Androgenic and estrogenic indices in human newborns and infants: the MIREC-ID study.

Prenatal sex steroid exposure plays an important role in determining child development. Yet, measurement of prenatal hormonal exposure has been limited by the paucity of newborn/infant data and the invasiveness of fetal hormonal sampling. Here we provide descriptive data from the MIREC-ID study (n=173 girls; 162 boys) on a range of minimally invasive physical indices thought to reflect prenatal exposure to androgens [anogenital distances (AGDs); penile length/width, scrotal/vulvar pigmentation], to estrogens [vaginal maturation index (VMI) - the degree of maturation of vaginal wall cells] or to both androgens/estrogens [2nd-to-4th digit ratio (2D:4D); areolar pigmentation, triceps/sub-scapular skinfold thickness, arm circumference]. VMI was found to be associated with triceps skinfold thickness (ß=0.265, P=0.005), suggesting that this marker may be sensitive to estrogen levels produced by adipose tissue in girls. Both estrogenic and androgenic markers (VMI: ß=0.338, P=0.031; 2D:4D - right: ß=-0.207, P=0.040; left: ß=-0.276, P=0.006; AGD-fourchette - ß=0.253, P=0.036) were associated with areolar pigmentation in girls, supporting a role for the latter as an index of both androgen and estrogen exposure. We also found AGD-penis (distance from the anus to the penis) to be associated with scrotal pigmentation (ß=0.290, P=0.048), as well as right arm circumference (ß=0.462, P<0.0001), supporting the notion that these indices may be used together as markers of androgen exposure in boys. In sum, these findings support the use of several physical indices at birth to convey a more comprehensive picture of prenatal exposure to sex hormones.

Exposure to phthalates, bisphenol A and metals in pregnancy and the association with impaired glucose tolerance and gestational diabetes mellitus: The MIREC study.

BACKGROUND: Studies from several countries report increases in rates of gestational diabetes mellitus (GDM) over recent decades. Exposure to environmental chemicals could contribute to this trend. OBJECTIVES: To determine the associations between plasticisers and metals measured in early pregnancy with impaired glucose tolerance (IGT) and GDM in a Canadian pregnancy cohort. METHODS: Women enrolled in the Maternal-Infant Research on Environmental Chemicals (MIREC) Study were included if they had a singleton delivery and did not have pre-existing diabetes. Eleven phthalate metabolites and total bisphenol A (BPA) were measured in first-trimester urine samples, and four metals (lead, cadmium, mercury and arsenic) were measured in first-trimester blood samples. IGT and GDM were assessed in accordance with standard guidelines by chart review. Chemical concentrations were grouped by quartiles, and associations with outcomes were examined using logistic regression with adjustment for maternal age, race, pre-pregnancy BMI, and education. Restricted cubic spline analysis was performed to help assess linearity and nature of any dose-response relationships. RESULTS: Of 2001 women recruited into the MIREC cohort, 1274 met the inclusion criteria and had outcome data and biomonitoring data measured for at least one of the chemicals we examined. Elevated odds of GDM were observed in the highest quartile of arsenic exposure (OR = 3.7, 95% CI = 1.4-9.6) in the adjusted analyses. A significant dose-response relationship was observed in a cubic spline model between arsenic and odds of GDM (p < 0.01). No statistically significant associations were observed between phthalates or BPA or other metals with IGT or GDM. CONCLUSIONS: Our findings add to the growing body of evidence supporting the role of maternal arsenic exposure as a risk factor for gestational diabetes.

Application of a national administrative case definition for the identification of pre-existing diabetes mellitus in pregnancy.

INTRODUCTION: Accurate ascertainment of pregnant women with pre-existing diabetes allows for the comprehensive surveillance of maternal and neonatal outcomes associated with this chronic disease. METHOD: To determine the accuracy of case definitions for pre-existing diabetes mellitus when applied to a pregnant population, a cohort of women who were pregnant in Nova Scotia, Canada, between 1991 and 2003 was obtained from a population-based provincial perinatal database, the Nova Scotia Atlee Perinatal Database (NSAPD). Person-level data from administrative databases using hospital discharge abstract data and outpatient physician services data were linked to this cohort. Various algorithms for defining diabetes mellitus from the administrative data, including the algorithm suggested by the National Diabetes Surveillance System (NDSS), were compared to a reference standard definition from the NSAPD. RESULTS: Validation of the NDSS case definition applied to this pregnant population demonstrated a sensitivity of 87% and a positive predictive value (PPV) of 66.4%. Use of ICD-9 and ICD-10 diagnostic codes among hospitalizations with diabetes mellitus in pregnancy showed important increases in sensitivity and PPV, especially for those pregnancies delivered in tertiary centres. In this population, pregnancy-related administrative data from the hospitalization database alone appear to be a more accurate data source for identifying pre-existing diabetes than applying the NDSS case definition, particularly when pregnant women are delivered in a tertiary hospital. CONCLUSION: Although the NDSS definition of diabetes performs reasonably well compared to a reference standard definition of diabetes, using this definition for evaluating maternal and perinatal outcomes associated with diabetes in pregnancy will result in a certain degree of misclassification and, therefore, biased estimates of outcomes.

Validity of autism diagnoses using administrative health data.

It is necessary to monitor autism prevalence in order to plan education support and health services for affected children. This study was conducted to assess the accuracy of administrative health databases for autism diagnoses. Three administrative health databases from the province of Nova Scotia were used to identify diagnoses of autism spectrum disorders (ASD): the Hospital Discharge Abstract Database, the Medical Services Insurance Physician Billings Database and the Mental Health Outpatient Information System database. Seven algorithms were derived from combinations of requirements for single or multiple ASD claims from one or more of the three administrative databases. Diagnoses made by the Autism Team of the IWK Health Centre, using state-of-the-art autism diagnostic schedules, were compared with each algorithm, and the sensitivity, specificity and C-statistic (i.e. a measure of the discrimination ability of the model) were calculated. The algorithm with the best test characteristics was based on one ASD code in any of the three databases (sensitivity=69.3%). Sensitivity based on an ASD code in either the hospital or the physician billing databases was 62.5%. Administrative health databases are potentially a cost efficient source for conducting autism surveillance, especially when compared to methods involving the collection of new data. However, additional data sources are needed to improve the sensitivity and accuracy of identifying autism in Canada.

Low levels of maternal serum PAPP-A in early pregnancy and the risk of adverse outcomes.

OBJECTIVES: To determine if low maternal serum level of pregnancy associated plasma protein A (PAPP-A) measured in early pregnancy can predict adverse pregnancy outcomes and to examine the gestational age (GA) sampling interval for these outcomes. METHODS: This was a nested case-control study from a prospective cohort of women recruited at <20 weeks of gestation in Halifax, NS. Cases (n=248) were defined as women who had a fetal loss or developed preeclampsia, severe pregnancy-induced hypertension (PIH), or small for gestational age infant (SGA). Controls (n=244) were frequency matched to cases by GA at the time of serum sampling (6 to <20 weeks GA). Participant information was obtained from questionnaires and medical chart reviews. RESULTS: Women with a low PAPP-A measure [0.4 MoM). However, performance as a screening test was poor [sensitivity=38.7%; specificity=81.6%; positive likelihood ratio (LR)=2.1; negative LR=0.75]. In the adjusted model, the 10- to 14-week GA period was the only time period where low PAPP-A was significantly associated with adverse outcomes. CONCLUSIONS: Women with a low PAPP-A early in their pregnancy have twice the risk of an adverse outcome, though PAPP-A as a one-time single marker test has limited value.

Diabetes mellitus following gestational diabetes: role of subsequent pregnancy.

OBJECTIVE: This study was designed to determine the rate of diabetes up to 13 years after pregnancies complicated by gestational diabetes and to identify risk factors for developing diabetes. The role of a subsequent pregnancy, with and without gestational diabetes, was also examined. DESIGN: This was a retrospective cohort study of women with gestational diabetes. POPULATION AND SETTING: Women who had gestational diabetes in their first pregnancy between 1989 and 2002 were identified through a population-based perinatal database in Nova Scotia, Canada. METHODS: Subsequent diagnoses of diabetes, up to 13 years after the first pregnancy, were obtained from physician billing and hospital discharge databases. Cox proportional hazards regression models were used to estimate adjusted relative risks (RR) and 95% confidence intervals. MAIN OUTCOME MEASURES: Diagnosis of diabetes after pregnancy. RESULTS: Of the 1401 nulliparous women with gestational diabetes, 251 women (17.9%) developed diabetes in the follow-up period. The cumulative incidence at 1, 5, and 10 years was 5.9, 14.8, and 22.2%, respectively. Factors significantly associated with an increased risk of developing diabetes mellitus included a pre-pregnancy weight of > or = 86 kg (RR = 1.8, 95% CI 1.2-2.9), insulin therapy during the index pregnancy (RR = 4.1, 95% CI 2.1-7.9), neonatal hypoglycaemia (RR = 2.6, 95% CI 1.6-4.2), and a subsequent pregnancy with gestational diabetes (RR = 2.3, 95% CI 1.6-3.4). CONCLUSION: Indicators of the severity of gestational diabetes, defined by insulin use, neonatal hypoglycaemia, and recurrent gestational diabetes in a subsequent pregnancy, are important in predicting a subsequent diagnosis of diabetes. Our findings do not support the theory that subsequent pregnancy, per se, increases the risk of developing diabetes.

Dilatation of the ascending aorta in paediatric patients with bicuspid aortic valve: frequency, rate of progression and risk factors.

OBJECTIVES: To describe the incidence and rate of dilatation of the ascending aorta in children with bicuspid aortic valve (BAV) and to determine factors that predict rapid aortic dilatation. DESIGN: Retrospective cohort study. SETTING: Regional tertiary care children's hospital. PATIENTS: All children aged 0-18 years seen at the authors' institution between 1990 and 2003 with an "isolated" BAV. All patients had had more than one technically adequate echocardiogram, at least six months apart, with concomitant height and weight data. INTERVENTIONS: Offline echocardiographic measurements of multiple levels of the aortic root were completed for each participant at each serial echocardiogram. These measurements were then compared with expected measurements derived from a normal local control population. MAIN OUTCOME MEASURES: Rate of change of the ascending aorta size over time, where aortic size is expressed as the number of standard deviations above or below the mean size expected for a given body surface area (z score). RESULTS: 279 echocardiograms spanning a period of from 9 months to 13.3 years were analysed for 88 patients with BAV. The ascending aorta in the BAV group was larger than expected for body surface area at diagnosis and continued to increase in relative size at each of the four subsequent follow-up echocardiograms. Ascending aortic z score increased at an average rate of 0.4/year. A faster rate of increase in z score was predicted by both larger initial aortic valve gradient and non-use of beta blockers. CONCLUSIONS: Children with BAV are at risk of having a dilated ascending aorta. This risk increases with longer follow up.

Haloacetic acids in drinking water and risk for stillbirth.

BACKGROUND: Trihalomethanes (THMs) occurring in public drinking water sources have been investigated in several epidemiological studies of fetal death and results support a modest association. Other classes of disinfection by-products found in drinking water have not been investigated. AIMS: To investigate the effects of haloacetic acid (HAA) compounds in drinking water on stillbirth risk. METHODS: A population based case-control study was conducted in Nova Scotia and Eastern Ontario, Canada. Estimates of daily exposure to total and specific HAAs were based on household water samples and questionnaire information on water consumption at home and work. RESULTS: The analysis included 112 stillbirth cases and 398 live birth controls. In analysis without adjustment for total THM exposure, a relative risk greater than 2 was observed for an intermediate exposure category for total HAA and dichloroacetic acid measures. After adjustment for total THM exposure, the risk estimates for intermediate exposure categories were diminished, the relative risk associated with the highest category was in the direction of a protective effect, and all confidence intervals included the null value. CONCLUSIONS: No association was observed between HAA exposures and stillbirth risk after controlling for THM exposures.

Congenital anomalies and other birth outcomes among infants born to women living near a hazardous waste site in Sydney, Nova Scotia.

Using data from the Nova Scotia Atlee Perinatal Database, rates of adverse birth outcomes were compared among residents of Sydney, Nova Scotia and residents of Cape Breton County, Nova Scotia (excluding Sydney) with birth outcomes among residents of the rest of Nova Scotia. There was a small but statistically significant increase in the rate of major congenital anomalies in Sydney (2.8%) compared to the rest of Nova Scotia (2.3%) (adjusted RR = 1.25, 95% CI = 1.04-1.51). Rates of anomaly sub-groups were consistently elevated in Sydney compared to the rest of Nova Scotia, but most were not statistically significant. For the most part, the increased rates of congenital anomalies observed among residents of Sydney were not evident in the neighbouring community. Since Sydney and the rest of Cape Breton County share a similar risk factor and socio-demographic profile, other factors likely explain the increased rates observed in Sydney.

A preterm birth prevention project in Nova Scotia, Canada.

OBJECTIVE: The Halifax County Preterm Birth Prevention Project was designed to evaluate the effectiveness of a population-based preterm birth (PTB) prevention program in Nova Scotia from January 1995 through June 1997 (n = 10,326). METHODS: Preterm birth rates, adjusted for risk status and maternal age, were evaluated over time in Halifax County and compared to non-Halifax County parturients in Nova Scotia. Physician participation was evaluated by means of a mailed survey. RESULTS: There was no appreciable change in the overall (<37 weeks) or early (<34 weeks) PTB rates within or outside Halifax County during the intervention period compared to the preintervention period. Although not significant, the very (<30 weeks) PTB rate in Halifax County decreased by 40% from 0.53 to 0.32%, while outside Halifax County it remained stable (0.43-0.42%). There was a statistically significant decrease in early and very PTB associated with spontaneous labour, as well as an apparent shift in the timing of delivery from very preterm to preterm (> or =30 weeks). Participation among responding physicians was greater for high-risk than low-risk women, but full compliance with project recommendations was low. CONCLUSION: The overall ineffectiveness of the Halifax County Preterm Birth Prevention Project may reflect the reluctance of practitioners to fully incorporate the recommended prevention strategies into their practice. However, such interventions may reduce the risk of spontaneous early preterm birth.

Causes and consequences of recent increases in preterm birth among twins.

OBJECTIVE: To examine the causes and consequences of the recent increase in preterm birth among twins. METHODS: We studied all twin births among residents of the province of Nova Scotia, Canada, between 1988 and 1997. Rates of preterm birth, preterm labor induction, preterm cesarean, small-for-gestational age (SGA), respiratory distress syndrome (RDS), stillbirth, perinatal mortality, and infant mortality were compared between past and more recent years. Changes in perinatal mortality were examined using logistic regression to adjust for the effects of other determinants. RESULTS: The study included 2516 twin births (73 stillbirths and 2443 live births). The rate of preterm birth increased from 42.3% in 1988-1992 to 48.2% of twin live births in 1993-1997 (14% increase, P =.04). Twin live births born after preterm labor induction increased from 3.5% in 1988-1989 to 8.6% in 1996-1997 (P for trend =.007). Of live births between 34 and 36 weeks' gestation, the proportion born SGA decreased from 17.5% in 1988-1992 to 9.2% in 1993-1997 (P =.005). Over the same period, rates of prophylactic maternal steroid therapy increased substantially and rates of RDS declined. Perinatal mortality rates among pregnancies reaching 34 weeks decreased from 12.9 per 1000 total births in 1988-1992 to 4.2 per 1000 total births in 1993-1997 (P =.05). CONCLUSION: Increases in preterm labor induction appear to be responsible for the recent increase in preterm birth among twins. These changes have been accompanied by decreases in perinatal morbidity and mortality among twin pregnancies that reach 34 weeks' gestation.

Nodal vessels disease as a risk factor for atrial fibrillation after coronary artery bypass graft surgery.

OBJECTIVE: Atrial fibrillation (AF) is common after coronary artery bypass graft (CABG) surgery. Atrial ischaemia due to diseased atrioventricular (AV) and sinoatrial (SA) arteries has been proposed as a cause of AF post-CABG. We examined if the presence of diseased nodal arteries was a significant predictor of the development of AF post-CABG. METHODS: 100 consecutive cases (AF post-CABG) were compared to 100 consecutive controls (No AF post-CABG) with respect to pre-operative angiographic evidence of diseased nodal arteries. Cases and controls identified from the Society of Thoracic Surgeons database underwent detailed chart reviews to obtain data on potential risk factors. Patients were excluded if they were undergoing anything but a routine CABG procedure, were older than 65 years, or had previous AF. All angiograms were reviewed by a single radiologist blinded to outcome. The effect of grafting diseased nodal arteries on the development of AF post-CABG was also measured. A multiple logistic regression model was utilized to measure the effect of disease in each artery on the development of AF post-CABG. RESULTS: Cases and controls were comparable regarding potential risk factors, with the exception that the AF group was older than the non-AF group. Significant AV artery disease was detected in 78 cases compared to 74 controls (adjusted odds ratio (OR) OR=1.04, CI, 0.51-2.12, P=0.82). Significant SA artery disease was detected in 34 cases compared to 21 controls (adjusted OR=2.093, CI: 1.06-4.09, P=0.03). Six of ten patients having revascularization of their SA nodal artery developed AF versus 28 of 45 of those who did not (OR=0.91, CI: 0.18-5.06, P=0.58). Forty-eight of 87 patients having revasacularization of their AV nodal artery developed AF versus 30 of 65 of those who did not (OR=1.44, CI: 0.72-2.88, P=0.27). CONCLUSION: The presence of a diseased SA artery is significantly associated with AF post-CABG. Such association may be used to identify a subset of patients who might be targeted with prophylaxis.

Relation between trihalomethane compounds and birth defects.

OBJECTIVES: To evaluate the risk of birth defects relative to exposure to specific trihalomethanes in public water supplies. METHODS: A retrospective cohort study was conducted based on data from a population based perinatal database in Nova Scotia, Canada and from the results of routine water monitoring tests. The cohort consisted of women who had a singleton birth in Nova Scotia between 1988 and 1995 and who lived in an area with a municipal water supply. The birth defects analyzed included neural tube defects, cardiovascular defects, cleft defects, and chromosomal abnormalities. Two of the four trihalomethane compounds occur in large enough concentrations to be analyzed (chloroform and bromodichloromethane (BDCM)). RESULTS: Exposure to BDCM at concentrations of 20 microg/l or over was associated with an increased risk of neural tube defects (adjusted relative risk (RR) 2.5, 95% confidence interval (95% CI) 1.2 to 5.1) whereas exposure to chloroform was not. Exposure to BDCM of 20 microg/l and over was associated with decreased risks of cardiovascular anomalies (RR 0.3, 95% CI 0.2 to 0.7). There was a suggestion of an increased risk of chromosomal abnormalities associated with exposure to chloroform, and no evidence of any association between either trihalomethane compound and cleft defects. CONCLUSIONS: In this cohort, differences were found in the RR associated with exposure to chloroform and BDCM for each of the congenital anomalies under study. These findings point to the importance of examining specific byproduct compounds relative to risk for these birth outcomes and in particular implicate BDCM and other correlated disinfection byproducts in the aetiology of neural tube defects.

Rates and risk factors for recurrence of gestational diabetes.

OBJECTIVE: To determine the recurrence rate of gestational diabetes (GDM) during a subsequent pregnancy among women who had GDM during an index pregnancy and to identify factors associated with the probability of recurrence RESEARCH DESIGN AND METHODS: A retrospective longitudinal study was performed in Nova Scotia, Canada, of women who were diagnosed as having GDM during a pregnancy between the years of 1980 and 1996 and who had at least one subsequent pregnancy during this time period. When only the index and first subsequent pregnancy were analyzed, the cohort included 651 women. The recurrence rate of GDM in the pregnancy after the pregnancy with the initial diagnosis of GDM was determined. Multivariate regression models were constructed to model the recurrence of GDM in a subsequent pregnancy as functions of potential predictors to estimate RRs and CIs. RESULTS: The rate of recurrence of GDM in the pregnancy subsequent to the index pregnancy was found to the 35.6% (95% CI = 31.9-39.3%). Multivariate regression models showed that infant birth weight in the index pregnancy and maternal prepregnancy weight before the subsequent pregnancy were predictive of recurrent GDM. CONCLUSIONS: In this large cohort of women, slightly more than one-third of the subjects had diabetes in a subsequent pregnancy, which is consistent with recurrence rates in other predominately white populations. Strategies to reduce the occurrence of neonatal macrosomia and maternal prepregnancy obesity may help lower the rate of recurrence of GDM.

Maternal complications with placenta previa.

The purpose of this study is to describe the maternal complications of placenta previa. A population-based retrospective cohort study including all women delivered in the province of Nova Scotia, Canada from 1988 to 1995 was performed. Patient information was obtained from the Nova Scotia Atlee Perinatal Database and maternal complications were described for all women undergoing cesarean delivery. Prognostic factors for the risk of hysterectomy in woman with placenta previa were analyzed by multiple logistic regression. During the 8-year period, 308 cases of placenta previa were identified in 93,996 deliveries (0.33%). Maternal complications included hysterectomy [relative risk (RR) = 33.26], antepartum bleeding (RR = 9.81), intrapartum (RR = 2.48), and postpartum (RR = 1.86) hemorrhages, as well as blood transfusion (RR = 10.05), septicemia (RR = 5.55), and thrombophlebitis (RR = 4.85). Risk factors for need of hysterectomy in women with placenta previa include the presence of placenta accreta and previous cesarean delivery.

Relation between stillbirth and specific chlorination by-products in public water supplies.

During water treatment, chlorine reacts with naturally occurring organic matter in surface water to produce a number of by-products. Of the by-products formed, trihalomethanes (THMs) are among the highest in concentration. We conducted a retrospective cohort study to evaluate the relationship between the level of total THM and specific THMs in public water supplies and risk for stillbirth. The cohort was assembled from a population-based perinatal database in the Canadian province of Nova Scotia and consisted of almost 50,000 singleton deliveries between 1988 and 1995. Individual exposures were assigned by linking mother's residence at the time of delivery to the levels of specific THMs monitored in public water supplies. Analysis was conducted for all stillbirths and for cause-of-death categories based on the physiologic process responsible for the fetal death. Total THMs and the specific THMs were each associated with increased stillbirth risk. The strongest association was observed for bromodichloromethane exposure, where risk doubled for those exposed to a level of [greater and equal to] 20 microg/L compared to those exposed to a level < 5 microg/L (relative risk = 1. 98, 95% confidence interval, 1.23-3.49). Relative risk estimates associated with THM exposures were larger for asphyxia-related deaths than for unexplained deaths or for stillbirths overall. These findings suggest a need to consider specific chlorination by-products in relation to stillbirth risk, in particular bromodichloromethane and other by-product correlates. The finding of a stronger effect for asphyxia deaths requires confirmation and research into possible mechanisms.

Afferent innervation of outer and inner hair cells is normal in neonatally de-efferented cats.

It has been hypothesized that normal pruning of exuberant branching of afferent neurons in the developing cochlea is caused by the arrival of the olivocochlear efferent neurons and the resulting competition for synaptic sites on hair cells. This hypothesis was supported by a report that afferent innervation density on mature outer hair cells (OHCs) is elevated in animals deefferented at birth, before the olivocochlear system reaches the outer hair cell area (Pujol and Carlier [1982] Dev. Brain Res. 3:151-154). In the current study, this claim was evaluated quantitatively at the electron microscopic level in four cats that were de-efferented at birth and allowed to survive for 6-11 months. A semiserial section analysis of 156 OHCs from de-efferented and normal ears showed that, although de-efferentation essentially was complete in all four cases, the number and distribution of afferent terminals on OHCs was indistinguishable from normal, and the morphology of afferent synapses was normal in both the inner hair cell area and the OHC area. Thus, the postnatal presence of an efferent system is not required for the normal development of cochlear afferent innervation, and the synaptic competition hypothesis is not supported.

Maternal outcomes associated with weight change between pregnancies.

OBJECTIVE: Weight change between pregnancies was examined to determine if there were an association between weight gain (or loss) and delivery by cesarean section, gestational diabetes or pregnancy-induced hypertension. METHODS: A cohort study was conducted which included Nova Scotia residents with two or more singleton deliveries between 1988 and 1996. Weight change between pregnancies was calculated as the difference in weight from a woman's initial pre-pregnancy weight and the pre-pregnancy weight recorded from her final recorded pregnancy. RESULTS: Weight change between pregnancies was examined in 19,932 women. Women in the highest weight gain category were at an increased risk for developing gestational diabetes (RR = 1.59, 95% CI 1.22-2.08), independent of their weight prior to the final pregnancy, and other confounders. Weight gain (or loss) between pregnancies was not associated with the other outcomes. INTERPRETATION: Weight gain between pregnancy is an independent risk factor for gestational diabetes.