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1.  Trends in the prevalence of cerebral palsy among very preterm infants (<31 weeks’ gestational age) 
Paediatrics & Child Health  2014;19(4):185-189.
The birth prevalence of cerebral palsy varies over time among very preterm infants, and the reasons are poorly understood.
To describe the variation in the prevalence of cerebral palsy among very preterm infants over time, and to relate these differences to other maternal or neonatal factors.
A population-based cohort of very preterm infants was evaluated over a 20-year period (1988 to 2007) divided into four equal epochs.
The prevalence of cerebral palsy peaked in the third epoch (1998 to 2002) while mortality rate peaked in the second epoch (1993 to 1997). Maternal anemia, tocolytic use and neonatal need for home oxygen were highest in the third epoch.
Lower mortality rates did not correlate well with the prevalence of cerebral palsy. Maternal risk factors, anemia and tocolytic use, and the newborn need for home oxygen were highest during the same epoch as the peak prevalence of cerebral palsy.
PMCID: PMC4028643  PMID: 24855414
Cerebral palsy; Infant; Population-based; Premature
2.  A Randomized Trial of Planned Cesarean or Vaginal Delivery for Twin Pregnancy 
The New England journal of medicine  2013;369(14):1295-1305.
Twin birth is associated with a higher risk of adverse perinatal outcomes than singleton birth. It is unclear whether planned cesarean section results in a lower risk of adverse outcomes than planned vaginal delivery in twin pregnancy.
We randomly assigned women between 32 weeks 0 days and 38 weeks 6 days of gestation with twin pregnancy and with the first twin in the cephalic presentation to planned cesarean section or planned vaginal delivery with cesarean only if indicated. Elective delivery was planned between 37 weeks 5 days and 38 weeks 6 days of gestation. The primary outcome was a composite of fetal or neonatal death or serious neonatal morbidity, with the fetus or infant as the unit of analysis for the statistical comparison.
A total of 1398 women (2795 fetuses) were randomly assigned to planned cesarean delivery and 1406 women (2812 fetuses) to planned vaginal delivery. The rate of cesarean delivery was 90.7% in the planned-cesarean-delivery group and 43.8% in the planned-vaginal-delivery group. Women in the planned-cesarean-delivery group delivered earlier than did those in the planned-vaginal-delivery group (mean number of days from randomization to delivery, 12.4 vs. 13.3; P = 0.04). There was no significant difference in the composite primary outcome between the planned-cesarean-delivery group and the planned-vaginal-delivery group (2.2% and 1.9%, respectively; odds ratio with planned cesarean delivery, 1.16; 95% confidence interval, 0.77 to 1.74; P = 0.49).
In twin pregnancy between 32 weeks 0 days and 38 weeks 6 days of gestation, with the first twin in the cephalic presentation, planned cesarean delivery did not significantly decrease or increase the risk of fetal or neonatal death or serious neonatal morbidity, as compared with planned vaginal delivery. (Funded by the Canadian Institutes of Health Research; number, NCT00187369; Current Controlled Trials number, ISRCTN74420086.)
PMCID: PMC3954096  PMID: 24088091 CAMSID: cams3905
3.  Effects of socioeconomic position and clinical risk factors on spontaneous and iatrogenic preterm birth 
The literature shows a variable and inconsistent relationship between socioeconomic position and preterm birth. We examined risk factors for spontaneous and iatrogenic preterm birth, with a focus on socioeconomic position and clinical risk factors, in order to explain the observed inconsistency.
We carried out a retrospective population-based cohort study of all singleton deliveries in Nova Scotia from 1988 to 2003. Data were obtained from the Nova Scotia Atlee Perinatal Database and the federal income tax T1 Family Files. Separate logistic models were used to quantify the association between socioeconomic position, clinical risk factors and spontaneous preterm birth and iatrogenic preterm birth.
The study population included 132,714 singleton deliveries and the rate of preterm birth was 5.5%. Preterm birth rates were significantly higher among the women in the lowest (versus the highest) family income group for spontaneous (rate ratio 1.14, 95% confidence interval (CI) 1.03, 1.25) but not iatrogenic preterm birth (rate ratio 0.95, 95% CI 0.75, 1.19). Adjustment for maternal characteristics attenuated the family income-spontaneous preterm birth relationship but strengthened the relationship with iatrogenic preterm birth. Clinical risk factors such as hypertension were differentially associated with spontaneous (rate ratio 3.92, 95% CI 3.47, 4.44) and iatrogenic preterm (rate ratio 14.1, 95% CI 11.4, 17.4) but factors such as diabetes mellitus were not (rate ratio 4.38, 95% CI 3.21, 5.99 for spontaneous and 4.02, 95% CI 2.07, 7.80 for iatrogenic preterm birth).
Socioeconomic position and clinical risk factors have different effects on spontaneous and iatrogenic preterm. Recent temporal increases in iatrogenic preterm birth appear to be responsible for the inconsistent relationship between socioeconomic position and preterm birth.
PMCID: PMC3987165  PMID: 24670050
Spontaneous preterm birth; Iatrogenic preterm birth; Risk factors; Pregnancy complications; Socioeconomic status
4.  A Population-Based Case-Control Study of Drinking-Water Nitrate and Congenital Anomalies Using Geographic Information Systems (GIS) to Develop Individual-Level Exposure Estimates 
Animal studies and epidemiological evidence suggest an association between prenatal exposure to drinking water with elevated nitrate (NO3-N) concentrations and incidence of congenital anomalies. This study used Geographic Information Systems (GIS) to derive individual-level prenatal drinking-water nitrate exposure estimates from measured nitrate concentrations from 140 temporally monitored private wells and 6 municipal water supplies. Cases of major congenital anomalies in Kings County, Nova Scotia, Canada, between 1988 and 2006 were selected from province-wide population-based perinatal surveillance databases and matched to controls from the same databases. Unconditional multivariable logistic regression was performed to test for an association between drinking-water nitrate exposure and congenital anomalies after adjusting for clinically relevant risk factors. Employing all nitrate data there was a trend toward increased risk of congenital anomalies for increased nitrate exposure levels though this was not statistically significant. After stratification of the data by conception before or after folic acid supplementation, an increased risk of congenital anomalies for nitrate exposure of 1.5–5.56 mg/L (2.44; 1.05–5.66) and a trend toward increased risk for >5.56 mg/L (2.25; 0.92–5.52) was found. Though the study is likely underpowered, these results suggest that drinking-water nitrate exposure may contribute to increased risk of congenital anomalies at levels below the current Canadian maximum allowable concentration.
PMCID: PMC3945569  PMID: 24503976
Nitrate; Congenital anomalies; Drinking-water; Geographic Information Systems (GIS)
5.  Infant mortality in Alberta and all of Canada 
PMCID: PMC554850  PMID: 15795390
6.  The Role of Maternal Smoking in Effect of Fetal Growth Restriction on Poor Scholastic Achievement in Elementary School 
Fetal growth restriction and maternal smoking during pregnancy are independently implicated in lowering intellectual attainment in children. We hypothesized that only reduction of fetal growth that is attributable to extrinsic causes (e.g., maternal smoking) affects intellectual development of a child. Cross-sectional survey of 3,739 students in Nova Scotia (Canada) in 2003 was linked with the perinatal database, parental interviews on socio-demographic factors and the performance on standardized tests when primarily 11–12 years of age, thereby forming a retrospective cohort. Data was analyzed using hierarchical logistic regression with correction for clustering of children within schools. The risk of poor test result among children born small-for-gestational-age (SGA) to mothers who smoked was 29.4%, higher than in any other strata of maternal smoking and fetal growth. The adjusted odds ratio among SGA children born to mothers who smoked was the only one elevated compared to children who were not growth restricted and born to mothers who did not smoke (17.0%, OR = 1.46, 95% CI 1.02, 2.09). Other perinatal, maternal and socio-demographic factors did not alter this pattern of effect modification. Heterogeneity of etiology of fetal growth restriction should be consider in studies that address examine its impact on health over life course.
PMCID: PMC3315254  PMID: 22470300
fetal growth retardation; tobacco smoking; maternal exposure; educational achievement; retrospective cohort study; cross-sectional sample
9.  Antenatal Steroid Therapy for Fetal Lung Maturation and the Subsequent Risk of Childhood Asthma: A Longitudinal Analysis 
Journal of Pregnancy  2010;2010:789748.
This study was designed to test the hypothesis that fetal exposure to corticosteroids in the antenatal period is an independent risk factor for the development of asthma in early childhood with little or no effect in later childhood. A population-based cohort study of all pregnant women who resided in Nova Scotia, Canada, and gave birth to a singleton fetus between 1989 and 1998 was undertaken. After a priori specified exclusions, 80,448 infants were available for analysis. Using linked health care utilization records, incident asthma cases developed after 36 months of age were identified. Extended Cox proportional hazards models were used to estimate hazard ratios while controlling for confounders. Exposure to corticosteroids during pregnancy was associated with a risk of asthma in childhood between 3–5 years of age: adjusted hazard ratio of 1.19 (95% confidence interval: 1.03, 1.39), with no association noted after 5 years of age: adjusted hazard ratio for 5–7 years was 1.06 (95% confidence interval: 0.86, 1.30) and for 8 or greater years was 0.74 (95% confidence interval: 0.54, 1.03). Antenatal steroid therapy appears to be an independent risk factor for the development of asthma between 3 and 5 years of age.
PMCID: PMC3065803  PMID: 21490744
10.  An Outcome-based Approach for the Creation of Fetal Growth Standards: Do Singletons and Twins Need Separate Standards? 
American Journal of Epidemiology  2009;169(5):616-624.
Contemporary fetal growth standards are created by using theoretical properties (percentiles) of birth weight (for gestational age) distributions. The authors used a clinically relevant, outcome-based methodology to determine if separate fetal growth standards are required for singletons and twins. All singleton and twin livebirths between 36 and 42 weeks’ gestation in the United States (1995–2002) were included, after exclusions for missing information and other factors (n = 17,811,922). A birth weight range was identified, at each gestational age, over which serious neonatal morbidity and neonatal mortality rates were lowest. Among singleton males at 40 weeks, serious neonatal morbidity/mortality rates were lowest between 3,012 g (95% confidence interval (CI): 3,008, 3,018) and 3,978 g (95% CI: 3,976, 3,980). The low end of this optimal birth weight range for females was 37 g (95% CI: 21, 53) less. The low optimal birth weight was 152 g (95% CI: 121, 183) less for twins compared with singletons. No differences were observed in low optimal birth weight by period (1999–2002 vs. 1995–1998), but small differences were observed for maternal education, race, parity, age, and smoking status. Patterns of birth weight-specific serious neonatal morbidity/neonatal mortality support the need for plurality-specific fetal growth standards.
PMCID: PMC2640160  PMID: 19126584
birth weight; fetal development; gestational age; infant mortality; morbidity
11.  A randomized trial of aggressive versus conservative phototherapy for hyperbilirubinemia in infants weighing less than 1500 g: Short- and long-term outcomes 
Paediatrics & Child Health  2007;12(10):853-858.
Treatment regimens for hyperbilirubinemia vary for very low birth weight infants. The present study seeks to determine whether the initiation of conservative phototherapy is as effective as aggressive phototherapy in reducing peak bilirubin levels without increasing adverse effects.
The present randomized, controlled study included infants with birth weights between 500 g and 1500 g, stratified into two birth weight groups. In one group, aggressive phototherapy was commenced by 12 h of age, while in the other group, conservative phototherapy was commenced if serum bilirubin levels exceeded 150 μmol/L. The primary outcome variables were peak serum bilirubin levels and hours of phototherapy. Secondary outcomes were age at peak bilirubin levels, number of infants with rebound hyperbilirubinemia, and number of adverse short- and long-term outcomes.
Of 174 eligible infants, 95 consented to participate −49 in the conservative arm and 46 in the aggressive arm. Ninety-two infants completed the study. There was no significant difference in peak bilirubin levels except in infants who weighed less than 1000 g −171.2±26 μmol/L (conservative) versus 139.2±46 μmol/L (aggressive); P<0.02. There was no difference in duration of phototherapy or rebound hyperbilirubinemia. There were no differences in short-term adverse outcomes. Of the 87 infants who survived until hospital discharge, 82 (94%) had some follow-up and 75 (86%) attended follow-up until 18 months corrected age. The incidence of cerebral palsy, abnormal mental developmental index at 18 months corrected age, or combined outcome of cerebral palsy and death did not significantly differ between the two groups.
In infants weighing less than 1000 g, peak bilirubin levels were significantly higher using conservative phototherapy regimens and there was a tendency for poor neurodevelopmental outcome.
PMCID: PMC2532565  PMID: 19043499
Hyperbilirubinemia; Paediatrics; Phototherapy; Population-based; Preterm
12.  Socioeconomic status and perinatal outcomes in a setting with universal access to essential health care services 
The health care system in Canada provides essential health services to all women irrespective of socioeconomic status. Our objective was to determine whether perinatal and infant outcomes varied by family income and other socioeconomic factors in this setting.
We included all 92 914 women who delivered in Nova Scotia between 1988 and 1995 following a singleton pregnancy. Family income was obtained for 76 440 of these women through a confidential link to income tax records and was divided into 5 groups. Outcomes studied included pregnancy complications, preterm birth, small-for-gestational-age live birth, perinatal death, serious neonatal morbidity, postneonatal death and infant death. Logistic regression models were used to adjust for potential confounders.
Compared with women in the highest family income group, those in the lowest income group had significantly higher rates of gestational diabetes (crude rate ratio [RR] 1.44, 95% confidence interval [CI] 1.21–1.73), preterm birth (crude RR 1.20, 95% CI 1.06–1.35), small-for-gestational-age live birth (crude RR 1.81, 95% CI 1.66–1.97) and postneonatal death (crude RR 5.54, 95% CI 2.21–13.9). The opposite was true for rates of perinatal death (crude RR 0.74, 95% CI 0.56–0.96), and there was no significant difference between the 2 groups in the composite of perinatal death or serious neonatal morbidity (crude RR 1.01, 95% CI 0.82–1.24). Adjustment for behavioural and lifestyle factors accentuated or attenuated socioeconomic differences.
Lower family income is associated with increased rates of gestational diabetes, small-for-gestational-age live birth and postneonatal death despite health care services being widely available at no out-of-pocket expense.
PMCID: PMC1963370  PMID: 17846440
13.  Study protocol: a double blind placebo controlled trial examining the effect of domperidone on the composition of breast milk [NCT00308334] 
Domperidone, a drug that enhances upper gastric motility, is an anti-dopaminergic medication that also elevates prolactin levels. It has been shown to safely increase the milk supply of lactating women. To date, researchers have analyzed the effects of domperidone on lactating woman with respect to the quantity of their milk production, adverse effects, and drug levels in the breast milk. However, the effect of domperidone on the macronutrient composition of breast milk has not been studied and current guidelines for fortification of human milk for premature infants do not distinguish between those women using or those not using domperidone. The purpose of this study is to evaluate the effect of domperidone (given to lactating mothers of very preterm infants) on the macronutrient composition of breast milk.
Mothers of infants delivered at less than 31 weeks gestation, who are at least 3 weeks postpartum, and experiencing lactational failure despite non-pharmacological interventions, will be randomized to receive domperidone (10 mg three times daily) or placebo for a 14-day period.
Breast milk samples will be obtained the day prior to beginning treatment and on days 4, 7 and 14. The macronutrient (protein, fat, carbohydrate and energy) and macromineral content (calcium, phosphorus and sodium) will be analyzed and compared between the two groups. Additional outcome measures will include milk volumes, serum prolactin levels (measured on days 0, 4, and 10), daily infant weights and breastfeeding rates at 2 weeks post study completion and at discharge. Forty-four participants will be recruited into the study. Analysis will be carried out using the intention to treat approach.
If domperidone causes significant changes to the nutrient content of breast milk, an alteration in feeding practices for preterm infants may need to be made in order to optimize growth, nutrition and neurodevelopment outcomes.
PMCID: PMC1562444  PMID: 16719919
14.  Does the risk of cerebral palsy increase or decrease with increasing gestational age? 
It is generally accepted that the risk of cerebral palsy decreases with increasing gestational age of live born infants. However, recent studies have shown that cerebral palsy often has prenatal antecedents including congenital malformations, vascular insults and maternal infection. Cerebral palsy is therefore better viewed as occurring among fetuses, rather than among infants. We explored the epidemiologic implications of this change in perspective.
We used recently published data from Shiga Prefecture, Japan and from North-East England to examine the pattern of gestational age-specific rates of cerebral palsy under these alternative perspectives. We first calculated gestational age-specific rates of cerebral palsy as per convention, by dividing the number of cases of cerebral palsy identified among live births within any gestational age category by the number of live births in that gestational age category. Under the alternative formulation, we calculated gestational age-specific rates of cerebral palsy by dividing the number of cases of cerebral palsy identified among live births within any gestational age category by the number of fetuses who were at risk of being born at that gestation and being afflicted with cerebral palsy.
Under the conventional formulation, cerebral palsy rates decreased with increasing gestational age from 63.9 per 1,000 live births at <28 weeks gestation to 0.9 per 1,000 live births at 37 or more weeks gestation. When fetuses were viewed as potential candidates for cerebral palsy, cerebral palsy rates increased with increasing gestational age from 0.08 per 1,000 fetuses at risk at <28 weeks gestation to 0.9 per 1,000 fetuses at risk at 37 or more weeks gestation.
The fetuses-at-risk approach is the appropriate epidemiologic formulation for calculating the gestational age-specific rate of cerebral palsy from a causal perspective. It shows that the risk of cerebral palsy increases as gestational duration increases. This compelling view of cerebral palsy risk may help refocus research aimed at understanding and preventing cerebral palsy.
PMCID: PMC317470  PMID: 14693037
15.  A parsimonious explanation for intersecting perinatal mortality curves: understanding the effect of plurality and of parity 
Birth weight- and gestational age-specific perinatal mortality curves intersect when compared across categories of maternal smoking, plurality, race and other factors. No simple explanation exists for this paradoxical observation.
We used data on all live births, stillbirths and infant deaths in Canada (1991–1997) to compare perinatal mortality rates among singleton and twin births, and among singleton births to nulliparous and parous women. Birth weight- and gestational age-specific perinatal mortality rates were first calculated by dividing the number of perinatal deaths at any given birth weight or gestational age by the number of total births at that birth weight or gestational age (conventional calculation). Gestational age-specific perinatal mortality rates were also calculated using the number of fetuses at risk of perinatal death at any given gestational age.
Conventional perinatal mortality rates among twin births were lower than those among singletons at lower birth weights and earlier gestation ages, while the reverse was true at higher birth weights and later gestational ages. When perinatal mortality rates were based on fetuses at risk, however, twin births had consistently higher mortality rates than singletons at all gestational ages. A similar pattern emerged in contrasts of gestational age-specific perinatal mortality among singleton births to nulliparous and parous women. Increases in gestational age-specific rates of growth-restriction with advancing gestational age presaged rising rates of gestational age-specific perinatal mortality in both contrasts.
The proper conceptualization of perinatal risk eliminates the mortality crossover paradox and provides new insights into perinatal health issues.
PMCID: PMC166132  PMID: 12780942
16.  Influence of definition based versus pragmatic birth registration on international comparisons of perinatal and infant mortality: population based retrospective study 
Objectives To examine variations in the registration of extremely low birthweight and early gestation births and to assess their effect on perinatal and infant mortality rankings of industrialised countries.
Design Retrospective population based study.
Setting Australia, Canada, European countries, and the United States for 2004; Australia, Canada, and New Zealand for 2007.
Population National data on live births and on fetal, neonatal, and infant deaths.
Main outcome measures Reported proportions of live births with birth weight/gestational age of less than 500 g, less than 1000 g, less than 24 weeks, and less than 28 weeks; crude rates of fetal, neonatal, and infant mortality; mortality rates calculated after exclusion of births under 500 g, under 1000 g, less than 24 weeks, and less than 28 weeks.
Results The proportion of live births under 500 g varied widely from less than 1 per 10 000 live births in Belgium and Ireland to 10.8 per 10 000 live births in Canada and 16.9 in the United States. Neonatal deaths under 500 g, as a proportion of all neonatal deaths, also ranged from less than 1% in countries such as Luxembourg and Malta to 29.6% in Canada and 31.1% in the United States. Rankings of countries based on crude fetal, neonatal, and infant mortality rates differed substantially from rankings based on rates calculated after exclusion of births with a birth weight of less than 1000 g or a gestational age of less than 28 weeks.
Conclusions International differences in reported rates of extremely low birthweight and very early gestation births probably reflect variations in registration of births and compromise the validity of international rankings of perinatal and infant mortality.
PMCID: PMC3281499  PMID: 22344455

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