Genetic effects on the timing of parturition and links to fetal birth weight.

The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of gestational duration (n = 195,555), identifying 22 associated loci (24 independent variants) and an enrichment in genes differentially expressed during labor. A meta-analysis of preterm delivery (18,797 cases, 260,246 controls) revealed six associated loci and large genetic similarities with gestational duration. Analysis of the parental transmitted and nontransmitted alleles (n = 136,833) shows that 15 of the gestational duration genetic variants act through the maternal genome, whereas 7 act both through the maternal and fetal genomes and 2 act only via the fetal genome. Finally, the maternal effects on gestational duration show signs of antagonistic pleiotropy with the fetal effects on birth weight: maternal alleles that increase gestational duration have negative fetal effects on birth weight. The present study provides insights into the genetic effects on the timing of parturition and the complex maternal-fetal relationship between gestational duration and birth weight.

Maternal characteristics and pregnancy outcomes in the NICE birth cohort: an assessment of self-selection bias.

BACKGROUND: Prospective birth cohorts are essential for identifying associations between exposures and outcomes. However, voluntary participation introduces a potential bias due to self selection since the persons that chose to participate may differ in background characteristics and behaviors. OBJECTIVES: To investigate potential bias due to self-selection in the Nutritional impact on Immunological maturation during Childhood in relation to the Environment (NICE) birth cohort in northern Sweden. METHODS: Women in the NICE birth cohort (N = 621) were compared to nonparticipating pregnant women in Norrbotten County in northern Sweden who were eligible for participation (N = 4976) regarding maternal characteristics and lifestyle. Maternal characteristics and pregnancy outcomes were compared between the groups and associations between exposures (smoking, folic acid, BMI, parity, education) and pregnancy outcomes (birth weight and gestational age) were analyzed by linear regression analyses, examining any interaction with the group. RESULTS: NICE participants were more highly educated, older and more likely to cohabit than the non-participants. They more often took folic acid and multivitamin supplements and less often smoked during early pregnancy. Pregnancy outcomes (mode of delivery, gestational age at delivery, birth weight and APGAR score) did, however, not differ significantly between participants and non-participants. Smoking, BMI, education and parity affected gestational age and birth weight, but the associations were of similar magnitude in participants and non-participants, with no significant effect on the group. CONCLUSION: Self-selection to the NICE study was evident in some factors related to lifestyle and socioeconomic characteristics but did not appear to skew pregnancy outcomes or alter well-known effects of certain lifestyle parameters on 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.

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 investigated 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 µg/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. Adhering to the dietary recommendations may help ensure an adequate supply of selenium for a healthy pregnancy and optimal fetal development.

Autozygosity mapping and time-to-spontaneous delivery in Norwegian parent-offspring trios.

Parental genetic relatedness may lead to adverse health and fitness outcomes in the offspring. However, the degree to which it affects human delivery timing is unknown. We use genotype data from ≃25 000 parent-offspring trios from the Norwegian Mother, Father and Child Cohort Study to optimize runs of homozygosity (ROH) calling by maximizing the correlation between parental genetic relatedness and offspring ROHs. We then estimate the effect of maternal, paternal and fetal autozygosity and that of autozygosity mapping (common segments and gene burden test) on the timing of spontaneous onset of delivery. The correlation between offspring ROH using a variety of parameters and parental genetic relatedness ranged between -0.2 and 0.6, revealing the importance of the minimum number of genetic variants included in an ROH and the use of genetic distance. The optimized compared to predefined parameters showed a ≃45% higher correlation between parental genetic relatedness and offspring ROH. We found no evidence of an effect of maternal, paternal nor fetal overall autozygosity on spontaneous delivery timing. Yet, through autozygosity mapping, we identified three maternal loci TBC1D1, SIGLECs and EDN1 gene regions reducing the median time-to-spontaneous onset of delivery by ≃2-5% (P-value < 2.3 × 10-6). We also found suggestive evidence of a fetal locus at 3q22.2, near the RYK gene region (P-value = 2.0 × 10-6). Autozygosity mapping may provide new insights on the genetic determinants of delivery timing beyond traditional genome-wide association studies, but particular and rigorous attention should be given to ROH calling parameter selection.

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.

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 ρ = 0.32 (95% confidence interval (CI): 0.31, 0.33) for full siblings with one-year gap to ρ = 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 ρ = 0.28 (95% CI: 0.26, 0.3) in 1973, and ρ = 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.

[Preterm delivery: an overview on epidemiology, pathophysiology and consequences for the individual and the society]. / Förtidsbörd största perinatala problemet - 5,7 procent av graviditeter i Sverige slutar för tidigt, inte klarlagt varför ­ kostar miljardbelopp varje år.

Preterm delivery in Sweden constitutes 5.7 % of all deliveries, which is among the lowest rates in the world. There has not been any increase in the proportion of iatrogenic preterm deliveries during the last decades.The main hypothesis concerning the causality of preterm delivery is still that of the ascending infection from the vagina to the uterus and inflammation resulting in contractions, rupture of membranes and delivery. The mechanisms behind parturition at term are still elusive and this is also true for preterm delivery. The genetic contribution to preterm delivery is about 25-30 %. The first genes that are associated with preterm delivery and gestational duration have recently been published. Huge progress has been made in care of preterm born infants. Sweden has among the lowest rates of mortality and morbidity in the world, especially in the lowest gestational weeks. New modes of care, family-centered care and hospital-assisted home care, have empowered the parents and reduced the cost for care.

Long-term Risk of Neuropsychiatric Disease After Exposure to Infection In Utero.

Importance: The developmental origins of mental illness are incompletely understood. Although the development of autism and schizophrenia are linked to infections during fetal life, it is unknown whether more common psychiatric conditions such as depression might begin in utero. Objective: To estimate the risk of psychopathologic conditions imparted from fetal exposure to any maternal infection while hospitalized during pregnancy. Design, Setting, and Participants: A total of 1 791 520 Swedish children born between January 1, 1973, and December 31, 2014, were observed for up to 41 years using linked population-based registries. Children were excluded if they were born too late to contribute person-time, died before being at risk for the outcome, or were missing particular model data. Infection and psychiatric diagnoses were derived using codes from hospitalizations. Directed acyclic graphs were developed from a systematic literature review to determine Cox proportional hazards regression models for risk of psychopathologic conditions in the children. Results were evaluated using probabilistic and simple bias analyses. Statistical analysis was conducted from February 10 to October 17, 2018. Exposures: Hospitalization during pregnancy with any maternal infection, severe maternal infection, and urinary tract infection. Main Outcomes and Measures: Inpatient diagnosis of autism, depression, bipolar disorder, or psychosis among offspring. Results: A total of 1 791 520 Swedish-born children (48.6% females and 51.4% males) were observed from birth up to age 41 years, with a total of 32 125 813 person-years. Within the directed acyclic graph framework of assumptions, fetal exposure to any maternal infection increased the risk of an inpatient diagnosis in the child of autism (hazard ratio [HR], 1.79; 95% CI, 1.34-2.40) or depression (HR, 1.24; 95% CI, 1.08-1.42). Effect estimates for autism and depression were similar following a severe maternal infection (autism: HR, 1.81; 95% CI, 1.18-2.78; depression: HR, 1.24; 95% CI, 0.88-1.73) or urinary tract infection (autism: HR, 1.89; 95% CI, 1.23-2.90; depression: HR, 1.30; 95% CI, 1.04-1.61) and were robust to moderate unknown confounding. Within the directed acyclic graph framework of assumptions, the relationship between infection and depression was vulnerable to bias from loss to follow-up, but separate data from the Swedish Death Registry demonstrated increased risk of suicide among individuals exposed to pregnancy infection. No evidence was found for increased risk of bipolar disorder or psychosis among children exposed to infection in utero. Conclusions and Relevance: These findings suggest that fetal exposure to a maternal infection while hospitalized increased the risk for autism and depression, but not bipolar or psychosis, during the child's life. These results emphasize the importance of avoiding infections during pregnancy, which may impart subtle fetal brain injuries contributing to development of autism and depression.

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

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.

Levels of exhaled carbon monoxide in healthy active and passive smokers.

BACKGROUND: Cigarette smoke is the major and most common indoor source of carbon monoxide. CO combines with haemoglobin to form carboxyhaemoglobin (COHb) which hinders oxygen transport and causes myocardial infarction and coronary heart disease. CO damages the endothelium of large and medium arteries and contributes to the development of atherosclerosis. MATERIAL AND METHOD: Participants in the study included 148 active and 306 passive smokers. In both groups the largest proportion of respondents were aged 30-49. Numbers of male and female participants were identical among the active smokers, while the majority of the passive smokers were women. Majority of the participants in both groups lived in large towns (over 100,000 inhabitants). The levels of exhaled CO were measured with Micro+smokerlyzer distributed in Poland by Synecpol. Every participant was provided with relevant instructions and the test was conducted by trained researchers. RESULTS: The mean level of exhaled carbon monoxide in active smokers was 12.57 ppm with higher levels found in men. The highest mean level of eCO was found in participants with body weight between 60 kg and 80 kg (mean eCO = 13.39 ppm). The highest levels were observed in participants living in towns with 51,000-100,000 inhabitants. In passive smokers, the mean level of exhaled carbon monoxide was 3.55 +/- 1.26 ppm with higher levels found in men. CONCLUSIONS: For non-smokers, the study identified a significant relationship between the level of exhaled CO and the participants' gender (p < 0.05), weight (p = 0.003), and height (p = 0.0005). For smokers, there is a relationship between the level of eCO and the daily cigarette consumption (p = 0.01), the type of cigarettes most frequently smoked (p < 0.05) and the favoured cigarette brand (p = 0.005).

[Analysis of the PNIF measurement (Peak Nas Inspiratory Flow) in ECAP study (The Epidemiology of Allergic Diseases in Poland)]. / Analiza wyników badania PNIF (Peak Nasal Inspiratory Flow) w swietle badan ECAP (Epidemiologia Chorób Alergicznych w Polsce).

INTRODUCTION: Measurement of PNIF is often used as a indicator in provocation studies or used for assessment the therapeutic effect of medicines. Unfortunately, there is a lack of norm for this parameter. Therefore, the aim of this study was to assess a few variables which are advisable to estimate the norm for PNIF measurements. MATERIAL AND METHODS: The study was a part of the ECAP study (The Epidemiology of Allergic Diseases in Poland). Study group was selected randomly: children aged 6-7, 13-14 and adults. Subjects were inhabitants of 8 cities: Bialystok, Gdansk, Katowice, Kraków, Lublin, Poznan, Warszawa i Wroclaw and one village district: zamojski and krasnystawski. PNIF level had been measured among qualified respondents by In-Check inspiratory flow meter manufactured by Clement. Clark. PNIF level was measured before and after application of Oxalin (0,05%) aimed at improve patency of nasal passages. The study was conducted three times, the highest value was noted. RESULTS: There were 4674 qualified subjects, of which 27,6% were children aged 6-7, 27,7%-children aged 13-14 and 44,7%-adults. Results were quantified by Statistica 10 programme and Microsoft Excel programme. Analysis were conducted in regards of sex, age, health status and study area. SEX: Statistically significant higher level of PNIF, as before as after application of medicine, were observed among man than woman. Average level of PNIF after application of medicine among adult man were 151,99 l/min (SD=61,73 l/min), boys aged 13-14-127,62 l/min (SD=53,0), boys aged 6-7- 54,44 l/min (SD=33,44 l/min). Average level of PNIF after application of medicine among adult woman were 119,31 l/min (SD= 45,71 l/min), girls aged 13-14- 109,13 l/min (SD=42,86 l/ min), girls aged 6-7- 61,35 l/min (SD= 31,56 l/min). AGE: There was observed statistically significant difference between age's groups. Average level of PNIF among adults were 131,91 l/min (SD=54,82 l/min), children aged 13-14- 118,68 l/min (SD=49,23 l/min), children aged 6-7- 64,27 l/min (SD=32,64 l/min). Health status: Statistically significant higher level of PNIF were observed among healthy people than sick subjects, among all age's group, except among children aged 6-7. Average level of PNIF, after application of medicine were following: among adults: sick - 128,94 l/min (SD=54,66 l/min), healthy-134,94 l/min (SD=54,84 l/min), children aged 13-14: sick- 116,73 l/min (SD=48,48 l/min), healthy- 120,68 l/min (SD=49,92 l/min) and children aged 6-7: sick- 64,8 l/min (SD=32,25 l/min), healthy- 63,79 l/min (SD=33,0 l/min). Also there was noted statistically significant difference between subject with periodic allergic rhinitis than chronic allergic rhinitis. STUDY AREA: Statistically significant higher level of PNIF was observed among subjects living in urban area than rural area, as before as after application of medicine, among all age's groups. CONCLUSIONS: There were found statistically significant differences between age, sex, health status and study area. PNIF measurement is valuable study assessing. PNIF measurement is valuable parameter assessing rhinitis status.