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RationaleExperimental studies suggest that exposures may impact respiratory health across generations via epigenetic changes transmitted specifically through male germ cells. Studies in humans are however limited. We aim to identify epigenetic marks in offspring associated with father’s preconception smoking.MethodsWe conducted epigenome-wide association studies (EWAS) in the RHINESSA cohort on father’s any preconception smoking (N=875 offspring) and father’s pubertal onset smoking ResultsFather’s smoking commencing preconception was associated with methylation of blood DNA in offspring at two Cytosine-phosphate-Guanine sites (CpGs) (False Discovery Rate (FDR) PRR5andCENPP. Father’s pubertal onset smoking was associated with 19 CpGs (FDR TLR9, DNTT, FAM53B, NCAPG2, PSTPIP2, MBIP, C2orf39, NTRK2, DNAJC14, CDO1, PRAP1, TPCN1, IRS1andCSF1R). These differentially methylated sites were hypermethylated and associated with promoter regions capable of gene silencing. Some of these sites were associated with offspring outcomes in this cohort including ever-asthma (NTRK2), ever-wheezing (DNAJC14, TPCN1), weight (FAM53B, NTRK2) and BMI (FAM53B, NTRK2) (P< 0.05). Pathway analysis showed enrichment for gene ontology pathways including regulation of gene expression, inflammation and innate immune responses.ConclusionFather’s preconception smoking, particularly in puberty, is associated with offspring DNA methylation, providing evidence that epigenetic mechanisms may underly epidemiological observations that pubertal paternal smoking increases risk of offspring asthma, low lung function and obesity.

Emerging evidence suggests that exposures in prepuberty, particularly in fathers-to-be, may impact the phenotype of future offspring. Analyses of the RHINESSA cohort find that offspring of father’s exposed to tobacco smoking or overweight that started in prepuberty demonstrate poorer respiratory health in terms of more asthma and lower lung function. A role of prepuberty onset smoking for offspring fat mass is suggested in the RHINESSA and ALSPAC cohorts, and historic studies suggest that ancestral nutrition during prepuberty plays a role for grand-offspring’s health and morbidity. Support for causal relationships between ancestral exposures and (grand-)offspring’s health in humans has been enhanced by advancements in statistical analyses that optimize the gain while accounting for the many complexities and deficiencies in human multigeneration data. The biological mechanisms underlying such observations have been explored in experimental models. A role of sperm small RNA in the transmission of paternal exposures to offspring phenotypes has been established, and chemical exposures and overweight have been shown to influence epigenetic programming in germ cells. For example, exposure of adolescent male mice to smoking led to differences in offspring weight and alterations in small RNAs in the spermatozoa of the exposed fathers. It is plausible that male prepuberty may be a time window of particular susceptibility, given the extensive epigenetic reprogramming taking place in the spermatocyte precursors at this age. In conclusion, epidemiological studies in humans, mechanistic research, and biological plausibility, all support the notion that exposures in the prepuberty of males may influence the phenotype of future offspring., Emerging research from human multigeneration cohorts, historic studies, and mechanistic research indicates that prepuberty is an important window of susceptibility with regard to health and disease of future offspring.

Emerging research suggests environmental exposures before conception may adversely affect allergies and lung diseases in future generations. Most studies are limited as they have focused on single exposures, not considering that these diseases have a multifactorial origin in which environmental and lifestyle factors are likely to interact. Traditional exposure assessment methods fail to capture the interactions among environmental exposures and their impact on fundamental biological processes, as well as individual and temporal factors. A valid estimation of exposure preconception is difficult since the human reproductive cycle spans decades and the access to germ cells is limited. The exposome is defined as the cumulative measure of external exposures on an organism (external exposome), and the associated biological responses (endogenous exposome) throughout the lifespan, from conception and onwards. An exposome approach implies a targeted or agnostic analysis of the concurrent and temporal multiple exposures, and may, together with recent technological advances, improve the assessment of the environmental contributors to health and disease. This review describes the current knowledge on preconception environmental exposures as related to respiratory health outcomes in offspring. We discuss the usefulness and feasibility of using an exposome approach in this research, advocating for the preconception exposure window to become included in the exposome concept.

Publisher's version (útgefin grein), Objective: Most women live to experience menopause and will spend 4–8 years transitioning from fertile age to full menstrual stop. Biologically, reproductive ageing is a continuous process, but by convention, it is defined categorically as pre-, peri- and postmenopause; categories that are sometimes supported by measurements of sex hormones in blood samples. We aimed to develop and validate a new tool, a reproductive ageing score (RAS), that could give a simple and yet precise description of the status of reproductive ageing, without hormone measurements, to be used by health professionals and researchers. Methods: Questionnaire data on age, menstrual regularity and menstrual frequency was provided by the large multicentre population-based RHINE cohort. A continuous reproductive ageing score was developed from these variables, using techniques of fuzzy mathematics, to generate a decimal number ranging from 0.00 (nonmenopausal) to 1.00 (postmenopausal). The RAS was then validated with sex hormone measurements (follicle stimulating hormone and 17β-estradiol) and interview-data provided by the large population-based ECRHS cohort, using receiver-operating characteristics (ROC). Results: The RAS, developed from questionnaire data of the RHINE cohort, defined with high precision and accuracy the menopausal status as confirmed by interview and hormone data in the ECRHS cohort. The area under the ROC curve was 0.91 (95% Confidence interval (CI): 0.90–0.93) to distinguish nonmenopausal women from peri- and postmenopausal women, and 0.85 (95% CI: 0.83–0.88) to distinguish postmenopausal women from nonmenopausal and perimenopausal women. Conclusions: The RAS provides a useful and valid tool for describing the status of reproductive ageing accurately, on a continuous scale from 0.00 to 1.00, based on simple questions and without requiring blood sampling. The score allows for a more precise differentiation than the conventional categorisation in pre-, peri- and postmenopause. This is useful for epidemiological research and clinical trials., We thank all participants, field workers and coordinators of the RHINE study and the ECRHS for their efforts as well as Ersilia Bifulco and Sandra Suske from the Core Facility for Metabolomics at the University of Bergen where the hormone measurements were performed. Further we are very grateful for the support of the Department of Applied Mathematics of the University of Málaga (Spain) and we want to thank Elinor Bartle for revising grammar and language.

Objective: Some studies of women with polycystic ovary syndrome (PCOS) report increased prevalence of hypertensive disorders in pregnancy, while others do not. Several of these studies do not control for obesity. We aimed to study whether PCOS is associated with hypertensive disorders in pregnancy and whether it is dependent on body mass index (BMI). Study design: We present a cross-sectional analysis of 3732 women from Denmark, Estonia, Iceland, Norway and Sweden, born in 1945–72, who participated in the Respiratory Health In Northern Europe (RHINE) study and answered an extensive women's health questionnaire on menstruation, PCOS, infertility, pregnancy history and childbirth. The main outcome measurement was hypertensive disorders of pregnancy. We adjusted for smoking, age, infertility treatment and study center. Effect modification by BMI was assessed. Results: PCOS was related to hypertensive disorders in pregnancy with a relative risk (RR) of 1.62 (95% CI 1.09–2.42). This relationship was found among underweight women with a BMI of 2 [RR = 5.2 (95% CI 1.66–16.5)] and obese women with a BMI of ≥30 kg/m 2 [RR = 2.36 (95% CI 1.29–4.31)], but not among normal-weight women, BMI 18.5–25 kg/m 2 [1.08 (0.53–2.20)], or overweight women, BMI 25–30 kg/m 2 [1.24 (0.50–3.08)] (p-interaction = 0.041). Conclusion: Polycystic ovary syndrome is associated with hypertensive disorders in pregnancy. This association only occurs among underweight and obese women and not among normal-weight and slightly overweight women.

Epidemiological studies suggest that father’s smoking might influence their future children’s health, but few studies have addressed whether paternal line effects might be related to altered DNA methylation patterns in the offspring. To investigate a potential association between fathers’ smoking exposures and offspring DNA methylation using epigenome-wide association studies. We used data from 195 males and females (11–54 years) participating in two population-based cohorts. DNA methylation was quantified in whole blood using Illumina Infinium MethylationEPIC Beadchip. Comb-p was used to analyse differentially methylated regions (DMRs). Robust multivariate linear models, adjusted for personal/maternal smoking and cell-type proportion, were used to analyse offspring differentially associated probes (DMPs) related to paternal smoking. In sensitivity analyses, we adjusted for socio-economic position and clustering by family. Adjustment for inflation was based on estimation of the empirical null distribution in BACON. Enrichment and pathway analyses were performed on genes annotated to cytosine-phosphate-guanine (CpG) sites using the gometh function in missMethyl. We identified six significant DMRs (Sidak-corrected P values: 0.0006–0.0173), associated with paternal smoking, annotated to genes involved in innate and adaptive immunity, fatty acid synthesis, development and function of neuronal systems and cellular processes. DMP analysis identified 33 CpGs [false discovery rate (FDR)

Publisher's version (útgefin grein), Emerging evidence suggests that parents’ preconception exposures may influence offspring health. We aimed to investigate maternal and paternal smoking onset in specific time windows in relation to offspring body mass index (BMI) and fat mass index (FMI). We investigated fathers (n = 2111) and mothers (n = 2569) aged 39–65 years, of the population based RHINE and ECRHS studies, and their offspring aged 18–49 years (n = 6487, mean age 29.6 years) who participated in the RHINESSA study. BMI was calculated from self-reported height and weight, and FMI was estimated from bioelectrical impedance measures in a subsample. Associations with parental smoking were analysed with generalized linear regression adjusting for parental education and clustering by study centre and family. Interactions between offspring sex were analysed, as was mediation by parental pack years, parental BMI, offspring smoking and offspring birthweight. Fathers’ smoking onset before conception of the offspring (onset ≥15 years) was associated with higher BMI in the offspring when adult (β 0.551, 95%CI: 0.174–0.929, p = 0.004). Mothers’ preconception and postnatal smoking onset was associated with higher offspring BMI (onset, Co-ordination of the RHINESSA study has received funding from the Research Council of Norway (Grants No. 274767, 214123, 228174, 230827 and 273838), ERC StG project BRuSH #804199, the European Union's Horizon 2020 research and innovation program under grant agreement No. 633212 (the ALEC Study WP2), the Bergen Medical Research Foundation, and the Western Norwegian Regional Health Authorities (Grants No. 912011, 911892 and 911631). Study centres have further received local funding from the following: Bergen: the above grants for study establishment and co-ordination, and, in addition, World University Network (RDF and Sustainability grant), Norwegian Labour Inspection, and the Norwegian Asthma and Allergy Association. Albacete and Huelva: SEPAR. Fondo de Investigación Sanitaria (FIS PS09). Gøteborg, Umeå and Uppsala: the Swedish Lung Foundation, the Swedish Asthma and Allergy Association. Reykjavik: Iceland University. Melbourne: NHMRC, Melbourne University, Tartu: the Estonian Research Council (Grant No. PUT562). Århus: The Danish Wood Foundation (Grant No. 444508795), the Danish Working Environment Authority (Grant No. 20150067134). The RHINE study received funding by Norwegian Research Council, Norwegian Asthma and Allergy Association, Danish Lung Association, Swedish Heart and Lung Foundation, Vårdal Foundation for Health Care Science and Allergy Research, Swedish Asthma and Allergy Association, Swedish Lung Foundation, Icelandic Research Council, and Estonian Science Foundation. The co-ordination of ECRHS was supported by European Union's Horizon 2020 research and innovation program under grant agreement No. 633212 (the ALEC Study), the European Commission frameworks 5 and 7 (ECRHS I and II) and the Medical Research Council (ECRHS III).

Publisher's version (útgefin grein), Life course data on obesity may enrich the quality of epidemiologic studies analysing health consequences of obesity. However, achieving such data may require substantial resources. We investigated the use of body silhouettes in adults as a tool to reflect obesity in the past. We used large population-based samples to analyse to what extent self-reported body silhouettes correlated with the previously measured (9–23 years) body mass index (BMI) from both measured (European Community Respiratory Health Survey, N = 3 041) and self-reported (Respiratory Health In Northern Europe study, N = 3 410) height and weight. We calculated Spearman correlation between BMI and body silhouettes and ROC-curve analyses for identifying obesity (BMI ≥30) at ages 30 and 45 years. Spearman correlations between measured BMI age 30 (±2y) or 45 (±2y) and body silhouettes in women and men were between 0.62–0.66 and correlations for self-reported BMI were between 0.58–0.70. The area under the curve for identification of obesity at age 30 using body silhouettes vs previously measured BMI at age 30 (±2y) was 0.92 (95% CI 0.87, 0.97) and 0.85 (95% CI 0.75, 0.95) in women and men, respectively; for previously self-reported BMI, 0.92 (95% CI 0.88, 0.95) and 0.90 (95% CI 0.85, 0.96). Our study suggests that body silhouettes are a useful epidemiological tool, enabling retrospective differentiation of obesity and non-obesity in adult women and men., The project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 633212. The co-ordination of ECRHS I and ECRHS I was supported by the European Commission. The co-ordination of ECRHS III was supported by the Medical Research Council (Grant Number 92091). The co-ordination of the RHINE study is led by Professor C. Janson at the Uppsala University. The funding sources for the local ECRHS and RHINE studies are provided in the on-line supplement.

Background: Nicotine exposure can affect the epigenome of germ cells but little is known about routes of transmission or functional relevance in offspring Aim: To investigate associations between fathers´smoking and changes in offspring DNA methylation, and explore biological impact of methylated loci and annotated genes. Methods: DNA methylation (DNAm) of participants from multigenerational databases (Bergen centre ECRHS/RHINESSA n=98/95) was quantified in whole blood using the Illumina Infinium MethylationEPIC BeadChip. Robust multivariate linear model was used with offspring DNAm as outcome and paternal smoking as exposure, including relevant covariates (offspring/maternal smoking) and cell type proportion. ToppGene and topKEGG was used for pathway analysis. Results: Ever-smoking prevalence was 54% in offspring (mean age 31.3 years) and 42.1% in fathers. At False Discovery Rate (FDR) Conclusion: Fathers´smoking was associated with differential methylation in their children, in particular located to genes involved in Tobacco Use Disorder and ADHD, suggesting an epigenetic contribution and a paternal role in addiction susceptibility and behavioral dysfuntion. (Funding EU Grant 633212, HV)

RESULTS We found 26 maternal deaths during the period, 14 of which were due to direct causes and 12 to indirect causes. The maternal mortality ratio was 8.7/100 000 live births. Fourteen of the deaths were registered in official statistics. Of the 12 deaths that were not included in the statistics, 11 were found through matching the registers and one had been reported directly by the hospital. The most common causes of death were hypertensive disorders during pregnancy (n = 6), thromboembolism (n = 4) and mental illness (n = 4). None of the deaths due to thromboembolism appeared in official statistics. The same applied to nine of the 12 indirect maternal deaths. We found a potential for improved medical care in 14 of 26 cases. Half of these were deaths due to hypertensive disorders during pregnancy or thromboembolism. INTERPRETATION Maternal death was considerably underreported in Norwegian official statistics during the period studied. Greater attention should be given to better blood-pressure treatment, stabilisation and timely delivery in the case of hypertension during pregnancy, and to screening for possible pulmonary embolism. The same applies to mental illness and internal medical disorders in pregnant women.

BACKGROUND: Whereas it is generally accepted that maternal environment plays a key role in child health, emerging evidence suggests that paternal environment before conception also impacts child health. We aimed to investigate the association between children's asthma risk and parental smoking and welding exposures prior to conception.METHODS: In a longitudinal, multi-country study, parents of 24 168 offspring aged 2-51 years provided information on their life-course smoking habits, occupational exposure to welding and metal fumes, and offspring's asthma before/after age 10 years and hay fever. Logistic regressions investigated the relevant associations controlled for age, study centre, parental characteristics (age, asthma, education) and clustering by family.RESULTS: Non-allergic early-onset asthma (asthma without hay fever, present in 5.8%) was more common in the offspring with fathers who smoked before conception {odds ratio [OR] = 1.68 [95% confidence interval (CI) = 1.18-2.41]}, whereas mothers' smoking before conception did not predict offspring asthma. The risk was highest if father started smoking before age 15 years [3.24 (1.67-6.27)], even if he stopped more than 5 years before conception [2.68 (1.17-6.13)]. Fathers' pre-conception welding was independently associated with non-allergic asthma in his offspring [1.80 (1.29-2.50)]. There was no effect if the father started welding or smoking after birth. The associations were consistent across countries.CONCLUSIONS: Environmental exposures in young men appear to influence the respiratory health of their offspring born many years later. Influences during susceptible stages of spermatocyte development might be important and needs further investigation in humans. We hypothesize that protecting young men from harmful exposures may lead to improved respiratory health in future generations.

There is limited information about potential impact of maternal age on the respiratory health of offspring. We investigated the association of maternal age at delivery with adult offspring's lung function, respiratory symptoms and asthma, and potential differences according to offspring sex.10 692 adults from 13 countries participating in the European Community Respiratory Health Survey (ECRHS) II responded to standardised interviews and provided lung function measurements and serum for IgE measurements at age 25–55 years. In logistic and linear multilevel mixed models we adjusted for participants’ characteristics (age, education, centre, number of older siblings) and maternal characteristics (smoking in pregnancy, education) while investigating for differential effects by sex. Maternal age was validated in a subsample using data from the Norwegian birth registry.Increasing maternal age was associated with increasing forced expiratory volume in 1 s (2.33 mL per year, 95% CI 0.34–4.32 mL per year), more consistent in females (ptrend 0.025) than in males (ptrend 0.14). Asthma (OR 0.85, 95% CI 0.79–0.92) and respiratory symptoms (OR 0.87, 95% CI 0.82–0.92) decreased with increasing maternal age (per 5 years) in females, but not in males (pinteraction 0.05 and 0.001, respectively). The results were consistent across centres and not explained by confounding factors.Maternal ageing was related to higher adult lung function and less asthma/symptoms in females. Biological characteristics in offspring related to maternal ageing are plausible and need further investigation.

Objectives Umbilical venous pulsation is an important sign of hemodynamic compromise, but is also found under normal physiological conditions. Mathematical modeling suggests that vascular compliance is a determinant for pulsation, and we tested this by studying velocity pulsation at three sites on the umbilical vein. Methods In a cross-sectional study of 279 low-risk pregnancies (20–40 weeks' gestational age) blood flow velocity in the umbilical vein was determined before, within and after the umbilical ring in the fetal abdominal wall, and the incidence and magnitude of pulsation (the difference between the maximum and minimum velocity during a pulse, and pulsatility index) were noted. Based on the fact that the vessel cross-sectional area is an important determinant of compliance, we measured the diameter and time-averaged maximum velocity to reflect variation in diameter and compliance at the three sites. Results The incidence of umbilical venous pulsation was higher at the umbilical ring in the abdominal wall (242/279, 87%, 95% CI 82–90) than in the cord (43/198, 22%, 95%CI 16–27) or intra-abdominally (84/277, 30%, 95% CI 25–36) (P < 0.001). When pulsation was observed intra-abdominally, the pulsatility was not different from that at the umbilical ring (P = 0.16). However, the lowest pulsatility was found in the cord vein (P < 0.0001), where the largest vein diameter was found. Conclusion The high incidence of venous pulsation at the umbilical ring where diameter and compliance are low supports the suggestion that local compliance is an important factor influencing pulsation in fetal veins. Copyright © 2003 ISUOG. Published by John Wiley & Sons, Ltd.

Studies using mothers’ self-reported information on birth and pregnancy characteristics are common, but the validity of such data is uncertain. We evaluated questionnaire data from the RHINE III study on reproductive health provided by 715 mothers from Bergen, Norway, about their 1629 births between 1967 and 2010, using the Medical Birth Registry of Norway (MBRN) as gold standard. Validity of dichotomous variables (gender, preterm birth [42 weeks’ gestation], induction of labour, forceps delivery, vacuum delivery, caesarean section, were assessed by sensitivity, specificity, positive and negative predictive values (PPV and NPV) and Cohen’s kappa. Paired t-test, Pearson’s correlation coefficient and Bland-Altman plots were used to validate birthweight, stratified by mother’s level of education, parity, birth year and child’s asthma status. Child’s gender and caesarean section showed high degree of validity (kappa = 0.99, sensitivity and specificity 100%). Instrumental delivery and extremely preterm birth showed good agreement with sensitivity 75–92%. Preterm birth and induction of labour showed moderate agreement. Post-term delivery was poorly reported. The validity appeared to be independent of recall time over 45 years, and of the child’s asthma status. Maternally reported birth and pregnancy information is feasible and cheap, showed high validity for important birth and pregnancy parameters, and showed similar risk-associations compared to registry data.

Norway has low maternal mortality, but such deaths are underreported even in high-income countries. Our goal was to identify the exact number of maternal deaths, the causes of death and the potential for improvement through medical care in Norway.We traced maternal deaths in the period from 1 January 2005 to 31 December 2009 by linking the Medical Birth Registry and the Cause of Death Registry, supplemented with data from maternity clinics. We identified the cause of death and the lessons that could be learned by a meticulous review of each case.We found 26 maternal deaths during the period, 14 of which were due to direct causes and 12 to indirect causes. The maternal mortality ratio was 8.7/100,000 live births. Fourteen of the deaths were registered in official statistics. Of the 12 deaths that were not included in the statistics, 11 were found through matching the registers and one had been reported directly by the hospital. The most common causes of death were hypertensive disorders during pregnancy (n = 6), thromboembolism (n = 4) and mental illness (n = 4). None of the deaths due to thromboembolism appeared in official statistics. The same applied to nine of the 12 indirect maternal deaths. We found a potential for improved medical care in 14 of 26 cases. Half of these were deaths due to hypertensive disorders during pregnancy or thromboembolism.Maternal death was considerably underreported in Norwegian official statistics during the period studied. Greater attention should be given to better blood-pressure treatment, stabilisation and timely delivery in the case of hypertension during pregnancy, and to screening for possible pulmonary embolism. The same applies to mental illness and internal medical disorders in pregnant women.

Objective To determine the occurrence of high venous velocities at the umbilical ring in the normal early second trimester, based on the assumption that a narrow umbilical ring may cause obstruction and increased venous blood velocity at the abdominal wall. Design Cross-sectional study. Setting Hospital antenatal clinic. Population One hundred and one low risk singleton pregnancies specifically recruited for the study. Methods Ultrasound was used at 11–19 weeks to determine the diameter and velocity in the umbilical vein at the fetal end of the cord and at the inlet through the abdominal wall. Outcome measures 10th, 50th and 90th centiles were estimated for the time-averaged maximum velocity in the cord and at the abdominal inlet. The increase of velocity as the blood entered the abdominal wall was calculated in percent of the velocity in the cord. Results During weeks 11-12 there was hardly any difference between blood velocity in the umbilical vein at the umbilical ring and that in the cord. From week 13 onwards it was increasingly common to find blood acceleration at the umbilical ring of 50–500%. Velocity increment >50% was found in 0/12 fetuses (0%) at 11–12 weeks, 5/20 (25%) at 13–14 weeks, and in 21/28 (75%) at 17–19 weeks. Conclusions Blood velocity is higher in the umbilical vein at the abdominal wall than the cord, particularly after 13 weeks of gestation. If acceleration of blood velocity at the umbilical ring is a sign of a narrow inlet, it seems that a progressive tightening occurs during the second trimester.

Prophylactic anti-D is a very safe and effective therapy for the suppression of anti-D immunization and thus prevention of haemolytic disease of the foetus and newborn. However, migration from countries with low health standards and substantial cuts in public health expenses have increased the incidence of anti-D immunization in many "developed" countries. Therefore, this forum focuses on prenatal monitoring standards and treatment strategies in pregnancies with anti-D alloimmunization. The following questions were addressed, and a response was obtained from 12 centres, mainly from Europe.

Objective The turgor of Wharton’s jelly depends on osmotic and hydrostatic pressures. We tested the hypothesis that umbilical ring constriction has an impact on umbilical venous hemodynamics and thus on the volume of Wharton’s jelly. Methods In a cross-sectional study of 237 low-risk singleton pregnancies, the cross-sectional area of the fetal end of the umbilical cord was determined using sonography at 20–41 weeks of gestation. The inner area of the two arteries and the vein was also measured and subtracted from the cord area to calculate the area of Wharton’s jelly. Based on the Bernoulli equation, the degree of vein constriction at the umbilical ring was assessed using the blood velocity increment at the abdominal inlet. Regression analysis and SD-score statistics were used to construct mean values and to assess the effects. The dataset was also analyzed for genderspecific effects. Results The umbilical cord cross-sectional area increased with gestational age during the period 20–31 weeks, remaining essentially stable thereafter. The Wharton’s jelly increased with gestational age from 20 until 31–32 weeks of gestation and remained at the same level for the rest of the pregnancy. At mid-gestation, on average 70% of the cord cross-sectional area was occupied by Wharton’s jelly; at 31 weeks and later this value was 60%. Umbilical vein constriction was associated with reduced umbilical cord cross-sectional area and Wharton’s jelly in female fetuses (P = 0.0007 and P = 0.003, respectively), but not in male fetuses. Conclusions Under physiological conditions, umbilical ring constriction affects umbilical vein hemodynamics, with corresponding effects on the umbilical cord crosssectional area and the amount of Wharton’s jelly. Interestingly, the effects are gender-specific. Copyright  2006 ISUOG. Published by John Wiley & Sons, Ltd.

Background Umbilical vein constriction at the fetal abdominal inlet is a common finding after week 13, when the period of umbilical herniation is brought to an end. Aims To test the hypothesis that a constricting umbilical ring within physiological ranges affects fetal hemodynamics by either pooling blood in the placenta or restricting nutrient transfer to the fetus and thus shift the birthweight/placental weight (BW/PW) ratio. A constriction could also cause pressure changes and elongation of the cord and possibly be a disadvantage during labour. Study design Cross-sectional. Subjects 359 Low-risk singleton pregnancies at 13–40 weeks of gestation. Outcome measures Standard deviation score ( z -score) and regression analysis were used to determine the effect of umbilical vein constriction (expressed by increased blood velocity) on birthweight/placental weight ratio (BW/PW), cord length, Apgar score and emergency delivery due to fetal distress. Results Umbilical venous constriction had a mild but significant effect on BW/PW in male ( p =0.018) but not in female fetuses. Increased constriction was also associated with increased length of the cord but only in female fetuses ( p =0.019). Cord length was positively related to birthweight and placental weight, but an increased length of the cord was also associated with decreasing BW/PW ratio for the male fetuses only ( p =0.044). Increasing degree of venous constriction was associated with Apgar score ≤7 at 1 ( p =0.009) but not at 5 min after birth and was not associated with emergency delivery. Conclusion Physiological umbilical venous constriction exerts a mild but significant gender-specific hemodynamic impact on intrauterine development.

Objectives To determine the degree of constriction of the umbilical vein at the abdominal wall in the second half of pregnancy. Methods A total of 283 low-risk singleton pregnancies were recruited for a cross-sectional study, and examined once at 20–40 weeks of gestation. Two sets of ultrasound measurements of the umbilical vein were taken: one at the fetal end of the umbilical cord and another at the inlet through the abdominal wall, the umbilical ring. The diameter was determined as an average of ≥5 repeat measurements. The blood velocity was recorded at the same site. Results The time-averaged maximum venous blood velocity in the cord was low (mean 13–19 cm/s during 20–40 weeks of gestation), and the corresponding mean diameter 3.6–8.2 mm. In contrast, the mean of the venous blood velocity at the umbilical ring was 34–41 cm/s and the diameter was 2.8–5.9 mm during the same period. Of 191 pairs of observations, 41 (21%) had a velocity increment of ≥300 %, which corresponds to a diameter reduction to half or more at the umbilical ring. Conclusion Constriction of the umbilical ring is a common phenomenon in the second half of pregnancy. Copyright  2002 John Wiley & Sons, Ltd.

Objectives: Our goal was to determine the degree of shunting through the ductus venosus in the human fetus and its possible association with fetal growth. Study Design: Blood flow in the umbilical vein and the fetal ductus venosus was measured in 197 low-risk pregnancies in a cross-sectional ultrasonographic study at a gestational age of 18 to 41 weeks. The degree of shunting was compared to birth weight and ponderal index. Results: The average fraction shunted through the ductus venosus was 28% to 32% at 18 to 20 weeks, decreased to 22% at 25 weeks, and reached 18% at 31 weeks (with wide ranges expressed in the 10th and 90th percentiles). Fetuses 90th percentile (95% confidence interval, 0.1%-2.7%; P = .04). Conclusions: In the human fetus a higher proportion of umbilical blood is directed to the liver and less is shunted through the ductus venosus, in comparison with what has previously been shown in animal experiments. (Am J Obstet Gynecol 2000;182:147-53.)

Retinal detachment is a rare complication of preeclampsia, eclampsia and abruptio placentae. We report a case of bilateral retinal detachment in association with severe preeclampsia complicated with abruptio placentae, Intrauterine fetal death and disseminated intravascular coagulation. In obstetric complications, placental thromboplastin may release into maternal circulation and activate the extrinsic coagulation system with resultant disseminated intravascular coagulation. This may be responsible for choroidal ischemia and consequent serous retinal detachment.

Objectives: Intra-abdominal umbilical vein (UV) distension is sometimes seen in cases of fetal demise. We hypothesize that such a UV distension may be a post-stenotic dilatation due to an umbilical ring constriction. Here we explore whether a stricture of the UV is related to UV distension and to adverse outcome. Methods: Referred high-risk pregnancies underwent Doppler assessment that included assessment of the UV at the umbilical ring. UV blood velocity >90th percentile at this site and gestational age (GA) was defined as a UV constriction. An intra-abdominal UV diameter >90th percentile was defined as distension. Pregancies were followed up with repeat observations. Placental weight and fetal outcome were noted. Results: Thirteen fetuses (11 singletons and two twins) that had UVstricture but no major anomalies were included. Median GA at first examination for 10 survivors was 27 (19–36) weeks and for three fetal deaths 24 (19–24) weeks. There was a median of 5 (range, 2–9) observations in each fetus (total 66). Nine of 13 fetuses had both UV constriction and dilatation at first examination. UV constriction >97.5th percentile and GA