False-Positive Newborn Screening for Cystic Fibrosis and Health Care Use.

OBJECTIVES: Evidence is mixed regarding the impact of false-positive (FP) newborn bloodspot screening (NBS) results on health care use. Using cystic fibrosis (CF) as an example, we determined the association of FP NBS results with health care use in infants and their mothers in Ontario, Canada. METHODS: We conducted a population-based cohort study of all infants with FP CF results (N = 1564) and screen-negative matched controls (N = 6256) born between April 2008 and November 2012 using linked health administrative data. Outcomes included maternal and infant physician and emergency visits and inpatient hospitalizations from the infant's third to 15th month of age. Negative binomial regression tested associations of NBS status with outcomes, adjusting for infant and maternal characteristics. RESULTS: A greater proportion of infants with FP results had >2 outpatient visits (16.2% vs 13.2%) and >2 hospital admissions (1.5% vs 0.7%) compared with controls; CF-related admissions and emergency department visits were not different from controls. Differences persisted after adjustment, with higher rates of outpatient visits (relative risk 1.39; 95% confidence interval 1.20-1.60) and hospital admissions (relative risk 1.67; 95% confidence interval 1.21-2.31) for FP infants. Stratified models indicated the effect of FP status was greater among those whose primary care provider was a pediatrician. No differences in health care use among mothers were detected. CONCLUSIONS: Higher use of outpatient services among FP infants may relate to a lengthy confirmatory testing process or follow-up carrier testing. However, increased rates of hospitalization might signal heightened perceptions of vulnerability among healthy infants.

Association Between MRI Exposure During Pregnancy and Fetal and Childhood Outcomes.

IMPORTANCE: Fetal safety of magnetic resonance imaging (MRI) during the first trimester of pregnancy or with gadolinium enhancement at any time of pregnancy is unknown. OBJECTIVE: To evaluate the long-term safety after exposure to MRI in the first trimester of pregnancy or to gadolinium at any time during pregnancy. DESIGN, SETTING, AND PARTICIPANTS: Universal health care databases in the province of Ontario, Canada, were used to identify all births of more than 20 weeks, from 2003-2015. EXPOSURES: Magnetic resonance imaging exposure in the first trimester of pregnancy, or gadolinium MRI exposure at any time in pregnancy. MAIN OUTCOMES AND MEASURES: For first-trimester MRI exposure, the risk of stillbirth or neonatal death within 28 days of birth and any congenital anomaly, neoplasm, and hearing or vision loss was evaluated from birth to age 4 years. For gadolinium-enhanced MRI in pregnancy, connective tissue or skin disease resembling nephrogenic systemic fibrosis (NSF-like) and a broader set of rheumatological, inflammatory, or infiltrative skin conditions from birth were identified. RESULTS: Of 1 424 105 deliveries (48% girls; mean gestational age, 39 weeks), the overall rate of MRI was 3.97 per 1000 pregnancies. Comparing first-trimester MRI (n = 1737) to no MRI (n = 1 418 451), there were 19 stillbirths or deaths vs 9844 in the unexposed cohort (adjusted relative risk [RR], 1.68; 95% CI, 0.97 to 2.90) for an adjusted risk difference of 4.7 per 1000 person-years (95% CI, -1.6 to 11.0). The risk was also not significantly higher for congenital anomalies, neoplasm, or vision or hearing loss. Comparing gadolinium MRI (n = 397) with no MRI (n = 1 418 451), the hazard ratio for NSF-like outcomes was not statistically significant. The broader outcome of any rheumatological, inflammatory, or infiltrative skin condition occurred in 123 vs 384 180 births (adjusted HR, 1.36; 95% CI, 1.09 to 1.69) for an adjusted risk difference of 45.3 per 1000 person-years (95% CI, 11.3 to 86.8). Stillbirths and neonatal deaths occurred among 7 MRI-exposed vs 9844 unexposed pregnancies (adjusted RR, 3.70; 95% CI, 1.55 to 8.85) for an adjusted risk difference of 47.5 per 1000 pregnancies (95% CI, 9.7 to 138.2). CONCLUSIONS AND RELEVANCE: Exposure to MRI during the first trimester of pregnancy compared with nonexposure was not associated with increased risk of harm to the fetus or in early childhood. Gadolinium MRI at any time during pregnancy was associated with an increased risk of a broad set of rheumatological, inflammatory, or infiltrative skin conditions and for stillbirth or neonatal death. The study may not have been able to detect rare adverse outcomes.

Maternal Origin and Risk of Neonatal and Maternal ICU Admission.

OBJECTIVES: To evaluate maternal world region of birth, as well as maternal country of origin, and the associated risk of admission of 1) a mother to a maternal ICU, 2) her infant to a neonatal ICU, or 3) both concurrently to an ICU. DESIGN: Retrospective population-based cohort study. SETTING: Entire province of Ontario, Canada, from 2003 to 2012. PATIENTS: All singleton maternal-child pairs who delivered in any Ontario hospital. MEASUREMENTS AND MAIN RESULTS: We explored how maternal world region of birth, and specifically, maternal country of birth for the top 25 countries, was associated with the outcome of 1) neonatal ICU, 2) maternal ICU, and 3) both mother and newborn concurrently admitted to ICU. Relative risks were adjusted for maternal age, parity, income quintile, chronic hypertension, diabetes mellitus, obesity, dyslipidemia, drug dependence or tobacco use, and renal disease. Compared with infants of Canadian-born mothers (110.7/1,000), the rate of neonatal ICU admission was higher in immigrants from South Asia (155.2/1,000), Africa (140.4/1,000), and the Caribbean (167.3/1,000; adjusted relative risk, 1.41; 95% CI, 1.36-1.46). For maternal ICU, the adjusted relative risk was 1.79 (95% CI, 1.43-2.24) for women from Africa and 2.21 (95% CI, 1.78-2.75) for women from the Caribbean. Specifically, mothers from Ghana (adjusted relative risk, 2.71; 95% CI, 1.75-4.21) and Jamaica (adjusted relative risk, 2.74; 95% CI, 2.12-3.53) were at highest risk of maternal ICU admission. The risk of both mother and newborn concurrently admitted to ICU was even more pronounced for Ghana and Jamaica. CONCLUSIONS: Women from Africa and the Caribbean and, in particular, Ghana and Jamaica, are at higher risk of admission to ICU around the time of delivery, as are their newborns.

Prognosis after maternal placental events and revascularization: PAMPER study.

BACKGROUND: Middle-aged women are at higher risk than men of death after coronary artery revascularization. Maternal placental syndromes (gestational hypertension, preeclampsia, placental abruption, and placental infarction) are associated with premature coronary artery disease, but their influence on survival after coronary artery revascularization is unknown. OBJECTIVE: The purpose of this study was to determine whether a history of maternal placental syndromes alters the risk of death after coronary artery revascularization in middle-aged women. STUDY DESIGN: We completed a population-based retrospective cohort study among all hospitals in Ontario, Canada, where universal health care includes all aspects of antenatal and delivery care as well as all outpatient and inpatient health care, which includes coronary revascularization. We included 1985 middle-aged women who underwent a first percutaneous coronary intervention or coronary artery bypass grafting between 1993 and 2012 and who had ≥1 previous delivery. We excluded those with cardiovascular disease ≤1 year before or coronary revascularization ≤90 days after any delivery. The main study outcome, determined a priori, was all-cause death. Hazard ratios were adjusted for age, socioeconomic status, parity, revascularization type, time since last delivery, hypertension, diabetes mellitus, obesity, dyslipidemia, tobacco or drug dependence, and kidney disease. RESULTS: Three hundred sixty-two of 1985 women (18.2%) who underwent coronary artery revascularization had a previous maternal placental syndrome event. The mean age at index coronary revascularization was 45 years; percutaneous coronary intervention comprised approximately 80% of procedures. After a mean follow-up time of approximately 5 years, 41 deaths (2.2 per 100 person-years) occurred in women with previous maternal placental syndromes and 83 deaths (1.1 per 100 person-years) in women without maternal placental syndrome (adjusted hazard ratio, 1.96; 95% confidence interval, 1.29-2.99). Of the maternal placental syndrome subtypes, the risk of death was significant in women with placental abruption (adjusted hazard ratio, 2.79; 95% confidence interval, 1.31-5.96), placental infarction (adjusted hazard ratio, 3.09; 95% confidence interval, 1.23-7.74), and preeclampsia (adjusted hazard ratio, 1.61; 95% confidence interval, 1.00-2.58). Women with maternal placental syndrome in ≥2 pregnancies had the highest adjusted hazard ratio of death (4.31; 95% confidence interval, 1.71-10.89). CONCLUSION: In middle-aged women who undergo coronary revascularization, previous maternal placental syndrome doubles the risk of death; recurrent maternal placental syndrome quadruples that risk. Some covariates and secondary measures may not have been well-captured and classified herein, leading to residual confounding.

Risk of cerebral palsy among the offspring of immigrants.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Immigration and ethnicity appear to attenuate the risk of CP, and this effect is not fully explained by known risk factors.

Heart failure and dysrhythmias after maternal placental syndromes: HAD MPS Study.

BACKGROUND: Maternal placental syndromes (MPS)-gestational hypertension, pre-eclampsia and placental abruption/infarction-are more prevalent in women with features of the metabolic syndrome (MetSyn). Both MPS and the MetSyn predispose to left ventricular impairment and sympathetic dominance after delivery. Whether this translates into a higher risk of heart failure (HF) and cardiac dysrhythmias is not known. OBJECTIVE: To determine the risk of new onset of HF and dysrhythmias among women after a prior MPS-affected pregnancy. METHODS: A retrospective cohort study was carried out of 1,130,764 individual women with a delivery in Ontario between 1992 and 2009, excluding those with cardiac or thyroid disease 1 year before delivery. The risk of a composite outcome of a hospitalisation for HF or an atrial or ventricular dysrhythmia was compared in women with and without MPS, starting 1 year after delivery. RESULTS: 75,242 individuals (6.7%) experienced a MPS. After a median duration of 7.8 years, the composite outcome occurred in 148 women with MPS (2.54 per 10,000 person-years) and 1062 women without MPS (1.28 per 10,000 person-years) (crude HR=2.00, 95% CI 1.68 to 2.38). The mean age at composite outcome was 37.8 years. The HR was 1.61 (95% CI 1.35 to 1.91) after adjustment for demographic characteristics, diabetes, obesity, dyslipidaemia and drug dependence or tobacco use, as well as coronary artery disease or thyroid disease >1 year after delivery. The adjusted HRs were minimally reduced by further adjusting for chronic hypertension (1.51, 95% CI 1.26 to 1.80) and were higher in women with MPS plus preterm delivery and poor fetal growth (2.42, 95% CI 1.25 to 4.67). CONCLUSIONS: Women with MPS are at higher risk of premature HF and dysrhythmias, especially when perinatal morbidity is present.

Major radiodiagnostic imaging in pregnancy and the risk of childhood malignancy: a population-based cohort study in Ontario.

BACKGROUND: 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). CONCLUSIONS: 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.

Health impact of hospital restrictions on seriously ill hospitalized patients: lessons from the Toronto SARS outbreak.

BACKGROUND: Restrictions on non-urgent hospital care imposed to control the 2003 Toronto severe acute respiratory syndrome outbreak led to substantial disruptions in hospital clinical practice, admission, and transfer patterns. OBJECTIVES: We assessed whether there were unintended health consequences to seriously ill hospitalized patients. STUDY DESIGN, SETTING, AND POPULATION: Population-based longitudinal cohort study of patients residing in Toronto or an urban control region with an incident admission for 1 of 7 serious conditions in the 3 years before, or the 4 months during or after restrictions. OUTCOME MEASURES: Short-term mortality, overall readmissions, cardiac readmissions for acute myocardial infarction patients, serious complications for very low birth weight babies, and quality of care measures, comparing adjusted rates across time periods within regions. RESULTS: Mortality, readmission, and complication rates did not change for any condition during or after severe acute respiratory syndrome restrictions. Although rates of invasive cardiac procedures for acute myocardial infarction patients decreased 11-37% in Toronto, rates of nonfatal cardiac outcomes did not change. CONCLUSIONS: Restrictions on non-urgent hospital utilization and hospital transfers may be a safe public health strategy to employ to control nosocomial outbreaks or provide hospital surge capacity for up to several months, in large, well-developed healthcare systems with good availability of community-based care.

Maternal obesity and the risk of placental vascular disease.

INTRODUCTION: While elevated maternal weight in early pregnancy is associated with a higher rate of preeclampsia, the risk of placental abruption and placental infarction is unknown. METHODS: We evaluated the risk of placental abruption, placental infarction, and preeclampsia in association with maternal weight quintile at approximately 17 weeks' gestation in 386 323 women with a singleton pregnancy who underwent maternal serum screening in Ontario. RESULTS: After adjusting for age, ethnicity, parity, diabetes mellitus, and tobacco use, the odds ratio (OR) for preeclampsia was 4.1 (95% confidence interval [CI] 3.8-4.4) comparing the highest and lowest weight quintiles. Conversely, there was a lower risk of placental abruption or placental infarction, despite further adjustment for preeclampsia, gestational hypertension and drug dependence (OR 0.81, 95% CI 0.75-0.87). CONCLUSION: Higher maternal weight in early pregnancy is associated with a higher risk of preeclampsia and a lower risk of placental abruption or placental infarction, a seeming paradox that requires further elucidation.

Metabolic syndrome features and risk of neural tube defects.

BACKGROUND: 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. METHODS: 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 > or = 90th centile among controls, non-white ethnicity and/or serum highly sensitive C-reactive protein (hsCRP) > or = 75th centile of controls. Since hsCRP naturally increases in pregnancy, analyses were performed with, and without, the inclusion of hsCRP in the model. RESULTS: 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). CONCLUSION: 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.

ICD-10 adaptations of the Ontario acute myocardial infarction mortality prediction rules performed as well as the original versions.

OBJECTIVE: To derive and validate an International Classification of Diseases-10 (ICD-10) version of the Ontario Acute Myocardial Infarction (AMI) mortality prediction rules, used to adjust for case-mix differences in studies of AMI patients using administrative data. STUDY DESIGN AND SETTING: We linked the records of all Ontario patients admitted with AMI (2002-2004) with mortality data. The original ICD-9 codes were mapped to ICD-10-CA (Canada) codes using both a translation produced by coding experts and a manual search of codes; the final codes were determined by consensus. Comorbidity prevalence and mortality rates were calculated. Multivariable logistic regression models were used to predict 30-day and 1-year mortality and the C-statistic was used to evaluate the discrimination of the models. RESULTS: We identified 37,271 AMI patients. The most common comorbidities were heart failure and dysrhythmias; 30-day and 1-year mortality rates were 12.3% and 21.8%, respectively; and mortality rates were highest among patients with shock, cancer, and acute renal failure. The C-statistics were 0.77 and 0.80, compared with 0.78 and 0.79 in the ICD-9 version, for 30-day and 1-year mortality, respectively. CONCLUSION: An ICD-10 version of the AMI mortality prediction rules predicted 30-day and 1-year mortality as well as the original ICD-9 version.

Effect of widespread restrictions on the use of hospital services during an outbreak of severe acute respiratory syndrome.

BACKGROUND: Restrictions on the nonurgent use of hospital services were imposed in March 2003 to control an outbreak of severe acute respiratory syndrome (SARS) in Toronto, Ont. We describe the impact of these restrictions on health care utilization and suggest lessons for future epidemics. METHODS: We performed a retrospective population-based study of the Greater Toronto Area (hereafter referred to as Toronto) and unaffected comparison regions (Ottawa and London, Ont.) before, during and after the SARS outbreak (April 2001-March 2004). We determined the adjusted rates of hospital admissions, emergency department and outpatient visits, diagnostic testing and drug prescribing. RESULTS: During the early and late SARS restriction periods, the rate of overall and medical admissions decreased by 10%-12% in Toronto; there was no change in the comparison regions. The rate of elective surgery in Toronto fell by 22% and 15% during the early and late restriction periods respectively and by 8% in the comparison regions. The admission rates for urgent surgery remained unchanged in all regions; those for some acute serious medical conditions decreased by 15%-21%. The rates of elective cardiac procedures declined by up to 66% in Toronto and by 71% in the comparison regions; the rates of urgent and semi-urgent procedures declined little or increased. High-acuity visits to emergency departments fell by 37% in Toronto, and inter-hospital patient transfers fell by 44% in the circum-Toronto area. Drug prescribing and primary care visits were unchanged in all regions. INTERPRETATION: The restrictions achieved modest reductions in overall hospital admissions and substantial reductions in the use of elective services. Brief reductions occurred in admissions for some acute serious conditions, high-acuity visits to emergency departments and inter-hospital patient transfers suggesting that access to care for some potentially seriously ill patients was affected.

Vitamin B12 and the risk of neural tube defects in a folic-acid-fortified population.

BACKGROUND: Low maternal vitamin B(12) status may be a risk factor for neural tube defects (NTDs). Prior studies used relatively insensitive measures of B(12), did not adjust for folate levels, and were conducted in countries without folic acid food fortification. In Canada, flour has been fortified with folic acid since mid-1997. METHODS: We completed a population-based case-control study in Ontario. We measured serum holotranscobalamin (holoTC), a sensitive indicator of B(12) status, at 15 to 20 weeks' gestation. There were 89 women with an NTD and 422 unaffected pregnant controls. A low serum holoTC was defined as less than 55.3 pmol/L, the bottom quartile value in the controls. RESULTS: The geometric mean serum holoTC levels were 67.8 pmol/L in cases and 81.2 pmol/L in controls. There was a trend of increasing risk with lower levels of holoTC, reaching an adjusted odds ratio of 2.9 (95% confidence interval = 1.2-6.9) when comparing the lowest versus highest quartile. CONCLUSIONS: There was almost a tripling in the risk for NTD in the presence of low maternal B(12) status, measured by holoTC. The benefits of adding synthetic B(12) to current recommendations for periconceptional folic acid tablet supplements or folic-acid-fortified foods need to be considered. It remains to be determined what fraction of NTD cases in a universally folate-fortified environment might be prevented by higher periconceptional intake of B(12).

Adverse perinatal outcomes associated with homelessness and substance use in pregnancy.

BACKGROUND: Women who are homeless during pregnancy may be exposed to poor nutrition, violence and substance use, yet the health status of their newborn infants has not been systematically evaluated. We undertook a study to provide preliminary estimates of the risk of adverse perinatal outcomes among Canadian women who are homeless or marginally housed during pregnancy, and the effect of concomitant substance use. METHODS: We conducted a retrospective cohort study at a single downtown hospital from October 2002 to December 2004, involving women who, during pregnancy, were homeless or underhoused (n = 80), substance users (n = 59) or neither (n = 3756). We noted neonatal measures such as birth weight and gestational age; the main study outcomes were preterm birth before 37 weeks' gestation, birth weight less than 2000 g and small for gestational age at birth. RESULTS: Homelessness or inadequate housing was associated with an odds ratio (adjusted for maternal age, gravidity and being a current smoker of tobacco) of 2.9 (95% confidence interval [CI] 1.4-6.1) for preterm delivery, 6.9 (95% CI 2.4- 20.0) for infant birth weight under 2000 g and 3.3 (95% CI 1.1- 10.3) for delivery of a newborn small for gestational age. Adjusted odds ratios for substance use during pregnancy were similar. In the combined presence of an underhoused or homeless state and maternal substance use, the adjusted risk estimates were 5.9 (95% CI 1.9-18.5), 16.6 (95% CI 3.5-79.3) and 5.6 (95% CI 1.1-28.7), respectively. INTERPRETATION: Homelessness and maternal substance use may reduce neonatal well-being through prematurity and low birth weight.

Greater maternal weight and the ongoing risk of neural tube defects after folic acid flour fortification.

OBJECTIVE: Maternal obesity is likely a risk factor for neural tube defects (NTDs). By late 1997, it became mandatory in Canada that all refined wheat flour be fortified with folic acid. Because overweight women may consume greater quantities of refined wheat flour, we questioned whether their risk of NTD changed after flour fortification. METHODS: A retrospective population-based study was conducted between 1994 and late 2000. We included all Ontarian women who underwent antenatal maternal screening at 15 to 20 weeks of gestation. Self-declared maternal date of birth, ethnicity, current weight, and the presence of pregestational diabetes mellitus were recorded in a standardized fashion on the maternal screening requisition sheet. The presence of NTDs was systematically detected both antenatally and postnatally. The risk of open NTD was evaluated across maternal weight quartiles and deciles, and an interaction between greater maternal weight and the presence of flour fortification was tested using multiple logistic regression analysis. RESULTS: A total of 292 open NTDs were detected among 420,362 women. The adjusted odds ratio (OR) for NTD was 1.2 (95% confidence interval [CI] 1.1-1.3) per 10-kg incremental rise in maternal weight. Comparing the highest with the lowest quartile of maternal weight, the adjusted OR for NTD was 2.6 (95% CI 1.8-4.0). A similar finding was observed for the highest compared with lowest weight deciles (adjusted OR 3.3, 95% CI 1.7-6.2). The interaction between elevated maternal weight and the presence of folic acid flour fortification was of borderline significance (P = .09). Before fortification, greater maternal weight was associated with a modestly increased risk of NTD (adjusted OR 1.4, 95% CI 1.0-1.8); after flour fortification, this effect was more pronounced (adjusted OR 2.8, 95% CI 1.2-6.6). CONCLUSION: These data emphasize the higher risk of NTD associated with increased maternal weight, even after universal folic acid flour fortification. Beyond periconceptional folic acid use, consideration should be given to testing whether prepregnancy weight reduction is an independent means of preventing NTD. LEVEL OF EVIDENCE: II-2.

Maternal ethnicity and risk of neural tube defects: a population-based study.

BACKGROUND: Maternal body mass and the presence of diabetes mellitus are probable risk factors for neural tube defects (NTDs). The association between maternal ethnicity and the risk of NTDs remains poorly understood, however. METHODS: We performed a retrospective population-based study and included all women in Ontario who underwent antenatal maternal screening (MSS) at 15 to 20 weeks' gestation between 1994 and late 2000. Self-declared maternal date of birth, ethnicity and weight and the presence of pregestational diabetes mellitus were recorded in a standardized fashion on the MSS requisition sheet. NTDs were detected antenatally by ultrasonography or fetal autopsy and postnatally by considering all live and stillborn affected infants beyond 20 weeks' gestation. The risk of open NTD was evaluated across the 5 broad ethnic groups used for MSS, with white ethnicity as the referent. RESULTS: Compared with white women (n = 290 799), women of First Nations origin (n = 1551) were at increased associated risk of an NTD-affected pregnancy (adjusted odds ratio [OR] 5.2, 95% confidence interval [CI] 2.1-12.9). Women of other ethnic origins were not at increased associated risk compared with white women (women of Asian origin [n = 75 590]: adjusted OR 0.9, 95% CI 0.6-1.3; black women [n = 25 966]: adjusted OR 0.6, 95% CI 0.3-1.1; women of "other" ethnic origin [n = 10 009]: adjusted OR 0.1, 95% CI 0.02-0.9). INTERPRETATION: The associated risk of NTD-affected pregnancies was higher among women of First Nations origin than among women of other ethnic origins. The mechanisms for this discrepancy should be explored.

Association between folic acid food fortification and congenital orofacial clefts.

By January 1998, most of Canada's cereal grain products were being fortified with folic acid. Among 336963 women who underwent antenatal maternal serum screening, the prevalence of orofacial clefts did not change from before (1.15 per 1000) to after (1.21 per 1000) food fortification (prevalence ratio, 1.06; 95% confidence interval, 0.86-1.30).

Folic acid food fortification is associated with a decline in neuroblastoma.

BACKGROUND: Neuroblastoma, an embryonic tumor, is the second most common pediatric tumor and is the most prevalent extracranial solid tumor in children. Results of previous studies have suggested that maternal vitamin intake may decrease the risk of several childhood cancers. In January 1997, Canada began fortifying flour with folic acid for the prevention of neural tube defects. The effect of folic acid fortification on the rate of neuroblastoma in offspring is not known. METHODS: We investigated the rates of neuroblastoma (<1 year), acute lymphoblastic leukemia, and hepatoblastoma registered by the Pediatric Oncology Group of Ontario, which captures 95% of all pediatric cancers in Ontario, before and after the introduction of folate fortification. RESULTS: An interventional time series analysis showed that the incidence of neuroblastoma declined from 1.57 cases per 10,000 births before to 0.62 case per 10,000 births after folic acid fortification (P <.0001). The crude incidence rate ratio (0.40; 95% confidence interval, 0.25-0.64) remained significant after adjustment for both age and disease stage at diagnosis (adjusted incidence rate ratio, 0.38; 95% confidence interval, 0.23-0.62). In contrast, there was no significant change in the rate of infant acute lymphoblastic leukemia (incidence rate ratio, 0.97; 95% confidence interval, 0.41-2.27) or hepatoblastoma (incidence rate ratio, 0.81; 95% confidence interval, 0.35-1.89). CONCLUSIONS: Folic acid fortification was associated with a 60% reduction in neuroblastoma but was not associated with any change in the rate of infant acute lymphoblastic leukemia or hepatoblastoma. Further investigation is needed into the role of metabolism in the formation and prevention of neuroblastoma and other embryonically determined cancers.

Increased blood product use among coronary artery bypass patients prescribed preoperative aspirin and clopidogrel.

BACKGROUND: The administration of antiplatelet drugs before coronary artery bypass graft surgery (CABG) is associated with an increased risk of major hemorrhage and related surgical reexploration. Little is known about the relative effect of combined clopidogrel and aspirin on blood product use around the time of CABG. We evaluated the associated risk between the combined use of aspirin and clopidogrel and the transfusion of blood products perioperatively. METHODS: We retrospectively studied a cohort of 659 individuals who underwent a first CABG, without concomitant valvular or aortic surgery, at a single large Canadian cardiac surgical centre between January 2000 and April 2002. The four study exposure groups were those prescribed aspirin (n = 105), clopidogrel (n = 11), the combination of both (n = 46), or neither drug (n = 497), within 7 days prior to CABG. The primary study outcome was the excessive transfusion of blood products during CABG and up to the second post-operative day, defined as > or = 2 units of packed red blood cells (PRBC), > or = 2 units of fresh frozen plasma, > or = 5 units of cryoprecipitate or > or = 5 units of platelets. Secondary outcomes included the mean number of transfused units of each type of blood product. RESULTS: A greater mean number of units of PRBC were transfused among those who received clopidogrel alone (2.9) or in combination with aspirin (2.4), compared to those on aspirin alone (1.9) or neither antiplatelet drug (1.4) (P = 0.001). A similar trend was seen for the respective mean number of transfused units of platelets (3.6, 3.7, 1.3 and 1.0; P < 0.001) and fresh frozen plasma (2.5, 3.1, 2.3, 1.6; P = 0.01). Compared to non-users, the associated risk of excessive blood product transfusion was highest among recipients of aspirin and clopidogrel together (adjusted OR 2.2, 95% CI 1.1-4.3). No significant association was seen among lone users of aspirin (adjusted OR 1.0, 95% CI 0.6-1.6) or clopidogrel (adjusted OR 0.7, 95% CI 0.2-2.5), compared to non-users. CONCLUSIONS: While combined use of aspirin and clopidogrel shortly before CABG surgery may increase the associated risk of excess transfusion of blood products perioperatively, several study limitations prevent any confident conclusions from being drawn. Beyond challenging these findings, future research might focus on the value of both intraoperative monitoring of platelet function, and the effectiveness of antifibrinolytic agents, at reducing the risk of postoperative bleeding.