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1.  Risk of adverse outcomes among infants of immigrant women according to birth-weight curves tailored to maternal world region of origin 
Infants of immigrant women in Western nations generally have lower birth weights than infants of native-born women. Whether this difference is physiologic or pathological is unclear. We determined whether the use of birth-weight curves tailored to maternal world region of origin would discriminate adverse neonatal and obstetric outcomes more accurately than a single birth-weight curve based on infants of Canadian-born women.
We performed a retrospective cohort study of in-hospital singleton live births (328 387 to immigrant women, 761 260 to nonimmigrant women) in Ontario between 2002 and 2012 using population health services data linked to the national immigration database. We classified infants as small for gestational age (< 10th percentile) or large for gestational age (≥ 90th percentile) using both Canadian and world region–specific birth-weight curves and compared associations with adverse neonatal and obstetric outcomes.
Compared with world region–specific birth-weight curves, the Canadian curve classified 20 431 (6.2%) additional newborns of immigrant women as small for gestational age, of whom 15 467 (75.7%) were of East or South Asian descent. The odds of neonatal death were lower among small-for-gestational-age infants of immigrant women than among those of nonimmigrant women based on the Canadian birth-weight curve (adjusted odds ratio [OR] 0.83, 95% confidence interval [CI] 0.72–0.95), but higher when small for gestational age was defined by the world region–specific curves (adjusted OR 1.24, 95% CI 1.08–1.42). Conversely, the odds of some adverse outcomes were lower among large-for-gestational-age infants of immigrant women than among those of nonimmigrant women based on world region–specific birth-weight curves, but were similar based on the Canadian curve.
World region–specific birth-weight curves seemed to be more appropriate than a single Canadian population-based curve for assessing the risk of adverse neonatal and obstetric outcomes among small- and large-for-gestational-age infants born to immigrant women, especially those from the East and South Asian regions.
PMCID: PMC4284190  PMID: 25384653
2.  A population-based study of premature mortality in relation to neighbourhood density of alcohol sales and cheque cashing outlets in Toronto, Canada 
BMJ Open  2014;4(12):e006032.
Alcohol overuse and poverty, each associated with premature death, often exist within disadvantaged neighbourhoods. Cheque cashing places (CCPs) may be opportunistically placed in disadvantaged neighbourhoods, where customers abound. We explored whether neighbourhood density of CCPs and alcohol outlets are each related to premature mortality among adults.
Retrospective population-based study.
140 neighbourhoods in Toronto, Ontario, 2005–2009.
Adults aged 20–59 years.
Our primary outcome was premature all-cause mortality among adults aged 20–59 years. Across neighbourhoods we explored neighbourhood density, in km2, of CCPs and alcohol outlets, and the relation of each to premature mortality. Poisson regression provided adjusted relative risks (aRRs) and 95% CIs, adjusting for material deprivation quintile (Q), crime Q and number of banks.
Intentional self-harm, accidental poisoning and liver disease were among the top five causes of premature death among males aged 20–59 years. The overall premature mortality rate was 96.3/10 000 males and 55.9/10 000 females. Comparing the highest versus lowest CCP density Q, the aRR for death was 1.25 (95% CI 1.15 to 1.36) among males and 1.11 (95% CI 0.99 to 1.24) among females. The corresponding aRR comparing the highest Q versus lowest Q alcohol outlet density in relation to premature mortality was 1.36 (95% CI 1.25 to 1.48) for males and 1.11 (95% CI 1.00 to 1.24) for females. The pattern of the relation between either CCPs or alcohol outlet density and premature mortality was typically J shaped.
There is a J-shaped relation between CCP or alcohol outlet density and premature mortality, even on controlling for conventional measures of poverty. Formal banking and alcohol reduction strategies might be added to health promotion policies aimed at reducing premature mortality in highly affected neighbourhoods.
PMCID: PMC4275686  PMID: 25518874
Premature mortality; Cheque cashing places; Cheque cashing outlets; Alcohol sales, ethanol, bars; Gender; Poverty
3.  Maternal and neonatal separation and mortality associated with concurrent admissions to intensive care units 
Concurrent admission of a mother and her newborn to separate intensive care units (herein referred to as co-ICU admission), possibly in different centres, can magnify family discord and stress. We examined the prevalence and predictors of mother–infant separation and mortality associated with co-ICU admissions.
We completed a population-based study of all 1 023 978 singleton live births in Ontario between Apr. 1, 2002, and Mar. 31, 2010. We included data for maternal–infant pairs that had co-ICU admission (n = 1216), maternal ICU admission only (n = 897), neonatal ICU (NICU) admission only (n = 123 236) or no ICU admission (n = 898 629). The primary outcome measure was mother–infant separation because of interfacility transfer.
The prevalence of co-ICU admissions was 1.2 per 1000 live births and was higher than maternal ICU admissions (0.9 per 1000). Maternal–newborn separation due to interfacility transfer was 30.8 (95% confidence interval [CI] 26.9–35.3) times more common in the co-ICU group than in the no-ICU group and exceeded the prevalence in the maternal ICU group and NICU group. Short-term infant mortality (< 28 days after birth) was higher in the co-ICU group (18.1 per 1000 live births; maternal age–adjusted hazard ratio [HR] 27.8, 95% CI 18.2–42.6) than in the NICU group (7.6 per 1000; age-adjusted HR 11.5, 95% CI 10.4–12.7), relative to 0.7 per 1000 in the no-ICU group. Short-term maternal mortality (< 42 days after delivery) was also higher in the co-ICU group (15.6 per 1000; age-adjusted HR 328.7, 95% CI 191.2–565.2) than in the maternal ICU group (6.7 per 1000; age-adjusted HR 140.0, 95% CI 59.5–329.2) or the NICU group (0.2 per 1000; age-adjusted HR 4.6, 95% CI 2.8–7.4).
Mother–infant pairs in the co-ICU group had the highest prevalence of separation due to interfacility transfer and the highest mortality compared with those in the maternal ICU and NICU groups.
PMCID: PMC3519169  PMID: 23091180
4.  Risk of Cerebral Palsy among the Offspring of Immigrants 
PLoS ONE  2014;9(7):e102275.
Cerebral palsy (CP) has a multifactorial etiology, and placental vascular disease may be one major risk factor. The risk of placental vascular disease may be lower among some immigrant groups. We studied the association between immigrant status and the risk of CP.
We conducted a population-based retrospective cohort study of all singleton and twin livebirths in Ontario between 2002–2008, and who survived ≥28 days after birth. Each child was assessed for CP up to age 4 years, based on either a single inpatient or ≥2 outpatient pediatric diagnoses of CP. Relative to non-immigrants (n = 566,668), the risk of CP was assessed for all immigrants (n = 177,390), and further evaluated by World region of origin. Cox proportional hazard ratios (aHR) were adjusted for maternal age, income, diabetes mellitus, obesity, tobacco use, Caesarean delivery, year of delivery, physician visits, twin pregnancy, preterm delivery, as well as small- and large-for-gestational age birthweight.
There were 1346 cases of CP, with a lower rate among immigrants (1.45 per 1000) than non-immigrants (1.92 per 1000) (aHR 0.77, 95% confidence interval [CI] 0.67 to 0.88). Mothers from East Asia and the Pacific (aHR 0.54, 95% CI 0.39 to 0.77) and the Caribbean (aHR 0.58, 95% CI 0.37 to 0.93) were at a significantly lower risk of having a child with CP. Whether further adjusting for preeclampsia, gestational hypertension, placental abruption or placental infraction, or upon using a competing risk analysis that further accounted for stillbirth and neonatal death, these results did not change.
Immigration and ethnicity appear to attenuate the risk of CP, and this effect is not fully explained by known risk factors.
PMCID: PMC4096602  PMID: 25019202
5.  Sex ratios among Canadian liveborn infants of mothers from different countries 
There has been much discussion about whether female feticide occurs in certain immigrant groups in Canada. We examined data on live births in Ontario and compared sex ratios in different groups according to the mother’s country or region of birth and parity.
We completed a population-based study of 766 688 singleton live births between 2002 and 2007. We used birth records provided by Ontario Vital Statistics for live births in the province between 23 and 41 weeks’ gestation. We categorized each newborn according to the mother’s country or region of birth, namely Canada (n = 486 599), Europe (n = 58 505), South Korea (n = 3663), China (n = 23 818), Philippines (n = 15 367), rest of East Asia (n = 18 971), Pakistan (n = 18 018), India (n = 31 978), rest of South Asia (n = 20 695) and other countries (n = 89 074). We calculated male:female ratios and 95% confidence intervals (CIs) for all live births by these regions and stratified them by maternal parity at the time of delivery (0, 1, 2 or ≥ 3).
Among infants of nulliparous women, the male:female ratio was about 1.05 overall. As parity increased, the ratio remained unchanged among infants of Canadian-born women. In contrast, the male:female ratio was significantly higher among infants of primiparous women born in South Korea (1.20, 95% CI 1.09–1.34) and India (1.11, 95% CI 1.07–1.15) than among infants of Canadian-born primiparous women. Among multiparous women, those born in India were significantly more likely than Canadian-born women to have a male infant (parity 2, ratio 1.36, 95% CI 1.27–1.46; parity ≥ 3, ratio 1.25, 95% CI 1.09–1.43).
Our study of male:female ratios in Ontario showed that multiparous women born in India were significantly more likely than multiparous women born in Canada to have a male infant.
PMCID: PMC3381774  PMID: 22508977
6.  The BRAzil MAGnesium (BRAMAG) trial: a randomized clinical trial of oral magnesium supplementation in pregnancy for the prevention of preterm birth and perinatal and maternal morbidity 
Preterm birth is the leading cause of infant mortality globally, including Brazil. We will evaluate whether oral magnesium citrate reduces the risk of placental dysfunction and its negative consequences for both the fetus and mother, which, in turn, should reduce the need for indicated preterm delivery.
We will complete a multicenter, randomized double-blind clinical trial comparing oral magnesium citrate 150 mg twice daily (n = 2000 women) to matched placebo (n = 1000 women), starting at 121/7 to 206/7 weeks gestation and continued until delivery. We will include women at higher risk for placental dysfunction, based on clinical factors from a prior pregnancy (e.g., prior preterm delivery, stillbirth or preeclampsia) or the current pregnancy (e.g., chronic hypertension, pre-pregnancy diabetes mellitus, maternal age > 35 years or pre-pregnancy maternal body mass index > 30 kg/m2). The primary perinatal outcome is a composite of preterm birth < 37 weeks gestation, stillbirth > 20 weeks gestation, neonatal death < 28 days, or SGA birthweight < 3rd percentile. The primary composite maternal outcome is preeclampsia arising < 37 weeks gestation, severe non-proteinuric hypertension arising < 37 weeks gestation, placental abruption, maternal stroke during pregnancy or ≤ 7 days after delivery, or maternal death during pregnancy or ≤ 7 days after delivery.
The results of this randomized clinical trial may be especially relevant in low and middle income countries that have high rates of prematurity and limited resources for acute newborn and maternal care.
Trial registration Identifier NCT02032186, registered December 19, 2013.
PMCID: PMC4096428  PMID: 25005784
Magnesium; Pregnancy; Prevention; Preeclampsia; Hypertension; Placenta; Perinatal; Preterm birth; Prematurity; Small for gestational age; Stillbirth
7.  Abdominal Visceral Adiposity in the First Trimester Predicts Glucose Intolerance in Later Pregnancy 
Diabetes Care  2009;32(7):1308-1310.
To assess whether abdominal adiposity in early pregnancy is associated with a higher risk of glucose intolerance at a later gestational stage.
Subcutaneous and visceral fat was measured with ultrasonography at ∼12 weeks' gestation. A 50-g glucose challenge test (GCT) was performed between 24 and 28 weeks' gestation. The risk of having a positive GCT (≥7.8 mmol/l) was determined in association with subcutaneous and visceral adipose tissue depths above their respective upper-quartile values relative to their bottom three quartile values.
Sixty-two women underwent GCTs. A visceral adipose tissue depth above the upper quartile value was significantly associated with a positive GCT in later pregnancy (adjusted odds ratio 16.9 [95% CI 1.5–194.6]). No associations were seen for subcutaneous adipose tissue.
Measurement of visceral adipose tissue depth in early pregnancy may be associated with glucose intolerance later in pregnancy.
PMCID: PMC2699729  PMID: 19389819
8.  Intracranial Pressure Monitoring in Severe Traumatic Brain Injury: Results from the American College of Surgeons Trauma Quality Improvement Program 
Journal of Neurotrauma  2013;30(20):1737-1746.
Although existing guidelines support the utilization of intracranial pressure (ICP) monitoring in patients with traumatic brain injury (TBI), the evidence suggesting benefit is limited. To evaluate the impact on outcome, we determined the relationship between ICP monitoring and mortality in centers participating in the American College of Surgeons Trauma Quality Improvement Program (TQIP). Data on 10,628 adults with severe TBI were derived from 155 TQIP centers over 2009–2011. Random-intercept multilevel modeling was used to evaluate the association between ICP monitoring and mortality after adjusting for important confounders. We evaluated this relationship at the patient level and at the institutional level. Overall mortality (n=3769) was 35%. Only 1874 (17.6%) patients underwent ICP monitoring, with a mortality of 32%. The adjusted odds ratio (OR) for mortality was 0.44 [95% confidence interval (CI), 0.31–0.63], when comparing patients with ICP monitoring to those without. It is plausible that patients receiving ICP monitoring were selected because of an anticipated favorable outcome. To overcome this limitation, we stratified hospitals into quartiles based on ICP monitoring utilization. Hospitals with higher rates of ICP monitoring use were associated with lower mortality: The adjusted OR of death was 0.52 (95% CI, 0.35–0.78) in the quartile of hospitals with highest use, compared to the lowest. ICP monitoring utilization rates explained only 9.9% of variation in mortality across centers. Results were comparable irrespective of the method of case-mix adjustment. In this observational study, ICP monitoring utilization was associated with lower mortality. However, variability in ICP monitoring rates contributed only modestly to variability in institutional mortality rates. Identifying other institutional practices that impact on mortality is an important area for future research.
PMCID: PMC3796332  PMID: 23731257
head injury; intracranial pressure; multilevel analysis; traumatic brain injury
9.  Vitamin B12 and homocysteine 
PMCID: PMC1283513  PMID: 16301712
10.  Cobalamin deficiency in elderly patients 
PMCID: PMC548390  PMID: 15710919
11.  Neural tube defects 
PMCID: PMC543965
12.  Preconception Care in Low- and Middle-Income Countries: New Opportunities and a New Metric 
PLoS Medicine  2013;10(9):e1001507.
Joel Ray and colleagues discuss the challenges and opportunities for improving pre-conception care for women in developing countries.
Please see later in the article for the Editors' Summary
PMCID: PMC3760777  PMID: 24019761
13.  Preeclampsia as a Risk Factor for Diabetes: A Population-Based Cohort Study 
PLoS Medicine  2013;10(4):e1001425.
Denice Feig and colleagues assess the association between gestational diabetes, gestational hypertension, and preeclampsia and the development of future diabetes in a database analysis of pregnant women in Ontario, Canada.
Women with preeclampsia (PEC) and gestational hypertension (GH) exhibit insulin resistance during pregnancy, independent of obesity and glucose intolerance. Our aim was to determine whether women with PEC or GH during pregnancy have an increased risk of developing diabetes after pregnancy, and whether the presence of PEC/GH in addition to gestational diabetes (GDM) increases the risk of future (postpartum) diabetes.
Methods and Findings
We performed a population-based, retrospective cohort study for 1,010,068 pregnant women who delivered in Ontario, Canada between April 1994 and March 2008. Women were categorized as having PEC alone (n = 22,933), GH alone (n = 27,605), GDM alone (n = 30,852), GDM+PEC (n = 1,476), GDM+GH (n = 2,100), or none of these conditions (n = 925,102). Our main outcome was a new diagnosis of diabetes postpartum in the following years, up until March 2011, based on new records in the Ontario Diabetes Database. The incidence rate of diabetes per 1,000 person-years was 6.47 for women with PEC and 5.26 for GH compared with 2.81 in women with neither of these conditions. In the multivariable analysis, both PEC alone (hazard ratio [HR] = 2.08; 95% CI 1.97–2.19) and GH alone (HR = 1.95; 95% CI 1.83–2.07) were risk factors for subsequent diabetes. Women with GDM alone were at elevated risk of developing diabetes postpartum (HR = 12.77; 95% CI 12.44–13.10); however, the co–presence of PEC or GH in addition to GDM further elevated this risk (HR = 15.75; 95% CI 14.52–17.07, and HR = 18.49; 95% CI 17.12–19.96, respectively). Data on obesity were not available.
Women with PEC/GH have a 2-fold increased risk of developing diabetes when followed up to 16.5 years after pregnancy, even in the absence of GDM. The presence of PEC/GH in the setting of GDM also raised the risk of diabetes significantly beyond that seen with GDM alone. A history of PEC/GH during pregnancy should alert clinicians to the need for preventative counseling and more vigilant screening for diabetes.
Please see later in the article for the Editors' Summary
Editors' Summary
Diabetes is a chronic disease that occurs either when the pancreas does not produce enough insulin (a hormone that regulates blood sugar), known as type 1 diabetes, or when the body cannot effectively use the insulin it produces—type 2 diabetes. Raised blood sugar, is a common effect of uncontrolled diabetes and over time leads to serious complications and even death. Worryingly, the global burden of type 2 diabetes is increasing worldwide, and the World Health Organization estimates that 90% of the 347 million people with diabetes currently have type 2 diabetes. Previous studies have shown that type 2 diabetes can be prevented or delayed in high risk groups by a range of lifestyle and treatment interventions and so it is important to identify potential high risk groups to screen for type 2 diabetes.
Why Was This Study Done?
Gestational diabetes (a form of diabetes that is related to pregnancy) is a major risk factor for developing type 2 diabetes. Therefore, diabetes prevention strategies should target women with gestational diabetes. Likewise, other common disorders of pregnancy possibly associated with insulin resistance, such as preeclampsia (a condition in which affected women have high blood pressure, fluid retention, and protein in their urine) and gestational hypertension (high blood pressure associated with pregnancy), may lead to the future development of type 2 diabetes. So women with these conditions may also benefit from diabetes prevention strategies. Therefore, in this large database study from Ontario, Canada, the researchers examined whether pregnant women with preeclampsia or gestational hypertension had an increased risk of developing diabetes in the years following pregnancy even if they did not have gestational diabetes.
What Did the Researchers Do and Find?
The researchers used a comprehensive Canadian health database to identify all women age 15 to 50 years of age who delivered in an Ontario hospital between April 1994 and March 2008. They then identified women who had preeclampsia, gestational hypertension, or gestational diabetes through hospital records and outpatient information. The researchers then used records from the Ontario Diabetes Database to record whether these women went on to develop diabetes in the period from 180 days after delivery until March 2011.
Using these methods, the researchers identified 1,010,068 pregnant women suitable for analysis, of whom 22,933 had only preeclampsia, 27,605 had only gestational hypertension, and 30,852 had only gestational diabetes: 2,100 women had both gestational diabetes and gestational hypertension and 1,476 women had gestational diabetes and preeclampsia. Overall, 35,077 women developed diabetes (3.5%) in the follow-up period (median of 8.5 years) at a median age of 37 years. In a modeling analysis, the researchers found that women with gestational diabetes had a 15-fold increased rate of developing diabetes compared to women without gestational diabetes, gestational hypertension, and preeclampsia, while women with gestational diabetes plus either preeclampsia or gestational hypertension had a 20- to 21-fold increased rate. These results were slightly reduced after adjusting for age, income quintile, hypertension prior to pregnancy, and co-morbidity, giving a hazard ratio (HR) of 1.95 for gestational hypertension alone, an HR of 2.08 for preeclampsia alone, an HR of 12.77 for gestational diabetes alone, an HR of 18.49 for gestational diabetes plus gestational hypertension and finally, an HR of 15.75 for gestational diabetes plus preeclampsia.
These Findings Mean?
These findings suggest that both preeclampsia and gestational hypertension without gestational diabetes are associated with a 2-fold increased incidence of diabetes in the years following pregnancy after controlling for several important variables. When combined with gestational diabetes, these conditions were associated with a further elevation in diabetes incidence additional to the 13-fold increased incidence resulting from gestational diabetes alone. A limitation of this study was the lack of information on obesity and body mass index, factors which are also associated with increased risk of developing diabetes. Nevertheless, these findings highlight a possible new risk factor for diabetes, and suggest that clinicians should be aware of the need for preventative measures and vigilant screening for diabetes in women with a history of preeclampsia or gestational hypertension.
Additional Information
Please access these Web sites via the online version of this summary at
NHS Choices has information about preeclampsia, gestational diabetes, and gestational hypertension
Living with diabetes is a useful resource for patients with diabetes
The Preeclampsia Foundation has more information about preeclampsia
PMCID: PMC3627640  PMID: 23610560
14.  Antenatal risk factors for peanut allergy in children 
Prenatal factors may contribute to the development of peanut allergy. We evaluated the risk of childhood peanut allergy in association with pregnancy exposure to Rh immune globulin, folic acid and ingestion of peanut-containing foods.
We conducted a web-based case-control survey using the Anaphylaxis Canada Registry, a pre-existing database of persons with a history of anaphylaxis. A total of 1300 case children with reported peanut allergy were compared to 113 control children with shellfish allergy. All were evaluated for maternal exposure in pregnancy to Rh immune globulin and folic acid tablet supplements, as well as maternal avoidance of dietary peanut intake in pregnancy.
Receipt of Rh immune globulin in pregnancy was not associated with a higher risk of peanut allergy (odds ratio [OR] 0.86, 95% confidence interval [CI] 0.51 to 1.45), nor was initiation of folic acid tablet supplements before or after conception (OR 0.53, 95% CI 0.19 to 1.48). Complete avoidance of peanut-containing products in pregnancy was associated with a non-significantly lower risk of peanut allergy (OR 0.53, 95% CI 0.27 to 1.03).
The risk of childhood peanut allergy was not modified by the following common maternal exposures in pregnancy: Rh immune globulin, folic acid or peanut-containing foods.
Clinical implications
Rh immune globulin, folic acid supplement use and peanut avoidance in pregnancy have yet to be proven to modulate the risk of childhood anaphylaxis to peanuts.
Capsule Summary
Identification of prenatal factors that contribute to peanut allergy might allow for prevention of this life-threatening condition. This article explores the role of three such factors.
PMCID: PMC3213059  PMID: 21970733
Allergy; peanut; shellfish; prenatal; antenatal; pregnancy; folic acid; Rh immune globulin; survey
15.  Major Radiodiagnostic Imaging in Pregnancy and the Risk of Childhood Malignancy: A Population-Based Cohort Study in Ontario 
PLoS Medicine  2010;7(9):e1000337.
In a record-linkage study, Joel Ray and colleagues examine the association between diagnostic imaging during pregnancy and later childhood cancers.
The association between fetal exposure to major radiodiagnostic testing in pregnancy—computed tomography (CT) and radionuclide imaging—and the risk of childhood cancer is not established.
Methods and Findings
We completed a population-based study of 1.8 million maternal-child pairs in the province of Ontario, from 1991 to 2008. We used Ontario's universal health care–linked administrative databases to identify all term obstetrical deliveries and newborn records, inpatient and outpatient major radiodiagnostic services, as well as all children with a malignancy after birth. There were 5,590 mothers exposed to major radiodiagnostic testing in pregnancy (3.0 per 1,000) and 1,829,927 mothers not exposed. The rate of radiodiagnostic testing increased from 1.1 to 6.3 per 1,000 pregnancies over the study period; about 73% of tests were CT scans. After a median duration of follow-up of 8.9 years, four childhood cancers arose in the exposed group (1.13 per 10,000 person-years) and 2,539 cancers in the unexposed group (1.56 per 10,000 person-years), a crude hazard ratio of 0.69 (95% confidence interval 0.26–1.82). After adjusting for maternal age, income quintile, urban status, and maternal cancer, as well as infant sex, chromosomal or congenital anomalies, and major radiodiagnostic test exposure after birth, the risk was essentially unchanged (hazard ratio 0.68, 95% confidence interval 0.25–1.80).
Although major radiodiagnostic testing is now performed in about 1 in 160 pregnancies in Ontario, the absolute annual risk of childhood malignancy following exposure in utero remains about 1 in 10,000. Since the upper confidence limit of the relative risk of malignancy may be as high as 1.8 times that of an unexposed pregnancy, we cannot exclude the possibility that fetal exposure to CT or radionuclide imaging is carcinogenic.
Please see later in the article for the Editors' Summary
Editors' Summary
In industrialized countries, childhood cancer (any form of cancer in a child aged 14 years or under) remains a major cause of death. With the exception of a few known risk factors, such as acquired genetic predisposition to cancer, which accounts for about 10% of all childhood cancers, the etiology of most childhood cancer remains unknown. There is thought to be an association between exposure to ionizing radiation in pregnancy and the subsequent risk of development of cancer in the exposed mother's child, but the evidence base to support this association is conflicting. For example, studies examining maternal exposure to plain radiographs in pregnancy and subsequent childhood cancer are inconsistent. Furthermore, although their use has dramatically increased over the past two decades, little is known about the cancer risk related to certain types of radiodiagnostic tests, such as CT and radionuclide imaging, both of which expose the fetus to considerably higher doses of radiation than plain radiographs administered at the same anatomical level.
Why Was This Study Done?
Many women could be exposed to major radiodiagnostic tests, such as those used in emergency situations, before they are aware that they are pregnant, as almost 50% of pregnancies are unplanned. This situation means that it is important to determine the subsequent cancer risk to any child exposed to maternal radiodiagnostic tests before birth.
What Did the Researchers Do and Find?
The researchers conducted a retrospective population-based cohort study of women who delivered a live infant in Ontario, Canada between April 1, 1992 and March 31, 2008. The basis of the research was an anonymized database for the whole province of Ontario, where universal health care, including prenatal care and radiodiagnostic testing, is available to all residents. Database characteristics allowed the researchers to link maternal radiation exposure (a major radiodiagnostic test performed on the mother up to one day before her delivery date) in a specific (index) pregnancy to a subsequent malignancy in the child. After birth, maternal-infant pairs were only followed up if the infant was delivered at term, weighed 2,500 g or more, and survived for at least 30 days.
The researchers were able to follow up 1,835,517 maternal-child pairs. The overall rate of exposure to major radiodiagnostic testing in pregnancy was 3.0 per 1,000 and occurred at an estimated mean gestational age of 15.7 weeks. A total of four childhood cancers occurred in the exposed group and 2,539 cancers in the unexposed group corresponding to a crude hazard ratio of 0.69, which did not significantly change after adjustments were made for potential confounding factors, such as maternal age, sex, and the presence of any chromosomal or congenital anomalies in the infant. The overall prevalence of childhood cancer following exposure to CT or radionuclide imaging in pregnancy is under 0.07%, giving an incidence rate of 1.13 per 10,000 person-years.
What Do These Findings Mean?
These findings can help inform clinicians and mothers about the risk of childhood malignancy following major radiodiagnostic testing in pregnancy. The absolute risk appears to be low, while the relative risk is not materially higher than that of unexposed controls. However, as the upper confidence limit of the relative risk of malignancy may be a maximum of 1.8 times that of an unexposed pregnancy, the possibility that fetal exposure to CT or radionuclide imaging is carcinogenic cannot be excluded. Because this finding means that a very slight risk may exist, beta hCG testing should continue to be done in all potentially pregnant women before undergoing major radiodiagnostic testing, and lead apron shielding used in all women of reproductive age, whether or not known to be pregnant. In addition, nonradiation-emitting imaging, such as MRI and ultrasonography, should be considered first, when clinically appropriate. However, some pregnant women will still be faced with the decision to undergo CT or nuclear imaging because the test is clinically warranted. The findings of this study suggest that when clinically indicated, major radiodiagnostic testing in pregnancy should be performed, along with brief counseling to help lessen the anxiety experienced by an expectant mother before and after the birth of her child.
Additional Information
Please access these Web sites via the online version of this summary at
For information for patients and caregivers on radiodiagnostic testing, see The Royal College of Radiologists
The National Cancer Institute provides information about childhood cancer
CureSearch for Children's Cancer provides additional information about research into childhood cancer
PMCID: PMC2935460  PMID: 20838660
16.  Newly diagnosed diabetes mellitus as a risk factor for serious liver disease 
The negative impact of diabetes mellitus is well recognized, yet little is known about the effect of this disease on the liver, an organ susceptible to nonalcoholic fatty liver disease related to insulin resistance. We evaluated whether adults with newly diagnosed diabetes were at increased risk of serious liver disease.
We used administrative health databases for the province of Ontario (1994–2006) to perform a population-based matched retrospective cohort study. The exposed group comprised 438 069 adults with newly diagnosed diabetes. The unexposed comparison group — those without known diabetes — consisted of 2 059 708 individuals, matched 5:1 to exposed persons, by birth year, sex and local health region. We excluded individuals with pre-existing liver or alcohol-related disease. The primary study outcome was the subsequent development of serious liver disease, namely, liver cirrhosis, liver failure and its sequelae, or receipt of a liver transplant.
The incidence rate of serious liver disease was 8.19 per 10 000 person-years among those with newly diagnosed diabetes and 4.17 per 10 000 person-years among those without diabetes. The unadjusted hazard ratio was 1.92 (95% confidence interval [CI] 1.83–2.01). After adjustment for age, income, urban residence, health care utilization and pre-existing hypertension, dyslipidemia, obesity and cardiovascular disease, the hazard ratio was 1.77 (95% CI 1.68–1.86).
Adults with newly diagnosed diabetes appeared to be at higher risk of advanced liver disease, also known as diabetic hepatopathy. Whether this reflects nonalcoholic fatty liver disease or direct glycemic injury of the liver remains to be determined.
PMCID: PMC2917963  PMID: 20566726
17.  Proliferation of prenatal ultrasonography 
The extent to which temporal increases in the use of prenatal ultrasonography reflect changes in maternal risk is unknown. In this population-based study, we examined the use of prenatal ultrasonography from 1996 to 2006 in Ontario.
With fiscal year 1996/97 as the baseline, we evaluated the relative risk (RR) and 95% confidence interval (CI) for the change in rates of ultrasonography for each subsequent year. The RR was adjusted for maternal age, income, rural residence, maternal comorbidities, receipt of genetics consultation or amniocentesis — all in the index pregnancy — and history of complications in a prior pregnancy.
The study sample consisted of 1 399 389 singleton deliveries. The rate of prenatal ultrasonography increased from 2055 per 1000 pregnancies in 1996 to 3264 per 1000 in 2006 (adjusted RR 1.55, 95% CI 1.54–1.55). The rate increased among both women with low-risk pregnancies (adjusted RR 1.54, 95% CI 1.53–1.55) and those with high-risk pregnancies (adjusted RR 1.55, 95% CI 1.54–1.57). The proportion of pregnancies with at least four ultrasound examinations in the second or third trimesters rose from 6.4% in 1996 to 18.7% in 2006 (adjusted RR 2.68, 95% CI 2.61–2.74). Paradoxically, this increase was more pronounced among low-risk pregnancies (adjusted RR 2.92, 95% CI 2.83–3.01) than among high-risk pregnancies (adjusted RR 2.25, 95% CI 2.16–2.35).
Substantial increases in the use of prenatal ultrasonography over the past decade do not appear to reflect changes in maternal risk. Nearly one in five women now undergo four or more ultrasound examinations during the second and third trimesters. Efforts to promote more appropriate use of prenatal ultrasonography for singleton pregnancies appear warranted.
PMCID: PMC2817321  PMID: 20048009
18.  Motor Vehicle Crashes in Diabetic Patients with Tight Glycemic Control: A Population-based Case Control Analysis 
PLoS Medicine  2009;6(12):e1000192.
Using a population-based case control analysis, Donald Redelmeier and colleagues found that tighter glycemic control, as measured by the HbA1c, is associated with an increased risk of a motor vehicle crash.
Complications from diabetes mellitus can compromise a driver's ability to safely operate a motor vehicle, yet little is known about whether euglycemia predicts normal driving risks among adults with diabetes. We studied the association between glycosylated hemoglobin (HbA1c) and the risk of a motor vehicle crash using a population-based case control analysis.
Methods and Findings
We identified consecutive drivers reported to vehicle licensing authorities between January 1, 2005 to January 1, 2007 who had a diagnosis of diabetes mellitus and a HbA1c documented. The risk of a crash was calculated taking into account potential confounders including blood glucose monitoring, complications, and treatments. A total of 57 patients were involved in a crash and 738 were not involved in a crash. The mean HbA1c was lower for those in a crash than controls (7.4% versus 7.9%, unpaired t-test, p = 0.019), equal to a 26% increase in the relative risk of a crash for each 1% reduction in HbA1c (odds ratio = 1.26, 95% confidence interval 1.03–1.54). The trend was evident across the range of HbA1c values and persisted after adjustment for measured confounders (odds ratio = 1.25, 95% confidence interval 1.02–1.55). The two other significant risk factors for a crash were a history of severe hypoglycemia requiring outside assistance (odds ratio = 4.07, 95% confidence interval 2.35–7.04) and later age at diabetes diagnosis (odds ratio per decade = 1.29, 95% confidence interval 1.07–1.57).
In this selected population, tighter glycemic control, as measured by the HbA1c, is associated with an increased risk of a motor vehicle crash.
Please see later in the article for the Editors' Summary
Editors' Summary
Around 8% of the US population has diabetes, a group of diseases in which the body cannot control levels of glucose (sugar) in the blood. It can lead to serious complications and premature death, but suitable treatment can control the disease and lower the risk of complications.
Type 1 diabetes occurs when the body's immune system prevents the production of insulin, the hormone that controls blood glucose. It accounts for 5%–10% of diabetes cases in adults and the vast majority of cases in childhood. Patients with type 1 diabetes need to inject insulin to survive. Type 2 diabetes is associated with older age, obesity, family history of diabetes, lack of physical activity, and race/ethnicity. As obesity rates rise worldwide, it is expected that the prevalence of type 2 diabetes will increase.
Why Was This Study Done?
Some complications of diabetes affect the ability to drive safely. Prolonged periods of high blood sugar levels can damage eyesight and nerves throughout the body, resulting in pain, tingling, and reduction of feeling or muscle control. Over time, some diabetics may become unaware of the early symptoms of an abnormally low blood sugar level (hypoglycemia) that can cause confusion, clumsiness, or fainting. Severe hypoglycemia can result in seizures or a coma.
It is common for driver licensing authorities to require evidence that a diabetic person's condition is well controlled before they issue a driving license. One measure of this is the percentage of hemoglobin in their blood that has joined up with glucose, known as HbA1c. This provides a measure of average blood glucose levels over the previous 8–12 weeks. A lower reading is considered an indicator of good diabetic control, but conversely, a blood glucose level that is too low can cause hypoglycemia. Normal nondiabetic HbA1c is between 3.5% and 5.5%, but 6.5% is considered good for people with diabetes.
In this study the researchers tested whether blood glucose levels, as measured by levels of HbA1c, were statistically associated with the risk of a motor vehicle crash.
What Did the Researchers Do and Find?
The authors studied 795 diabetic adults who had been in contact with the driver licensing authority in Ontario, Canada between January 1, 2005 and January 1, 2007 and for whom HbA1c levels were recorded. HbA1c levels varied between 4.4% and 14.7%.
Of the drivers considered, 57 were involved in a car crash and 738 were not. The authors found that lower HbA1c levels were associated with an increased risk of a motor vehicle crash, even when they took into account other factors such as time since diagnosis, treatment, age, age when diagnosed, and, if taking insulin, age insulin started.
The authors also found that the risk of a crash quadrupled when a driver had a history of severe hypoglycemia that required outside help and that there was an increase in risk when diabetes had first been diagnosed at an older age.
What Do These Findings Mean?
The authors conclude by emphasizing the difficulty in knowing whether someone with diabetes is fit to drive. They suggest that a patient's HbA1c level is neither necessary nor sufficient to determine whether a diabetic person is fit to drive and these results, which agree with some other studies, call into question the current legal framework of the US, UK, Canada, Germany, Holland, and Australia, which single out diabetic drivers for medical review.
The finding that lower HbA1c levels are associated with an increased risk of a crash is surprising, as it suggests that a driver is less safe if they control their diabetes well. However, a statistical link does not prove that one event causes another. Unknown social or medical factors might explain the results. In this case, the authors point out that a major drawback of their study is that it is not randomized and drivers have free will in choosing how tightly to control their diabetes and also how carefully they drive. The authors considered whether time spent driving might explain the results, but discounted this for several reasons. One more plausible explanation is that intensive treatment to attain a lower HbA1c level for better general health raises the risk of hypoglycemic episodes.
Additional Information
Please access these Web sites via the online version of this summary at
Wikipedia includes an article on diabetes (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The American Diabetes Association publishes information on diabetes in English and Spanish
The American Diabetes Association also publishes information on US states regulation of drivers with diabetes
The World Health Organization of the United Nations Diabetes Programme works to prevent diabetes, minimize complications, and maximize quality of life
PMCID: PMC2780354  PMID: 19997624
19.  Can studies of harm be harmful? 
PMCID: PMC2585131  PMID: 19047597
20.  Alcohol Sales and Risk of Serious Assault 
PLoS Medicine  2008;5(5):e104.
Alcohol is a contributing cause of unintentional injuries, such as motor vehicle crashes. Prior research on the association between alcohol use and violent injury was limited to survey-based data, and the inclusion of cases from a single trauma centre, without adequate controls. Beyond these limitations was the inability of prior researchers to comprehensively capture most alcohol sales. In Ontario, most alcohol is sold through retail outlets run by the provincial government, and hospitals are financed under a provincial health care system. We assessed the risk of being hospitalized due to assault in association with retail alcohol sales across Ontario.
Methods and Findings
We performed a population-based case-crossover analysis of all persons aged 13 years and older hospitalized for assault in Ontario from 1 April 2002 to 1 December 2004. On the day prior to each assault case's hospitalization, the volume of alcohol sold at the store in closest proximity to the victim's home was compared to the volume of alcohol sold at the same store 7 d earlier. Conditional logistic regression analysis was used to determine the associated relative risk (RR) of assault per 1,000 l higher daily sales of alcohol. Of the 3,212 persons admitted to hospital for assault, nearly 25% were between the ages of 13 and 20 y, and 83% were male. A total of 1,150 assaults (36%) involved the use of a sharp or blunt weapon, and 1,532 (48%) arose during an unarmed brawl or fight. For every 1,000 l more of alcohol sold per store per day, the relative risk of being hospitalized for assault was 1.13 (95% confidence interval [CI] 1.02–1.26). The risk was accentuated for males (1.18, 95% CI 1.05–1.33), youth aged 13 to 20 y (1.21, 95% CI 0.99–1.46), and those in urban areas (1.19, 95% CI 1.06–1.35).
The risk of being a victim of serious assault increases with alcohol sales, especially among young urban men. Akin to reducing the risk of driving while impaired, consideration should be given to novel methods of preventing alcohol-related violence.
In a population-based case-crossover analysis, Joel Ray and colleagues find that the risk of being a victim of serious assault increases with retail alcohol sales, especially among young urban men.
Editors' Summary
Alcohol has been produced and consumed around the world since prehistoric times. In the Western world it is now the most commonly consumed psychoactive drug (a substance that changes mood, behavior, and thought processes). The World Health Organization reports that there are 76.3 million persons with alcohol use disorders worldwide. Alcohol consumption is an important factor in unintentional injuries, such as motor vehicle crashes, and in violent criminal behavior. In the United Kingdom, for example, a higher proportion of heavy drinkers than light drinkers cause violent criminal offenses. Other figures suggest that people (in particular, young men) have an increased risk of committing a criminally violent offense within 24 h of drinking alcohol. There is also some evidence that suggests that the victims as well as the perpetrators of assaults have often been drinking recently, possibly because alcohol impairs the victim's ability to judge potentially explosive situations.
Why Was This Study Done?
The researchers wanted to know more about the relationship between alcohol and intentional violence. The recognition of a clear link between driving when impaired by alcohol and motor vehicle crashes has led many countries to introduce public awareness programs that stigmatize drunk driving. If a clear link between alcohol consumption by the people involved in violent crime could also be established, similar programs might reduce alcohol-related assaults. The researchers tested the hypothesis that the risk of being hospitalized due to a violent assault increases when there are increased alcohol sales in the immediate vicinity of the victim's place of residence.
What Did the Researchers Do and Find?
The researchers did their study in Ontario, Canada for three reasons. First, Ontario is Canada's largest province. Second, the province keeps detailed computerized medical records, including records of people hospitalized from being violently assaulted. Third, most alcohol is sold in government-run shops, and the district has the infrastructure to allow daily alcohol sales to be tracked. The researchers identified more than 3,000 people over the age of 13 y who were hospitalized in the province because of a serious assault during a 32-mo period. They compared the volume of alcohol sold at the liquor store nearest to the victim's home the day before the assault with the volume sold at the same store a week earlier (this type of study is called a “case-crossover” study). For every extra 1,000 l of alcohol sold per store per day (a doubling of alcohol sales), the overall risk of being hospitalized for assault increased by 13%. The risk was highest in three subgroups of people: men (18% increased risk), youths aged 13 to 20 y (21% increased risk), and those living in urban areas (19% increased risk). At peak times of alcohol sales, the risk of assault was 41% higher than at times when alcohol sales were lowest.
What Do These Findings Mean?
These findings indicate that the risk of being seriously assaulted increases with the amount of alcohol sold locally the day before the assault and show that the individuals most at risk are young men living in urban areas. Because the study considers only serious assaults and alcohol sold in shops (i.e., not including alcohol sold in bars), it probably underestimates the association between alcohol and assault. It also does not indicate whether the victim or perpetrator of the assault (or both) had been drinking, and its findings may not apply to countries with different drinking habits. Nevertheless, these findings support the idea that the consumption of alcohol contributes to the occurrence of medical injuries from intentional violence. Increasing the price of alcohol or making alcohol harder to obtain might help to reduce the occurrence of alcohol-related assaults. The researchers suggest that a particularly effective approach may be to stigmatize alcohol-related brawling, analogous to the way that driving under the influence of alcohol has been made socially unacceptable.
Additional Information.
Please access these Web sites via the online version of this summary at
This study is further discussed in a PLoS Medicine Perspective by Bennetts and Seabrook
The US National Institute on Alcohol Abuse and Alcoholism provides information on all aspects of alcohol abuse, including an article on alcohol use and violence among young adults
Alcohol-related assault is examined in the British Crime Survey
Alcohol Concern, the UK national agency on alcohol misuse, provides fact sheets on the health impacts of alcohol, young people's drinking, and alcohol and crime
The Canadian Centre for Addiction and Mental Health in Toronto provides information about alcohol addiction (in English and French)
PMCID: PMC2375945  PMID: 18479181
21.  Breast size and risk of type 2 diabetes mellitus 
Elevated waist circumference and body mass index (BMI), both traditional measures of obesity, are accepted risk factors for type 2 diabetes mellitus. Girls who are obese experience earlier onset of puberty and possibly greater breast development. We sought to evaluate whether a woman's breast size in late adolescence is associated with an increased risk of type 2 diabetes mellitus in adulthood.
In conjunction with the ongoing Nurses' Health Study II, which began to study risk factors for breast cancer among women in 1989, we conducted a prospective cohort study involving 92 106 of the participants. We assessed the risk of type 2 diabetes mellitus in relation to self-reported bra cup sizes, categorized as ≤ A, B, C and ≥ D cups, among participants at age 20.
The mean age of participants at baseline was 38.1 years. A total of 1844 new cases of type 2 diabetes mellitus arose at a mean age of 44.9 years during 886 443 person-years of follow-up. Relative to bra cup size ≤ A, the respective age-adjusted hazard ratios (and 95% confidence intervals [CIs]) were 2.30 (1.99–2.66) for B cup, 4.32 (3.71–5.04) for C cup and 4.99 (4.12–6.05) for ≥ D cup. Upon further adjustments for age at menarche, parity, physical activity, smoking status, diet, multivitamin use, family history of diabetes mellitus, BMI at age 18 and current BMI, the corresponding hazard ratios (and 95% CIs) were 1.37 (1.18–1.59) for B cup, 1.80 (1.53- 2.11) for C cup and 1.64 (1.34–2.01) for ≥ D cup. The addition of waist circumference to this model minimally changed the hazard ratios (and 95% CIs): 1.32 (1.14–1.53) for B cup, 1.71 (1.46–2.01) for C cup and 1.58 (1.29–1.94) for ≥ D cup.
A large bra cup size at age 20 may be a predictor of type 2 diabetes mellitus in middle-aged women. Whether this relation is independent of traditional indicators of obesity remains to be determined.
PMCID: PMC2211341  PMID: 18227448
22.  Metabolic Syndrome features and risk of neural tube defects 
Maternal obesity and pre-pregnancy diabetes mellitus, features of the metabolic syndrome (MetSyn), are individual risk factors for neural tube defects (NTD). Whether they, in combination with additional features of MetSyn, alter this risk is not known. We evaluated the risk of NTD in association with maternal features of the MetSyn.
We used a population-based case-control study design in the province of Ontario, Canada. Cases and controls were derived from women who underwent antenatal maternal screening (MSS) at 15 to 20 weeks' gestation. There were 89 maternal cases with, and 434 controls without, an NTD-affected singleton pregnancy. Maternal features of MetSyn were defined by the presence of pre-pregnancy diabetes mellitus, body weight ≥ 90th centile among controls, non-white ethnicity and/or serum highly sensitive C-reactive protein (hsCRP) ≥ 75th centile of controls. Since hsCRP naturally increases in pregnancy, analyses were performed with, and without, the inclusion of hsCRP in the model.
Mean hsCRP concentrations were exceptionally high among study cases and controls (6.1 and 6.4 mg/L, respectively). When hsCRP was excluded from the model, the adjusted odds ratios for NTD were 1.9 (95% confidence interval 1.1–3.4) in the presence 1 feature of MetSyn, and 6.1 (1.1–32.9) in the presence of 2 or more features. When hsCRP was included, the respective risk estimates were attenuated to 1.6 (0.88–2.8) and 3.1 (1.2–8.3).
We found about 2-fold and 6-fold higher risk for NTD in the presence 1, and 2 or more features, of the metabolic syndrome, respectively. It is not clear whether this risk is altered by the presence of a high serum hsCRP concentration.
PMCID: PMC2039731  PMID: 17880716
23.  Taking ACE inhibitors during early pregnancy 
Canadian Family Physician  2007;53(9):1439-1440.
QUESTION I knew that angiotensin-converting enzyme (ACE) inhibitors were risky to use during late pregnancy because they can cause renal shutdown in the fetus. Recently I heard of a study that claimed first-trimester exposure (when many patients still are unaware of their pregnancies) can also cause major malformations. Is this proven?
ANSWER A recent study did suggest an increased risk of malformations after first-trimester exposure to ACE inhibitors among women treated for hypertension. We believe this study had serious limitations that preclude drawing any conclusions at present.
PMCID: PMC2234619  PMID: 17872870
24.  “You're not my obstetrician” (and it may not matter) 
PMCID: PMC1942111  PMID: 17698827
25.  Results of the Recent Immigrant Pregnancy and Perinatal Long-term Evaluation Study (RIPPLES) 
People who immigrate to Western nations may experience fewer chronic health problems than original residents of those countries, which raises concerns about long-term environmental or lifestyle factors in those countries. We tested whether the “healthy immigrant effect” extends to the risk of placental dysfunction during the short interval of pregnancy.
We conducted a population-based retrospective cohort study of data for 796 105 women who had a first documented obstetric delivery in Ontario between 1995 and 2005. Recency of immigration was determined for each woman as the time from her enrolment in universal health insurance to her date of delivery, classified as less than 3 months, 3–5 months, 6–11 months, 12–23 months, 24–35 months, 36–47 months, 48–59 months and 5 years or more (the referent). The primary composite outcome was maternal placental syndrome (defined as a diagnosis of pre-eclampsia or eclampsia, placental abruption or placental infarction).
The mean age of the women was 28.8 years. Maternal placental syndrome occurred in 45 216 women (5.7%). The risk of this outcome was lowest among the women who had immigrated less than 3 months before delivery (3.8%) and highest among those living in Ontario at least 5 years (6.0%), for a crude odds ratio (OR) of 0.62 (95% confidence interval [CI] 0.54–0.71). After adjustment for maternal age, income status, pre-existing hypertension, diabetes mellitus, multiple gestation and receipt of prenatal ultrasonography, the risk of maternal placental syndrome was correlated with the number of months since immigration in a gradient manner (OR, 95% CI): less than 3 months (0.53, 0.47–0.61), 3–5 months (0.68, 0.61–0.76), 6–11 months (0.67, 0.63–0.71), 12–23 months (0.69, 0.66–0.73), 24–35 months (0.75, 0.70–0.79), 36–47 months (0.75, 0.70–0.80) and 48–59 months (0.82, 0.77–0.87).
There was a progressively lower risk of maternal placental syndromes associated with recency of immigration. The “healthy immigrant effect” may extend to common placental disorders, diminishes with the duration of residency and underscores the importance of nongenetic determinants of maternal health accrued over a brief period.
PMCID: PMC1863534  PMID: 17485694

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