Maternal pre-pregnancy body mass index and risk of preterm birth: a collaboration using large routine health datasets.

BACKGROUND: Preterm birth (PTB) is a leading cause of child morbidity and mortality. Evidence suggests an increased risk with both maternal underweight and obesity, with some studies suggesting underweight might be a greater factor in spontaneous PTB (SPTB) and that the relationship might vary by parity. Previous studies have largely explored established body mass index (BMI) categories. Our aim was to compare associations of maternal pre-pregnancy BMI with any PTB, SPTB and medically indicated PTB (MPTB) among nulliparous and parous women across populations with differing characteristics, and to identify the optimal BMI with lowest risk for these outcomes. METHODS: We used three UK datasets, two USA datasets and one each from South Australia, Norway and Denmark, together including just under 29 million pregnancies resulting in a live birth or stillbirth after 24 completed weeks gestation. Fractional polynomial multivariable logistic regression was used to examine the relationship of maternal BMI with any PTB, SPTB and MPTB, among nulliparous and parous women separately. The results were combined using a random effects meta-analysis. The estimated BMI at which risk was lowest was calculated via differentiation and a 95% confidence interval (CI) obtained using bootstrapping. RESULTS: We found non-linear associations between BMI and all three outcomes, across all datasets. The adjusted risk of any PTB and MPTB was elevated at both low and high BMIs, whereas the risk of SPTB was increased at lower levels of BMI but remained low or increased only slightly with higher BMI. In the meta-analysed data, the lowest risk of any PTB was at a BMI of 22.5 kg/m2 (95% CI 21.5, 23.5) among nulliparous women and 25.9 kg/m2 (95% CI 24.1, 31.7) among multiparous women, with values of 20.4 kg/m2 (20.0, 21.1) and 22.2 kg/m2 (21.1, 24.3), respectively, for MPTB; for SPTB, the risk remained roughly largely constant above a BMI of around 25-30 kg/m2 regardless of parity. CONCLUSIONS: Consistency of findings across different populations, despite differences between them in terms of the time period covered, the BMI distribution, missing data and control for key confounders, suggests that severe under- and overweight may play a role in PTB risk.

Linking a European cohort of children born with congenital anomalies to vital statistics and mortality records: A EUROlinkCAT study.

EUROCAT is a European network of population-based congenital anomaly (CA) registries. Twenty-one registries agreed to participate in the EUROlinkCAT study to determine if reliable information on the survival of children born with a major CA between 1995 and 2014 can be obtained through linkage to national vital statistics or mortality records. Live birth children with a CA could be linked using personal identifiers to either their national vital statistics (including birth records, death records, hospital records) or to mortality records only, depending on the data available within each region. In total, 18 of 21 registries with data on 192,862 children born with congenital anomalies participated in the study. One registry was unable to get ethical approval to participate and linkage was not possible for two registries due to local reasons. Eleven registries linked to vital statistics and seven registries linked to mortality records only; one of the latter only had identification numbers for 78% of cases, hence it was excluded from further analysis. For registries linking to vital statistics: six linked over 95% of their cases for all years and five were unable to link at least 85% of all live born CA children in the earlier years of the study. No estimate of linkage success could be calculated for registries linking to mortality records. Irrespective of linkage method, deaths that occurred during the first week of life were over three times less likely to be linked compared to deaths occurring after the first week of life. Linkage to vital statistics can provide accurate estimates of survival of children with CAs in some European countries. Bias arises when linkage is not successful, as early neonatal deaths were less likely to be linked. Linkage to mortality records only cannot be recommended, as linkage quality, and hence bias, cannot be assessed.

Fever in pregnancy and the risk of congenital malformations: a cohort study.

BACKGROUND: In a variety of animal species, hyperthermia in pregnancy has been recognized as teratogenic. Hyperthermia interferes with protein synthesis via heat-shock proteins, which can entail membrane disruption, cell death, vascular disruption, and placental infarction. This can induce severe fetal malformations or death. Fever during pregnancy, especially during embryogenesis, has also been associated with congenital malformations in human offspring. The purpose of this large cohort study of clinically recognized pregnancies was to investigate whether fever during first trimester was associated with an increased risk of congenital malformations in the offspring. METHODS: The Danish National Birth Cohort is a population-based cohort of 100,418 pregnant women and their offspring recruited in 1996 to 2002. Information on fever during pregnancy was collected prospectively by means of two telephone interviews. The study population comprised the 77,344 pregnancies enrolled in the Danish National Birth Cohort where self-reported information on fever during first trimester of pregnancy was available. Pregnancy outcomes were identified through linkage with the National Patient Registry. Congenital malformations within the first three and a half years of life were categorized according to EUROCAT's classification criteria. Logistic regression models were used to estimate the associations between fever in first trimester and overall congenital malformations and congenital malformations by subgroups. RESULTS: Eight thousand three hundred twenty-one women reported fever during first trimester (10.8%) and 2876 infants were diagnosed with a congenital malformation (3.7%). Fever during first trimester did not affect the risk of overall fetal congenital malformation (OR 0.99, 95% CI 0.88-1.12). The subgroup analyses indicated slightly higher risk of congenital anomalies in the eye, ear, face and neck (OR 1.29, 95% CI 0.78-2.12) and in the genitals (OR 1.17, 95% CI 0.79-1.12), whereas lower risk of malformations in the nervous system (OR 0.47, 95% CI 0.21-1.08), the respiratory system (OR 0.56, 95% CI 0.23-1.29) and in the urinary subgroup (OR 0.58, 95% CI 0.35-0.99) was suggested, the latter constituting the only statistically significant finding. CONCLUSIONS: Overall, this study did not show any association between maternal fever in pregnancy and risk of congenital anomalies.

Advanced paternal age and mortality of offspring under 5 years of age: a register-based cohort study.

STUDY QUESTION: Do children born to fathers of advanced age have an increased risk of dying before the age of 5 years? SUMMARY ANSWER: Children born to fathers aged 40 years or more have an increased risk of dying in early childhood due to an excess risk of fatal congenital anomalies, malignancies and external causes. WHAT IS KNOWN ALREADY: Advanced paternal age has previously been associated with adverse reproductive outcomes and some long-term health problems in the offspring. This is possibly due to specific point mutations, a condition known to increase in the sperm with increasing paternal age. STUDY DESIGN, SIZE, DURATION: A Danish population-based register study, designed as a prospective cohort study, of 1 575 521 live born children born from 1978 to 2004. The age of the child (in days) was used as the underlying time and the children entered the cohort the day they were born and were followed until 31 December 2009. The children were censored on date of turning 5 years, date of death or date of emigration, whichever occurred first. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data from population-covering registers from Statistics Denmark including the Integrated Database for Labour Market Research, the Medical Birth Registry and the Registry of Causes of Death was linked using the unique civil registry number. Hazard ratios (HR) with 95% confidence intervals (CI) were used to estimate the risk of under-five mortality. The effect of paternal age was examined using restricted cubic splines and paternal age groups. MAIN RESULTS AND THE ROLE OF CHANCE: Compared with children born to fathers aged 30-34 years, a statistically significant excess risk was found for children born to fathers aged 40-44 years [HR: 1.10 (95% CI: 1.00-1.21)] and children born to fathers aged 45+ years [HR: 1.16 (95% CI: 1.02-1.32)]. When only looking at 1-5 year olds, the relative risk (HR) among children born to fathers aged 40-44 years increased to 1.24 (95% CI: 1.00-1.53) and the risk in the oldest paternal age group (45+ years) rose to 1.65 (95% CI: 1.24-2.18). The results suggest that the elevated risk for children of fathers aged 40 years or more was primarily attributed to an elevated risk of dying from congenital malformations, malignancies and external causes. LIMITATIONS, REASONS FOR CAUTION: Specific causes of death might be misclassified; however, this is not likely to be dependent on paternal age. In some cases, the biological father may differ from the father registered. This misclassification is most likely non-differential. WIDER IMPLICATIONS OF THE FINDINGS: The excess risk of mortality among children born to older fathers is in accordance with the literature. The association needs further attention as it can provide valuable knowledge of the etiology of genetic diseases. Also, the association could become of greater importance in the future if the proportion of fathers aged 40+ years keeps growing. STUDY FUNDING/COMPETING INTEREST (S): None.