmark.
Participants
We identified all 677 021 singletons born in Denmark from 1997 to 2008 and linked the Apgar score from the Medical Birth Register with information on the women's prescriptions for AEDs during pregnancy from the Danish Register of Medicinal Product Statistics. We used the Danish National Hospital Registry to identify mothers diagnosed with epilepsy before birth of the child. Results were adjusted for smoking and maternal age.
Results
Among 2906 children exposed to AEDs, 55 (1.9%) were born with an Apgar score ≤7 as compared with 8797 (1.3%) children among 674 115 pregnancies unexposed to AEDs (adjusted relative risk (aRR)=1.41 (95% CI 1.07 to 1.85). When analyses were restricted to the 2215 children born of mothers with epilepsy, the aRR of having a low Apgar score associated with AED exposure was 1.34 (95% CI 0.90 to 2.01) When assessing individual AEDs, we found increased, unadjusted RR for exposure to carbamazepine (RR=1.86 (95% CI 1.01 to 3.42)), valproic acid (RR=1.85 (95% CI 1.04 to 3.30)) and topiramate (RR=2.97 (95% CI 1.26 to 7.01)) when compared to unexposed children.
Conclusions
Prenatal exposure to AEDs was associated with increased risk of being born with a low Apgar score, but the absolute risk of a low Apgar score was <2%. Risk associated with individual AEDs indicate that the increased risk is not a class effect, but that there may be particularly high risks of a low Apgar score associated with certain AEDs.
doi:10.1136/bmjopen-2014-007425
PMCID: PMC4567672  PMID: 26359281
EPIDEMIOLOGY; PERINATOLOGY
10.  Genetic Markers of Adult Obesity Risk Are Associated with Greater Early Infancy Weight Gain and Growth 
PLoS Medicine  2010;7(5):e1000284.
Ken Ong and colleagues genotyped children from the ALSPAC birth cohort and showed an association between greater early infancy gains in weight and length and genetic markers for adult obesity risk.
Background
Genome-wide studies have identified several common genetic variants that are robustly associated with adult obesity risk. Exploration of these genotype associations in children may provide insights into the timing of weight changes leading to adult obesity.
Methods and Findings
Children from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort were genotyped for ten genetic variants previously associated with adult BMI. Eight variants that showed individual associations with childhood BMI (in/near: FTO, MC4R, TMEM18, GNPDA2, KCTD15, NEGR1, BDNF, and ETV5) were used to derive an “obesity-risk-allele score” comprising the total number of risk alleles (range: 2–15 alleles) in each child with complete genotype data (n = 7,146). Repeated measurements of weight, length/height, and body mass index from birth to age 11 years were expressed as standard deviation scores (SDS). Early infancy was defined as birth to age 6 weeks, and early infancy failure to thrive was defined as weight gain between below the 5th centile, adjusted for birth weight. The obesity-risk-allele score showed little association with birth weight (regression coefficient: 0.01 SDS per allele; 95% CI 0.00–0.02), but had an apparently much larger positive effect on early infancy weight gain (0.119 SDS/allele/year; 0.023–0.216) than on subsequent childhood weight gain (0.004 SDS/allele/year; 0.004–0.005). The obesity-risk-allele score was also positively associated with early infancy length gain (0.158 SDS/allele/year; 0.032–0.284) and with reduced risk of early infancy failure to thrive (odds ratio  = 0.92 per allele; 0.86–0.98; p = 0.009).
Conclusions
The use of robust genetic markers identified greater early infancy gains in weight and length as being on the pathway to adult obesity risk in a contemporary birth cohort.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The proportion of overweight and obese children is increasing across the globe. In the US, the Surgeon General estimates that, compared with 1980, twice as many children and three times the number of adolescents are now overweight. Worldwide, 22 million children under five years old are considered by the World Health Organization to be overweight.
Being overweight or obese in childhood is associated with poor physical and mental health. In addition, childhood obesity is considered a major risk factor for adult obesity, which is itself a major risk factor for cancer, heart disease, diabetes, osteoarthritis, and other chronic conditions.
The most commonly used measure of whether an adult is a healthy weight is body mass index (BMI), defined as weight in kilograms/(height in metres)2. However, adult categories of obese (>30) and overweight (>25) BMI are not directly applicable to children, whose BMI naturally varies as they grow. BMI can be used to screen children for being overweight and or obese but a diagnosis requires further information.
Why Was This Study Done?
As the numbers of obese and overweight children increase, a corresponding rise in future numbers of overweight and obese adults is also expected. This in turn is expected to lead to an increasing incidence of poor health. As a result, there is great interest among health professionals in possible pathways between childhood and adult obesity. It has been proposed that certain periods in childhood may be critical for the development of obesity.
In the last few years, ten genetic variants have been found to be more common in overweight or obese adults. Eight of these have also been linked to childhood BMI and/or obesity. The authors wanted to identify the timing of childhood weight changes that may be associated with adult obesity. Knowledge of obesity risk genetic variants gave them an opportunity to do so now, without following a set of children to adulthood.
What Did the Researchers Do and Find?
The authors analysed data gathered from a subset of 7,146 singleton white European children enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC) study, which is investigating associations between genetics, lifestyle, and health outcomes for a group of children in Bristol whose due date of birth fell between April 1991 and December 1992. They used knowledge of the children's genetic makeup to find associations between an obesity risk allele score—a measure of how many of the obesity risk genetic variants a child possessed—and the children's weight, height, BMI, levels of body fat (at nine years old), and rate of weight gain, up to age 11 years.
They found that, at birth, children with a higher obesity risk allele score were not any heavier, but in the immediate postnatal period they were less likely to be in the bottom 5% of the population for weight gain (adjusted for birthweight), often termed “failure to thrive.” At six weeks of age, children with a higher obesity risk allele score tended to be longer and heavier, even allowing for weight at birth.
After six weeks of age, the obesity risk allele score was not associated with any further increase in length/height, but it was associated with a more rapid weight gain between birth and age 11 years. BMI is derived from height and weight measurements, and the association between the obesity risk allele score and BMI was weak between birth and age three-and-a-half years, but after that age the association with BMI increased rapidly. By age nine, children with a higher obesity risk allele score tended to be heavier and taller, with more fat on their bodies.
What Do These Findings Mean?
The combined obesity allele risk score is associated with higher rates of weight gain and adult obesity, and so the authors conclude that weight gain and growth even in the first few weeks after birth may be the beginning of a pathway of greater adult obesity risk.
A study that tracks a population over time can find associations but it cannot show cause and effect. In addition, only a relatively small proportion (1.7%) of the variation in BMI at nine years of age is explained by the obesity risk allele score.
The authors' method of finding associations between childhood events and adult outcomes via genetic markers of risk of disease as an adult has a significant advantage: the authors did not have to follow the children themselves to adulthood, so their findings are more likely to be relevant to current populations. Despite this, this research does not yield advice for parents how to reduce their children's obesity risk. It does suggest that “failure to thrive” in the first six weeks of life is not simply due to a lack of provision of food by the baby's caregiver but that genetic factors also contribute to early weight gain and growth.
The study looked at the combined obesity risk allele score and the authors did not attempt to identify which individual alleles have greater or weaker associations with weight gain and overweight or obesity. This would require further research based on far larger numbers of babies and children. The findings may also not be relevant to children in other types of setting because of the effects of different nutrition and lifestyles.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000284.
Further information is available on the ALSPAC study
The UK National Health Service and other partners provide guidance on establishing a healthy lifestyle for children and families in their Change4Life programme
The International Obesity Taskforce is a global network of expertise and the advocacy arm of the International Association for the Study of Obesity. It works with the World Health Organization, other NGOs, and stakeholders and provides information on overweight and obesity
The Centers for Disease Control and Prevention (CDC) in the US provide guidance and tips on maintaining a healthy weight, including BMI calculators in both metric and Imperial measurements for both adults and children. They also provide BMI growth charts for boys and girls showing how healthy ranges vary for each sex at with age
The Royal College of Paediatrics and Child Health provides growth charts for weight and length/height from birth to age 4 years that are based on WHO 2006 growth standards and have been adapted for use in the UK
The CDC Web site provides information on overweight and obesity in adults and children, including definitions, causes, and data
The CDC also provide information on the role of genes in causing obesity.
The World Health Organization publishes a fact sheet on obesity, overweight and weight management, including links to childhood overweight and obesity
Wikipedia includes an article on childhood obesity (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1000284
PMCID: PMC2876048  PMID: 20520848
11.  Maternal and perinatal risk factors for childhood cancer: record linkage study 
BMJ Open  2014;4(1):e003656.
Objective
To investigate maternal and perinatal risk factors for childhood cancer.
Study design
Case–control analysis of linked records from the Aberdeen Maternity and Neonatal Databank with the Scottish Cancer Registry and the General Registry of Births and Deaths in Scotland was carried out.
Setting
Aberdeen, Scotland.
Participants
Cases (n=176) comprised children diagnosed with cancer under 15 years or recorded as having died of cancer. Four controls per case were matched by age and gender.
Risk factors tested
Maternal age, body mass index, social class, marital status and smoking as well as pre-eclampsia, antepartum haemorrhage and previous miscarriage, gestational age, birth weight and Apgar scores were compared between groups to test for association with cancer. ORs with 95% CIs were calculated using conditional logistic regression in univariable and multivariable models.
Results
Of the maternal characteristics tested, mother's age at delivery (cases mean 28.9 (SD 5.6) years vs controls mean 30.2 (SD 4.6), p=0.002) and smoking status (38.6% smokers among cases, 29.7% among controls, p=0.034) were found to be different between groups. Of the perinatal factors tested, low Apgar score at 5 min (adjusted OR (AOR) 4.59, 95% CI 1.52 to 13.87) and delivery by caesarean section (AOR 1.95, 95% CI 1.30 to 2.92) showed statistically significant associations with childhood cancer in the multivariable model.
Conclusions
Younger maternal age, maternal smoking, delivery by caesarean section and low Apgar score at 5 min were independently associated with increased risk of childhood cancer. These general findings should be interpreted with caution as this study did not have the power to detect any association with individual diagnostic categories of childhood cancer.
doi:10.1136/bmjopen-2013-003656
PMCID: PMC3902197  PMID: 24394797
EPIDEMIOLOGY
12.  Parental and infant characteristics and childhood leukemia in Minnesota 
BMC Pediatrics  2008;8:7.
Background
Leukemia is the most common childhood cancer. With the exception of Down syndrome, prenatal radiation exposure, and higher birth weight, particularly for acute lymphoid leukemia (ALL), few risk factors have been firmly established. Translocations present in neonatal blood spots and the young age peak of diagnosis suggest that early-life factors are involved in childhood leukemia etiology.
Methods
We investigated the association between birth characteristics and childhood leukemia through linkage of the Minnesota birth and cancer registries using a case-cohort study design. Cases included 560 children with ALL and 87 with acute myeloid leukemia (AML) diagnoses from 28 days to 14 years. The comparison group was comprised of 8,750 individuals selected through random sampling of the birth cohort from 1976–2004. Cox proportional hazards regression specific for case-cohort studies was used to compute hazard ratios (HR) and 95% confidence intervals (CIs).
Results
Male sex (HR = 1.41, 95% CI 1.16–1.70), white race (HR = 2.32, 95% CI 1.13–4.76), and maternal birth interval ≥ 3 years (HR = 1.31, 95% CI 1.01–1.70) increased ALL risk, while maternal age increased AML risk (HR = 1.21/5 year age increase, 95% CI 1.0–1.47). Higher birth weights (>3798 grams) (HRALL = 1.46, 1.08–1.98; HRAML = 1.97, 95% CI 1.07–3.65), and one minute Apgar scores ≤ 7 (HRALL = 1.30, 95% CI 1.05–1.61; HRAML = 1.62, 95% CI 1.01–2.60) increased risk for both types of leukemia. Sex was not a significant modifier of the association between ALL and other covariates, with the exception of maternal education.
Conclusion
We confirmed known risk factors for ALL: male sex, high birth weight, and white race. We have also provided data that supports an increased risk for AML following higher birth weights, and demonstrated an association with low Apgar scores.
doi:10.1186/1471-2431-8-7
PMCID: PMC2292161  PMID: 18298855
13.  Maternal and Birth Characteristics and Childhood Embryonal Solid Tumors: A Population-Based Report from Brazil 
PLoS ONE  2016;11(10):e0164398.
Background
Several maternal and birth characteristics have been reported to be associated with an increased risk of many childhood cancers. Our goal was to evaluate the risk of childhood embryonal solid tumors in relation to pre- and perinatal characteristics.
Methods
A case-cohort study was performed using two population-based datasets, which were linked through R software. Tumors were classified as central nervous system (CNS) or non-CNS-embryonal (retinoblastoma, neuroblastoma, renal tumors, germ cell tumors, hepatoblastoma and soft tissue sarcoma). Children aged <6 years were selected. Adjustments were made for potential confounders. Odds ratios (OR) with 95% confidence intervals (CI) were computed by unconditional logistic regression analysis using SPSS.
Results
Males, high maternal education level, and birth anomalies were independent risk factors. Among children diagnosed older than 24 months of age, cesarean section (CS) was a significant risk factor. Five-minute Apgar ≤8 was an independent risk factor for renal tumors. A decreasing risk with increasing birth order was observed for all tumor types except for retinoblastoma. Among children with neuroblastoma, the risk decreased with increasing birth order (OR = 0.82 (95% CI 0.67–1.01)). Children delivered by CS had a marginally significantly increased OR for all tumors except retinoblastoma. High maternal education level showed a significant increase in the odds for all tumors together, CNS tumors, and neuroblastoma.
Conclusion
This evidence suggests that male gender, high maternal education level, and birth anomalies are risk factors for childhood tumors irrespective of the age at diagnosis. Cesarean section, birth order, and 5-minute Apgar score were risk factors for some tumor subtypes.
doi:10.1371/journal.pone.0164398
PMCID: PMC5074509  PMID: 27768709
14.  Early Infant Morbidity in the City of São Paulo, Brazil 
Background
Early infant morbidities may produce adverse outcomes in subsequent life. A low Apgar score is a convenient measure of early infant morbidity. We study determinants of early infant morbidity (sex, plurality, mode of delivery, prior losses, gestational age, prenatal care and birth weight, parity and maternal age, race, maternal education and community development) for the 1998-birth cohort, City of São Paulo, Brazil.
Methods
This study identified all deliveries that took place in the City of São Paulo during 1998. Information was extracted from 209,628 birth records. We used multivariate logistic regression to assess the effect of each independent variable on Apgar score less than seven at one minute and Apgar score less than seven at five minutes.
Results
Low birth weight, prematurity and community development were found to be strong predictors of morbidity. Maternal education showed strong negative correlation with both Apgar scores. The negative correlations between maternal schooling and Apgar scores were observed after prenatal care, parity and maternal age were included in the model. Unmeasured proximate factors may thus be the true source of disparity between educational groups. Children of very young adolescent mothers had lower Apgar scores at one minute (but not at five minutes) than those born to mothers 15 to 19. Parity one or higher was associated with decreased odds of low Apgar scores. Cesarean section and operative delivery were associated with higher odds of early infant morbidity.
Conclusion
Education may allow mothers to have better care in the peripartum period. More educated mothers may be more likely to recognize certain morbidities through the pregnancy period and the monitoring of such morbidities yields better infant outcomes. Also, having less than seven prenatal care visits was found to predict early infant morbidity and one way to increase the use of such services is to focus on aspects of care that may lead to easier accessibility and continuity of prenatal care. Physicians should inform mothers about the risks associated with high number of children for a next infant and also about the risks for the infant associated with unnecessary cesarean sections. Special attention should be paid to adolescent mothers, since much of their increased risk is likely to be minimized by counseling.
doi:10.1186/1478-7954-1-7
PMCID: PMC270079  PMID: 14613522
15.  Prenatal Exposure to Perfluorooctanoate (PFOA) and Perfluorooctanesulfonate (PFOS) and Maternally Reported Developmental Milestones in Infancy 
Environmental Health Perspectives  2008;116(10):1391-1395.
Background
Perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA) are fluorinated organic compounds present in the general population at low concentrations. Animal studies have shown that they may affect neuromuscular development at high concentrations.
Objectives
We investigated the association between plasma levels of PFOS and PFOA in pregnant women and motor and mental developmental milestones of their children.
Methods
We randomly selected 1,400 pairs of pregnant women and their children from the Danish National Birth Cohort. PFOS and PFOA were measured in maternal blood samples taken in early pregnancy. Apgar score was abstracted from the National Hospital Discharge Register in Denmark. Developmental milestones were reported by mothers using highly structured questionnaires when the children were around 6 months and 18 months of age.
Results
Mothers who had higher levels of PFOA and PFOS gave birth to children who had similar Apgar scores and reached virtually all of the development milestones at the same time as children born to mothers with lower exposure levels. Children who were born to mothers with higher PFOS levels were slightly more likely to start sitting without support at a later age.
Conclusion
We found no convincing associations between developmental milestones in early childhood and levels of PFOA or PFOS as measured in maternal plasma early in pregnancy.
doi:10.1289/ehp.11277
PMCID: PMC2569100  PMID: 18941583
maternal blood; mental developmental milestones; motor developmental milestones; PFOA; PFOS
16.  Birth Outcome in Women with Previously Treated Breast Cancer—A Population-Based Cohort Study from Sweden 
PLoS Medicine  2006;3(9):e336.
Background
Data on birth outcome and offspring health after the appearance of breast cancer are limited. The aim of this study was to assess the risk of adverse birth outcomes in women previously treated for invasive breast cancer compared with the general population of mothers.
Methods and Findings
Of all 2,870,932 singleton births registered in the Swedish Medical Birth Registry during 1973–2002, 331 first births following breast cancer surgery—with a mean time to pregnancy of 37 mo (range 7–163)—were identified using linkage with the Swedish Cancer Registry.
Logistic regression analysis was used. The estimates were adjusted for maternal age, parity, and year of delivery. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate infant health and mortality, delivery complications, the risk of preterm birth, and the rates of instrumental delivery and cesarean section.
The large majority of births from women previously treated for breast cancer had no adverse events. However, births by women exposed to breast cancer were associated with an increased risk of delivery complications (OR 1.5, 95% CI 1.2–1.9), cesarean section (OR 1.3, 95% CI 1.0–1.7), very preterm birth (<32 wk) (OR 3.2, 95% CI 1.7–6.0), and low birth weight (<1500 g) (OR 2.9, 95% CI 1.4–5.8). A tendency towards an increased risk of malformations among the infants was seen especially in the later time period (1988–2002) (OR 2.1, 95% CI 1.2–3.7).
Conclusions
It is reassuring that births overall were without adverse events, but our findings indicate that pregnancies in previously treated breast cancer patients should possibly be regarded as higher risk pregnancies, with consequences for their surveillance and management.
The large majority of births from women previously treated for breast cancer had no adverse events, but such pregnancies might benefit from increased surveillance and management.
Editors' Summary
Background.
More women of all ages are developing breast cancer than ever before. In the US, one woman in eight will now develop this disease during her lifetime. For most of these women, their breast cancer diagnosis will come late in life, but a fifth of breast cancers are diagnosed before the age of 50. These days, the long-term outlook for women with breast cancer is quite good; 80% of women who receive a diagnosis of breast cancer survive more than five years. These figures, together with a trend towards starting families later in life—since the late 1970s birth rates for women in their late 30s and 40s have more than doubled in the US, and in Sweden the average age for having a first baby is now 29 years—mean that many women who have had breast cancer want to have children. One estimate is that up to 7% of women who are fertile after treatment for breast cancer will later have children.
Why Was This Study Done?
Pregnancy seems to have no adverse affects on women who have had breast cancer—there is no evidence that pregnancy can trigger a relapse. However, little is known about whether the chemotherapy and radiotherapy used to treat breast cancer have any long-lasting effects that might result in a poor birth outcome such as stillbirth, low birth weight, premature delivery, or abnormalities in the baby (congenital abnormalities). In this study, the researchers assessed the risk of adverse birth outcomes in women previously treated for breast cancer in Sweden.
What Did the Researchers Do and Find?
Nearly three million singleton births that occurred between 1973 and 2002 are recorded in the Swedish Medical Birth Registry. The researchers linked this information with that in the Swedish Cancer Registry to identify 331 first births after treatment for invasive breast cancer (cancer that has spread from where it started to grow in the breast). The birth registry includes details on maternal age and health, child's birth weight, whether the delivery was preterm, and whether the child had any congenital abnormalities, so the researchers were able to compare birth outcomes in these 331 births with those in the general population. They discovered that most births after breast cancer treatment went smoothly. There was no increase in stillbirths, but there were slightly more delivery complications in the women who had had breast cancer than in the general population, and a slight increase in babies born prematurely or with low birth weight. Finally, a few more babies with congenital abnormalities were born to women after breast cancer treatment than to women in the general population.
What Do These Findings Mean?
Overall, these results should reassure women who are thinking about having children after breast cancer about the health of their future offspring. However, they do suggest that these women may need careful monitoring during late pregnancy and delivery. This result was not predicted by the researchers who performed the study. Before starting the study, they thought that there would be no difference in birth outcomes between patients previously treated for breast cancer and the general population. Furthermore, a recently published similar study in Denmark found no increased risk of preterm birth, low birth weight, or congenital abnormalities after breast cancer. Differences between the two countries in the accuracy of their registries or in the use of chemotherapy and radiotherapy treatments may account for this difference in results. Additional studies are now needed in other populations to resolve this discrepancy and to provide more information about how breast cancer treatment might affect birth outcomes. For example, the current study did not provide any information about whether specific chemotherapy regimens or different types of breast cancer might put women at a higher risk of adverse birth outcomes, or whether the time between the cancer diagnosis and treatment and the pregnancy made a difference.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030336.
MedlinePlus encyclopedia entry on breast cancer
National Cancer Institute information for patients and physicians on breast cancer, including links to pages on breast cancer and pregnancy
Cancer Research UK's information on breast cancer for patients, and statistics on breast cancer in the UK
• Wikipedia page on breast cancer (note: Wikipedia is a free online encyclopedia that anyone can edit)
Royal College of Obstetricians and Gynaecologists guidelines for physicians on pregnancy and breast cancer
doi:10.1371/journal.pmed.0030336
PMCID: PMC1564170  PMID: 16968117
17.  Risk of low Apgar score and socioeconomic position: a study of Swedish male births 
Aim
The aim of this study was to investigate the association between maternal socioeconomic position and a persistent low Apgar score (a score of < 7 at 1 and 5 min following birth).
Methods
The research is based on a population cohort study of 183 637 males born in Sweden between 1973 and 1976. Data from the Medical Birth Register were linked to Population and Housing Censuses.
Results
There was evidence that mothers working in non-manual (Odds ratio (OR) 0.83 (0.72–0.97)) and self-employed (OR 0.64 (0.44–0.93)) occupations were less likely to have an infant with a low Apgar score, compared to manual workers. There was evidence that the risk of a low Apgar score decreased as the mother's level of education increased, if the infant was born by instrumental (OR 0.86 (0.74–0.99)) or caesarean section (OR 0.80 (0.68–0.93)) delivery, but not by unassisted vaginal delivery (OR 1.01 (0.92–1.10)).
Conclusion
There was a lower risk of poor birth condition in male infants born to more educated and non-manual/self-employed mothers. These differences may contribute to our understanding of socioeconomic differences in infant health and development although the results may not be applicable due to changes over the last 30 years.
doi:10.1111/j.1651-2227.2008.00862.x
PMCID: PMC2582400  PMID: 18489620
Asphyxia neonatorum; Infant; Newborn; Obstetrical care; Socioeconomic status
18.  Apgar scores at 10 min and outcomes at 6–7 years following hypoxic-ischaemic encephalopathy 
Aim
To determine the association between 10 min Apgar scores and 6–7-year outcomes in children with perinatal hypoxic-ischaemic encephalopathy (HIE) enrolled in the National Institute of Child Health and Human Development Neonatal Research Network (NICHD NRN) whole body cooling randomised controlled trial (RCT).
Methods
Evaluations at 6–7 years included the Wechsler Preschool and Primary Scale of Intelligence III or Wechsler Intelligence Scale for Children IV and Gross Motor Functional Classification Scale. Primary outcome was death/moderate or severe disability. Logistic regression was used to examine the association between 10 min Apgar scores and outcomes after adjusting for birth weight, gestational age, gender, outborn status, hypothermia treatment and centre.
Results
In the study cohort (n=174), 64/85 (75%) of those with 10 min Apgar score of 0–3 had death/disability compared with 40/89 (45%) of those with scores >3. Each point increase in 10 min Apgar scores was associated with a significantly lower adjusted risk of death/disability, death, death/IQ <70, death/cerebral palsy (CP) and disability, IQ<70 and CP among survivors (all p<0.05). Among the 24 children with a 10 min Apgar score of 0, five (20.8%) survived without disability. The risk-adjusted probabilities of death/disability were significantly lower in cooled infants with Apgar scores of 0–3; there was no significant interaction between cooling and Apgar scores (p=0.26).
Conclusions
Among children with perinatal HIE enrolled in the NICHD cooling RCT, 10 min Apgar scores were significantly associated with school-age outcomes. A fifth of infants with 10 min Apgar score of 0 survived without disability to school age, suggesting the need for caution in limiting resuscitation to a specified duration.
doi:10.1136/archdischild-2013-303692
PMCID: PMC4166405  PMID: 23896791
19.  Association of Apgar score at five minutes with long-term neurologic disability and cognitive function in a prevalence study of Danish conscripts 
Background
Apgar score is used for rapid assessment of newborns. Low five-minute Apgar score has been associated with increased risk of severe neurologic outcome, but data on milder outcomes, particularly in the long term, are limited. We aimed to examine the association of five-minute Apgar score with prevalence of neurologic disability and with cognitive function in early adulthood.
Methods
We conducted a prevalence study among draft-liable men born in Denmark in 1978–1983 and presenting for the mandatory army evaluation in a northern Danish conscription district. We linked records of this evaluation, which includes medical exam and intelligence testing, with the conscripts' records in the Medical Birth Registry, containing perinatal data. We examined prevalence of neurologic disability and of low cognitive function according to five-minute Apgar score.
Results
Less than 1% (136/19,559) of the conscripts had 5-minute Apgar scores <7. Prevalence of neurologic disability was 2.2% (435/19,559) overall; among conscripts with Apgar scores <7, 7–9, and 10 (reference), it was 8.8%, 2.5%, and 2.2% respectively. The corresponding prevalences of low cognitive function (intelligence test score in the bottom quartile) were 34.9%, 27.2%, and 25.0%. The outcomes were more prevalent if Apgar score <7 was accompanied by certain fetal or obstetric adversities. After accounting for perinatal characteristics, 5-mintue Apgar score <7 was associated with prevalence ratios of 4.02 (95% confidence interval: 2.24; 7.24) for neurologic disability and 1.33 (0.94; 1.88) for low cognitive function.
Conclusion
A five-minute Apgar score <7 has a consistent association with prevalence of neurologic disability and with low cognitive function in early adulthood.
doi:10.1186/1471-2393-9-14
PMCID: PMC2670812  PMID: 19341459
20.  Prenatal Valproate Exposure and Risk of Autism Spectrum Disorders and Childhood Autism 
JAMA  2013;309(16):1696-1703.
Importance
Valproate is used for the treatment of epilepsy and other neuropsychological disorders and may be the only treatment option for women of childbearing potential. However, prenatal exposure to valproate may increase the risk of autism.
Objective
To determine whether prenatal exposure to valproate is associated with an increased risk of autism in offspring.
Design, Setting, and Participants
Population-based study of all children born alive in Denmark from 1996 to 2006. National registers were used to identify children exposed to valproate during pregnancy and diagnosed with autism spectrum disorders (childhood autism [autistic disorder], Asperger syndrome, atypical autism, and other or unspecified pervasive developmental disorders). We analyzed the risks associated with all autism spectrum disorders as well as childhood autism. Data were analyzed by Cox regression adjusting for potential confounders (maternal age at conception, paternal age at conception, parental psychiatric history, gestational age, birth weight, sex, congenital malformations, and parity). Children were followed up from birth until the day of autism spectrum disorder diagnosis, death, emigration, or December 31, 2010, whichever came first.
Main Outcomes and Measures
Absolute risk (cumulative incidence) and the hazard ratio (HR) of autism spectrum disorder and childhood autism in children after exposure to valproate in pregnancy.
Results
Of 655 615 children born from 1996 through 2006, 5437 were identified with autism spectrum disorder, including 2067 with childhood autism. The mean age of the children at end of follow-up was 8.84 years (range, 4-14; median, 8.85). The estimated absolute risk after 14 years of follow-up was 1.53% (95% CI, 1.47%- 1.58%) for autism spectrum disorder and 0.48% (95% CI, 0.46%-0.51%) for childhood autism. Overall, the 508 children exposed to valproate had an absolute risk of 4.42% (95% CI, 2.59%-7.46%) for autism spectrum disorder (adjusted HR, 2.9 [95% CI, 1.7-4.9]) and an absolute risk of 2.50% (95% CI, 1.30%-4.81%) for childhood autism (adjusted HR, 5.2 [95% CI, 2.7-10.0]). When restricting the cohort to the 6584 children born to women with epilepsy, the absolute risk of autism spectrum disorder among 432 children exposed to valproate was 4.15% (95% CI, 2.20%-7.81%) (adjusted HR, 1.7 [95% CI, 0.9-3.2]), and the absolute risk of childhood autism was 2.95% (95% CI, 1.42%-6.11%) (adjusted HR, 2.9 [95% CI, 1.4-6.0]) vs 2.44% (95% CI, 1.88%-3.16%) for autism spectrum disorder and 1.02% (95% CI, 0.70%-1.49%) for childhood autism among 6152 children not exposed to valproate.
Conclusions and Relevance
Maternal use of valproate during pregnancy was associated with a significantly increased risk of autism spectrum disorder and childhood autism in the offspring, even after adjusting for maternal epilepsy. For women of childbearing potential who use antiepileptic medications, these findings must be balanced against the treatment benefits for women who require valproate for epilepsy control.
doi:10.1001/jama.2013.2270
PMCID: PMC4511955  PMID: 23613074
21.  Fetal Growth and Childhood Cancer: A Population-Based Study 
Pediatrics  2013;132(5):e1265-e1275.
OBJECTIVE:
The etiology of childhood cancers is largely unknown. Studies have suggested that birth characteristics may be associated with risk. Our goal was to evaluate the risk of childhood cancers in relation to fetal growth.
METHODS:
We conducted a case-control study nested within Nordic birth registries. The study included cancer cases diagnosed in Denmark, Finland, Norway, and Sweden among children born from 1967 to 2010 and up to 10 matched controls per case, totaling 17 698 cases and 172 422 controls. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were derived from conditional logistic regression.
RESULTS:
Risks of all childhood cancers increased with increasing birth weight (Ptrend ≤ .001). Risks of acute lymphoid leukemia and Wilms tumor were elevated when birth weight was >4000 g and of central nervous system tumors when birth weight was >4500 g. Newborns large for gestational age were at increased risk of Wilms tumor (OR: 2.1 [95% CI: 1.2–3.6]) and connective/soft tissue tumors (OR: 2.1 [95% CI: 1.1–4.4]). In contrast, the risk of acute myeloid leukemia was increased among children born small for gestational age (OR: 1.8 [95% CI: 1.1–3.1]). Children diagnosed with central nervous system tumors at <1 year of age had elevated risk with increasing head circumference (Ptrend < .001). Those with head circumference >39 cm had the highest risk (OR: 4.7 [95% CI: 2.5–8.7]).
CONCLUSIONS:
In this large, Nordic population-based study, increased risks for several childhood tumors were associated with measures of fetal growth, supporting the hypothesis that tumorigenesis manifesting in childhood is initiated in utero.
doi:10.1542/peds.2013-1317
PMCID: PMC3813399  PMID: 24167169
birth weight; childhood cancer; fetal growth; nested case-control study; Nordic countries
22.  Permissive hypercapnia and risk for brain injury and developmental impairment 
Pediatrics  2008;122(3):e583-e589.
Objective
Permissive hypercapnia is a respiratory care strategy used to reduce the risk of lung injury. The goal of this study was to evaluate whether permissive hypercapnia is associated with higher risk for intraventricular hemorrhage (IVH) and early childhood behavioral and functional problems than normocapnia among very low birthweight (VLBW) infants.
Patients and Methods
VLBW infants from a statewide cohort were eligible for this study if they were born <32 weeks gestational age and survived at least 24 hours. Infants were classified as receiving a permissive hypercapnia (N=122), normocapnia (N=235), or unclassifiable (N=791) respiratory strategy during the first 24 hours after birth according to an algorithm based on PCO2 values and respiratory treatment decisions abstracted from medical records. IVH diagnosis was also abstracted from the medical record. Behavioral and functional outcomes were assessed by parent interview at 2-3 years. Logistic regression was used to evaluate the relationship between IVH and respiratory strategy; ordinary linear regression was used to evaluate differences in behavior and function scores between children by respiratory strategy.
Results
Infants who received a permissive hypercapnia strategy were not more likely to have IVH than those with normocapnia (odds ratio=1.0, 95% confidence interval: 0.59, 1.8). There were no differences in any of the behavioral or functional scores between children by respiratory strategy. There was a significant interaction between care strategy and one-minute Apgar score, indicating that infants with lower Apgar scores may be at higher risk for IVH with permissive hypercapnia.
Conclusion
This study suggests permissive hypercapnia does not increase risk for brain injury and impairment among VLBW children. The interaction between respiratory strategy and Apgar score is a potential worrisome exception to this conclusion. Future research should further evaluate the effect of elevated PCO2 levels among those sickest at birth.
doi:10.1542/peds.2008-1016
PMCID: PMC2561893  PMID: 18762492
Permissive hypercapnia; developmental follow-up; intraventricular hemorrhage; VLBW-very low birthweight
23.  Joint association of Apgar scores and early neonatal symptoms with minor disabilities at school age 
Objective: To examine whether the combination of a low five minute Apgar score and symptoms of neonatal encephalopathy is associated with minor impairments at school age.
Design: Population based cohort study.
Setting: Norway.
Participants: All 727 children of the cohort were born between 1983 and 1987, had normal birth weights, no congenital malformations, and no major neurological abnormalities. The cohort comprised three groups with five minute Apgar scores of 0–3, 4–6, and 7–10, and were followed from birth to 8–13 years of age by combining data from The Medical Birth Registry, questionnaires, hospital discharge summaries, and the National Insurance Scheme.
Main outcome measure: Neurodevelopmental impairments such as learning, behavioural, and minor motor difficulties.
Results: Children with a five minute Apgar score of 3 or less and signs consistent with neonatal encephalopathy had a significantly increased risk of developing minor motor impairments (odds ratio (OR) 12.8, 95% confidence interval (CI) 2.6 to 63.2), epilepsy (OR 7.0, 95% CI 1.3 to 39.2), need of extra resources in kindergarten (OR 7.0, 95% CI 1.3 to 39.2) or at school (OR 3.4, 95% CI 1.8 to 6.3), and had reduced performance in reading (OR 4.6, 95% CI 2.3 to 9.5) and mathematics (OR 3.3, 95% CI 1.5 to 7.3), compared with children with normal Apgar scores and no neonatal symptoms. They also more often had problems related to tractability, aggressivity, passivity, anxiety, academic performance, and fine motor development.
Conclusion: Children with low Apgar scores and subsequent signs of cerebral depression who do not develop cerebral palsy may still have an increased risk of developing a variety of neurodevelopmental impairments and learning difficulties.
doi:10.1136/fn.86.1.F16
PMCID: PMC1721350  PMID: 11815542
24.  Incidence and risk factors of hospitalization for bronchiolitis in preterm children: a retrospective longitudinal study in Italy 
BMC Pediatrics  2009;9:56.
Background
Bronchiolitis is a distressing, potentially life-threatening respiratory condition that affects infants. We evaluated the incidence and risk factors of hospitalization for broncholitis in preterm infants (i.e., a gestational age of <36 weeks) born between 2000 and 2006, and the use and impact of Palivizumab, a monoclonal antibody that in randomized clinical trials has been shown to lessen the severity of RSV-related bronchiolitis.
Methods
Retrospective cohort study that linked data from four health administrative databases in the Lazio region (a region of central Italy): the birth register, the hospital discharge register, and two ad-hoc databases that record the doses of Palivizumab administered at two local health units.
Results
Among 2407 preterm infants, 137 had at least one hospitalization for bronchiolitis in the first 18 months of life, an overall incidence rate of 4.70 per 100 person-years (95%CI: 3.98-5.56); similar incidence rates were observed by calendar year. A multiple Poisson model showed that the following characteristics were associated with higher incidence: younger age of the infant, the period between October-April, male gender, low Apgar score at birth, low birth weight, and low maternal educational level. At least one dose of Palivizumab was administered to 324 (13.5%) children; a dramatic increase from 2000 (2.8%) to 2006 (19.1%) (p < 0.01) was observed. Other factors independently associated with more frequent Palivizumab use were older maternal age, Italian-born mothers, female gender, low Apgar score, low birth weight, shorter gestational age, a diagnosis of broncho-dysplasia, and the month of birth. It is of note that none of the 34 children with congenital heart disease were prescribed Palivizumab. Performing several multiple Poisson models that also considered Palivizumab use as covariate, although the point estimates were in agreement with previous clinical trial results, we did not find in most of them a significant reduction for immunized children to be hospitalized for bronchiolitis.
Conclusion
In Italy the incidence of hospitalization for bronchiolitis, and its associated risk factors, are similar to that found in other countries. Although Palivizumab use is associated with the most important characteristics of severe prematurity, other aspects of its non-use in children with congenital heart disease, the age and the birth country of the mother suggest the need for public health measures that can reduce these health disparities. Finally, the estimated effectiveness of Palivizumab in routine practice, although not significant, confirms the results of previous clinical trials, but its impact on modifying the temporal trend in this population is still negligible.
doi:10.1186/1471-2431-9-56
PMCID: PMC2749027  PMID: 19744335
25.  Socio-demographic characteristics of women sustaining injuries during pregnancy: a study from the Danish National Birth Cohort 
BMJ Open  2012;2(4):e000826.
Objectives
To describe adverse birth outcomes associated with hospital-treated injuries that took place among women in the Danish National Birth Cohort.
Design
Longitudinal cohort study.
Setting
Denmark.
Participants
90 452 women and their offspring selected from the Danish National Birth Cohort.
Primary and secondary outcome measures
To determine if injured women were more likely to deliver an infant preterm, with low birth weight, stillborn or have a spontaneous abortion, the authors estimated HRs. ORs were generated to assess APGAR scores and infants born small for gestational age (SGA). Models were adjusted for maternal smoking and drinking during pregnancy, household socioeconomic status, eclampsia/pre-eclampsia or gestational diabetes status during pregnancy and maternal age at birth; estimates for preterm birth were also adjusted for prior history of preterm birth.
Results
In the cohort of 90 452 pregnant women, 3561 (3.9%) received medical treatment for an injury during pregnancy. Injured pregnant women were more likely to deliver infants that were stillborn or have pregnancies terminated by spontaneous abortion. The authors did not detect an adverse effect between injuries sustained during pregnancy and delivery of preterm, low birth weight or SGA infants, or infants with an APGAR score of <7.
Conclusions
The study shows that injuries occurring among women from an unselected population may not have an adverse effect on birth weight, gestational age, APGAR score or SGA status but may adversely affect the risk of stillbirth and spontaneous abortions in some situations.
Article summary
Article focus
We describe adverse birth outcomes associated with injuries that took place among pregnant women in the Danish National Birth Cohort and include in our assessment injury severity, cause and mechanism.
Key messages
Injured pregnant women were more likely to deliver infants that were stillborn or have pregnancies that were terminated by spontaneous abortion. We did not detect an adverse effect between injuries sustained during pregnancy and delivery of preterm, low birth weight or SGA infants, or infants with an APGAR score of <7.
Women sustaining head or neck injuries were more likely to deliver an infant SGA and have a stillbirth, though these results were not statistically significant.
Strengths and limitations of this study
Previous studies have selected pregnant trauma patients or emergency room patients; our study, however, presents injuries among pregnant women from a general population.
We only have data on late spontaneous abortions, and if injured fetuses are aborted early, we would not detect an association.
doi:10.1136/bmjopen-2012-000826
PMCID: PMC3391365  PMID: 22761281

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