Importance of the environment for gestational duration variability and correlation between relatives - results from the Medical Swedish Birth Registry, 1973-2012

It has been suggested that the intergenerational associations in gestational age at delivery are considerably affected by temporal changes in the environmental conditions. We explored whether changing environment affects familial resemblance of gestational age at delivery. Understanding how correlation changes in different settings allows to design better studies aimed to detect genes and environmental factors involved in the parturition process. The Swedish Medical Birth Register was used to retrieve births during 1973-2012. In total, 454,433 parent-child, 2,247,062 full sibling, 405,116 maternal half-sibling and 469,995 paternal half-sibling pairs were identified. A decreasing trend in correlation, associated with increasing age gaps, was observed among all siblings, with the largest drop for full siblings, from p = 0.32 (95% confidence interval (CI): 0.31, 0.33) for full siblings with one-year gap to p = 0.16 (95% CI: 0.10, 0.22) for full siblings with age gap above 20 years. A variation in association between full siblings born up to two years apart was observed; estimate p = 0.28 (95% CI: 0.26, 0.3) in 1973, and p = 0.36 (95% CI: 0.33, 0.38) in 2012. Observed variability in the association in gestational age at delivery between the relatives with respect to their birth year or age gap suggests the existence of temporally changing environmental factors

Placental weight centiles adjusted for age, parity and fetal sex

Introduction The weight of the placenta can be indicative of efficacy in nutrient and oxygen supply. Furthermore, it has been suggested that a measure of the placenta's ability to adequately supply nutrients to the fetus can be found in the relationship between birth weight and placental weight expressed as a ratio. Our aim was to develop age adjusted placenta weight and birth weight to placenta weight ratio reference curves that are stratified by maternal parity and fetal sex. Methods We included singleton, non-anomalous births with a gestational age inclusive of 28 + 0 weeks to 42 + 6 weeks. Excluded were pregnancies of multiplicity, fetuses with congenital abnormalities, stillbirths and pregnancies that had placental complications (ie placenta previa or abruption). Generalised additive model for location, shape and scale (GAMLSS) was used to fit reference curves. Results We stratified 97,882 pregnancies by maternal nulliparity status and fetal sex. Extensive assessment model goodness-of-fit showed appropriate modeling and accurate fit to the four parameters of distribution. Our results show accurate model fit of the reference curves to the data. We demonstrated that the influence that parity has on the placenta weight is far greater than that exerted by fetal sex, and that the difference is dependent on gestational age. Discussion This is the largest presentation of age and parity adjusted placenta weight and feto-placental weight ratio reference ranges to date. The difference observed between nulliparous and multiparous pregnancies could be explained by biological memory and the remnants of maternal endo-myometrial vascularity after the first pregnancy.publishedVersio

Maternal dietary selenium intake during pregnancy and neonatal outcomes in the norwegian mother, father, and child cohort study

Properly working antioxidant defence systems are important for fetal development. One of the nutrients with antioxidant activity is selenium. Increased maternal selenium intake has been associated with reduced risk for being small for gestational age and preterm delivery. Based on the Norwegian Mother, Father, and Child Cohort Study and the Medical Birth Registry of Norway, we in-vestigated the association of maternal selenium intake from food and dietary supplements during the first half of pregnancy (n = 71,728 women) and selenium status in mid-pregnancy (n = 2628 women) with neonatal health, measured as two composite variables (neonatal morbidity/mortality and neonatal intervention). Low maternal dietary selenium intake (<30 \ub5g/day) was associated with increased risk for neonatal morbidity/mortality (adjusted odds ratio (adjOR) 1.36, 95% confidence interval (95% CI) 1.08–1.69) and neonatal intervention (adjOR 1.16, 95% CI 1.01–1.34). Using continuous variables, there were no associations between maternal selenium intake (from diet or supplements) or whole-blood selenium concentration and neonatal outcome in the adjusted models. Our findings suggest that sufficient maternal dietary selenium intake is associated with neonatal outcome. Adher-ing to the dietary recommendations may help ensure an adequate supply of selenium for a healthy pregnancy and optimal fetal development

Methodological considerations in epidemiological studies in perinatal medicine

This thesis is based on two projects, each consisting of two papers. In these two projects we investigated factors affecting the variability in gestational duration, and associations between maternal diet and neonatal outcomes. In the first project we investigated factors affecting the variability in gestational duration with a particular interest in the genetic contributions. The contribution of genetic factors to trait’s variability is estimated by heritability analysis. For gestational duration, heritability estimates are up to 36%. However, genetic studies have identified a limited number of genetic variants. In the first project we aimed to assess whether an essential assumption underlying heritability analysis, constant environmental conditions, holds. In Paper I, we observed a substantial variability in the correlation estimate in gestational age at delivery between relatives with respect to their year of birth or age gap. This variability suggests the existence of temporally changing environmental factors. In Paper II, we showed that obstetrical practices and data handling contribute to changes in gestational duration over time. Two studies in this project suggest that the assumption of constant environmental conditions might not hold. This might explain the dissonance between the conclusions of heritability and genetic studies. The second project was an extension of previous studies performed in our research group. In these studies, we detected associations between maternal caffeine or selenium intakes and small for gestational age (SGA), and SGA and neonatal outcomes. Therefore, we hypothesized that the selected maternal food components and neonatal outcomes would be associated. In both studies (Papers III and IV), we did not detect associations between maternal caffeine or selenium intake and neonatal outcomes. The lack of associations may be the result of SGA babies having different neonatal outcomes based on the underlying SGA cause. One type of SGA might be related to maternal caffeine/selenium intake and not associated with neonatal outcomes; the other types might be caused by more aggressive factors leading to worse performance in the neonatal period. The results warrant caution when using SGA as a representation for neonatal outcomes

Caffeine exposure during pregnancy, small for gestational age birth and neonatal outcome – results from the Norwegian Mother and Child Cohort Study

Abstract Background Maternal caffeine intake has repeatedly been linked to babies being born small for gestational age (SGA). SGA babies are known to be at increased risk for adverse neonatal outcomes. The aim of this study was to explore the associations between prenatal caffeine exposure and neonatal health. Methods The study is based on 67,569 full-term singleton mother-infant pairs from the Norwegian Mother and Child Cohort Study. Caffeine consumption from different sources was self-reported in gestational week 22. Neonatal compound outcomes, namely (1) morbidity/mortality and (2) neonatal intervention, were created based on the Medical Birth Registry of Norway. Adjusted logistic regression was performed. Results Caffeine exposure was associated to SGA (OR = 1.16, 95%CI: 1.10; 1.23) and being born SGA was significantly associated with neonatal health (OR = 3.09, 95%CI: 2.54; 3.78 for morbidity/mortality; OR = 3.94, 95%CI: 3.50; 4.45 for intervention). However, prenatal caffeine exposure was neither associated with neonatal morbidity/mortality (OR = 1.01, 95%CI: 0.96; 1.07) nor neonatal intervention (OR = 1.02, 95%CI: 1.00; 1.05 for a 100 mg caffeine intake increase). Results did not change after additional adjustment for SGA status. Conclusions Moderate prenatal caffeine exposure (< 200 mg/day) does not seem to impair neonatal health, although prenatal caffeine exposure is associated with the child being born SGA and SGA with neonatal health. We suggest diversity in neonatal outcomes of SGA infants according to the underlying cause of low birth weight

Placental weight centiles adjusted for age, parity and fetal sex

Introduction The weight of the placenta can be indicative of efficacy in nutrient and oxygen supply. Furthermore, it has been suggested that a measure of the placenta's ability to adequately supply nutrients to the fetus can be found in the relationship between birth weight and placental weight expressed as a ratio. Our aim was to develop age adjusted placenta weight and birth weight to placenta weight ratio reference curves that are stratified by maternal parity and fetal sex. Methods We included singleton, non-anomalous births with a gestational age inclusive of 28 + 0 weeks to 42 + 6 weeks. Excluded were pregnancies of multiplicity, fetuses with congenital abnormalities, stillbirths and pregnancies that had placental complications (ie placenta previa or abruption). Generalised additive model for location, shape and scale (GAMLSS) was used to fit reference curves. Results We stratified 97,882 pregnancies by maternal nulliparity status and fetal sex. Extensive assessment model goodness-of-fit showed appropriate modeling and accurate fit to the four parameters of distribution. Our results show accurate model fit of the reference curves to the data. We demonstrated that the influence that parity has on the placenta weight is far greater than that exerted by fetal sex, and that the difference is dependent on gestational age. Discussion This is the largest presentation of age and parity adjusted placenta weight and feto-placental weight ratio reference ranges to date. The difference observed between nulliparous and multiparous pregnancies could be explained by biological memory and the remnants of maternal endo-myometrial vascularity after the first pregnancy

Changes in data management contribute to temporal variation in gestational duration distribution in the Swedish Medical Birth Registry

Multiple factors contribute to gestational duration variability. Understanding the sources of variability allows to design better association studies and assess public health measures. Here, we aimed to assess geographical and temporal changes in the determination of gestational duration and its reporting in Sweden between 1973 and 2012. Singleton live births between 1973 and 2012 were retrieved from the Swedish Medical Birth Register. Gestational duration trends in percentiles and rates of pre- and post-term deliveries were analyzed by plotting the values over time. Temporal changes in gestational duration based on ultrasound and last menstrual period (LMP) estimation methods were compared. Intervals between LMP date and LMP-based due date were analyzed to assess changes in expected gestational duration. In total, 3 940 577 pregnancies were included. From 1973 until 1985, the median of gestational duration estimated based on LMP or ultrasound decreased from 283 to 278 days, and remained stable until 2012. The distribution was relatively stable when ultrasound-based estimates were used. Until the mid-1990s, there was a higher incidence than expected of births occurring on every seventh gestational day from day 157 onward. On an average, these gestational durations were reported 1.8 times more often than adjacent durations. Until 1989, the most common expected gestational duration was 280 days, and thereafter, it was 279 days. The expected gestational duration varied from 279 to 281 days across different Swedish counties. During leap years, the expected gestational duration was one day longer. Consequently, leap years were also associated with significantly higher preterm and lower post-term delivery rates than non-leap years. Changes in data handling and obstetrical practices over the years contribute to gestational duration variation. The resulting increase in variability might reduce precision in association studies and hamper the assessment of public health measures aimed to improve pregnancy outcomes

Placental weight centiles adjusted for age, parity and fetal sex

Introduction The weight of the placenta can be indicative of efficacy in nutrient and oxygen supply. Furthermore, it has been suggested that a measure of the placenta's ability to adequately supply nutrients to the fetus can be found in the relationship between birth weight and placental weight expressed as a ratio. Our aim was to develop age adjusted placenta weight and birth weight to placenta weight ratio reference curves that are stratified by maternal parity and fetal sex. Methods We included singleton, non-anomalous births with a gestational age inclusive of 28 + 0 weeks to 42 + 6 weeks. Excluded were pregnancies of multiplicity, fetuses with congenital abnormalities, stillbirths and pregnancies that had placental complications (ie placenta previa or abruption). Generalised additive model for location, shape and scale (GAMLSS) was used to fit reference curves. Results We stratified 97,882 pregnancies by maternal nulliparity status and fetal sex. Extensive assessment model goodness-of-fit showed appropriate modeling and accurate fit to the four parameters of distribution. Our results show accurate model fit of the reference curves to the data. We demonstrated that the influence that parity has on the placenta weight is far greater than that exerted by fetal sex, and that the difference is dependent on gestational age. Discussion This is the largest presentation of age and parity adjusted placenta weight and feto-placental weight ratio reference ranges to date. The difference observed between nulliparous and multiparous pregnancies could be explained by biological memory and the remnants of maternal endo-myometrial vascularity after the first pregnancy.publishedVersio