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To assess the longitudinal variation of the ratio of umbilical and cerebral artery pulsatility index (UCR) in late preterm fetal growth restriction (FGR). A prospective European multicenter observational study included women with a singleton pregnancy, 32 856 women had 2770 measurements; 696 (81 %) had more than one measurement (median 3 (IQR 2-4). At inclusion, 63 (7 %) a UCR ≥ 0.9. These delivered earlier and had a lower birth weight and higher incidence of adverse outcome (30 % vs. 9 %, relative risk 3.2; 95 %CI 2.1-5.0) than women with a normal UCR at inclusion. Repeated measurements after an abnormal UCR at inclusion were abnormal again in 67 % (95 %CI 55-80), but after a normal UCR the chance of finding an abnormal UCR was 6 % (95 %CI 5-7 %). The risk of composite adverse outcome was similar using the first or subsequent UCR values. An abnormal UCR is likely to be abnormal again at a later measurement, while after a normal UCR the chance of an abnormal UCR is 5-7 % when repeated weekly. Repeated measurements do not predict outcome better than the first measurement, most likely due to the most compromised fetuses being delivered after an abnormal UCR.ZIEL: Beurteilung der longitudinalen Variation der umbilikozerebralen Ratio (UCR) der Pulsatilitätsindizes bei später fetaler Wachstumsrestriktion (FGR). Eine prospektive europäische multizentrische Beobachtungsstudie schloss Frauen mit Einlingsschwangerschaft (32 856 Frauen hatten 2770 Messungen; 696 (81 %) hatten mehr als eine Messung (Median 3, IQR 2–4). Bei Einschluss hatten 63 (7 %) eine UCR ≥ 0,9. Diese entbanden früher und hatten ein niedrigeres Geburtsgewicht und eine höhere Inzidenz für einen unerwünschten Outcome (30 % vs. 9 %, relatives Risiko 3,2; 95 %-KI 2,1–5,0) im Vergleich zu Frauen mit normaler UCR bei Einschluss. Wiederholte Messungen nach abnormaler UCR bei Einschluss waren in 67 % (95 %-KI 55–80) erneut abnormal, aber nach einer normalen UCR betrug die Wahrscheinlichkeit, eine abnormale UCR zu finden, 6 % (95 %-KI 5–7 %). Das Risiko für einen kombinierten unerwünschten Outcome war ähnlich, wenn man den ersten oder den nachfolgenden UCR-Wert verwendete. Eine abnormale UCR ist wahrscheinlich bei einer späteren Messung wieder abnormal, während nach einer normalen UCR die Wahrscheinlichkeit einer abnormalen UCR bei wöchentlicher Wiederholung 5–7 % beträgt. Wiederholte Messungen sagen das Ergebnis nicht besser voraus als die erste Messung, was höchstwahrscheinlich darauf zurückzuführen ist, dass die am stärksten gefährdeten Föten nach einer abnormalen UCR entbunden werden.

A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight after term delivery as a proxy for placental growth, we report genome-wide association analyses in the fetal (n= 65,405), maternal (n= 61,228), and paternal (n= 52,392) genomes, yielding 40 independent association signals. Twenty-six signals are confidently classified as fetal only, four maternal only, and three fetal and maternal. A maternal parent-of-origin effect is seen nearKCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but twelve loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with risk of preeclampsia or shorter gestational duration. Moreover, these analyses support a role for insulin produced by the fetus in regulating the growth of the placenta, providing a key link between fetal and placental growth.

PurposeSeveral clinical phenotypes including fetal hydrops, central conducting lymphatic anomaly or capillary malformations with arteriovenous malformations 2 (CM-AVM2) have been associated with EPHB4 (Ephrin type B receptor 4) variants, demanding new approaches for deciphering pathogenesis of novel variants of uncertain significance (VUS) identified in EPHB4, and for the identification of differentiated disease mechanisms at the molecular level.MethodsTen index cases with various phenotypes, either fetal hydrops, CM-AVM2, or peripheral lower limb lymphedema, whose distinct clinical phenotypes are described in detail in this study, presented with a variant in EPHB4. In vitro functional studies were performed to confirm pathogenicity.ResultsPathogenicity was demonstrated for six of the seven novel EPHB4 VUS investigated. A heterogeneity of molecular disease mechanisms was identified, from loss of protein production or aberrant subcellular localization to total reduction of the phosphorylation capability of the receptor. There was some phenotype–genotype correlation; however, previously unreported intrafamilial overlapping phenotypes such as lymphatic-related fetal hydrops (LRFH) and CM-AVM2 in the same family were observed.ConclusionThis study highlights the usefulness of protein expression and subcellular localization studies to predict EPHB4 variant pathogenesis. Our accurate clinical phenotyping expands our interpretation of the Janus-faced spectrum of EPHB4-related disorders, introducing the discovery of cases with overlapping phenotypes.

Objectives Single umbilical artery (SUA) is associated with congenital malformations in most organ systems, but reported findings have not been consistent. While it has been suggested that genetic and persisting environmental factors influence the development of SUA, it is not known whether there is an increased risk of recurrence in a subsequent pregnancy of the same woman. The aims of this study were to investigate the occurrence of, and risk factors for, SUA in Norway, to assess its association with congenital malformations and trisomies 13, 18 and 21 and to study the risk of recurrence of SUA in subsequent pregnancies. Methods This was a population-based study of all (n = 918 933) singleton pregnancies of > 16 weeks' gestation recorded in the Medical Birth Registry of Norway from 1999 to 2014. To identify risk factors and congenital malformations associated with SUA, generalized estimating equations and logistic regression were used to calculate odds ratios (OR) with 95% CIs. ORs were also calculated for the recurrence of SUA in subsequent pregnancy. Results The occurrence of SUA in our population was 0.46% (4241/918 933). Parity ≥ 4, smoking, maternal pregestational diabetes, epilepsy, chronic hypertension, previous Cesarean delivery and conception by assisted reproductive technology increased the odds of having SUA. There was a particularly strong association between SUA and gastrointestinal atresia or stenosis in the neonate, with ORs of 25.8 (95% CI, 17.0-39.1) and 20.3 (95% CI, 13.4-30.9) for esophageal and anorectal atresia or stenosis, respectively, followed by an OR of 5.9 (95% CI, 1.9-18.5) for renal agenesis. SUA was associated with an up to 7-8 times increased risk of congenital heart defects. There was an association with microcephaly, congenital hydrocephalus and other congenital malformations of the brain and spinal cord. Diaphragmatic hernia, limb reductions and cleft lip or palate had a weaker association with SUA, with ORs ranging from 4.8 to 2.8. The associations with trisomy 18 and 13 were equally strong (OR 14.4 (95% CI, 9.3-22.4) and OR 13.6 (95% CI, 6.7-27.8), respectively), and the risk of trisomy 21 was doubled (OR 2.1 (95% CI, 1.2-3.6)). Pregnancies with SUA, with or without an associated malformation, had a 2-fold increased risk for SUA in a subsequent pregnancy. Conclusions SUA is associated strongly with gastrointestinal atresia or stenosis, suggesting common developmental mechanisms. The increased risk of recurrence of SUA suggests that genetic and/or persisting environmental factors influence the risk. We found that SUA had equally strong associations with trisomies 13 and 18. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Purpose This study examines individual aggregation of postpartum hemorrhage (PPH), paternal contribution and how offspring birthweight and sex influence recurrence of PPH. Further, we wanted to estimate the proportion of PPH cases attributable to a history of PPH or current birthweight. Methods We studied all singleton births in Norway from 1967 to 2017 using data from Norwegian medical and administrational registries. Subsequent births in the parents were linked. Multilevel logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CI) for PPH defined as blood loss > 500 ml, blood loss > 1500 ml, or the need for blood transfusion in parous women. Main exposures were previous PPH, high birthweight, and fetal sex. We calculated adjusted population attributable fractions for previous PPH and current high birthweight. Results Mothers with a history of PPH had three- and sixfold higher risks of PPH in their second and third deliveries, respectively (adjusted OR 2.9; 95% CI 2.9–3.0 and 6.0; 5.5–6.6). Severe PPH (> 1500 ml) had the highest risk of recurrence. The paternal contribution to recurrence of PPH in deliveries with two different mothers was weak, but significant. If the neonate was male, the risk of PPH was reduced. A history of PPH or birthweight ≥ 4000 g each accounted for 15% of the total number of PPH cases. Conclusion A history of PPH and current birthweight exerted strong effects at both the individual and population levels. Recurrence risk was highest for severe PPH. Occurrence and recurrence were lower in male fetuses, and the paternal influence was weak.

Aim We evaluated the role of placental pathology in predicting adverse outcomes for neonates born extremely preterm (EPT) before 28 weeks of gestation. Methods This was a prospective observational study of 123 extremely preterm singletons born in a hospital in western Norway, and the placentas were classified according to the Amsterdam criteria. The associations between histologic chorioamnionitis (HCA), by the presence or the absence of a foetal inflammatory response (FIR+ or FIR−), maternal vascular malperfusion (MVM) as a whole and adverse neonatal outcomes were evaluated by logistic regression analyses. Adverse outcomes were defined as perinatal death, necrotising enterocolitis (NEC), bronchopulmonary dysplasia (BPD), brain pathology by magnetic resonance imaging at term-equivalent age, retinopathy of prematurity and early-onset neonatal sepsis. The results are reported as odds ratios (ORs) with 95% confidence intervals (CIs). Results HCA was associated with NEC (OR 12.2, 95% CI 1.1 to 137.1). HCA/FIR+ was associated with BPD (OR 14.9, 95% CI 1.8–122.3) and brain pathology (OR 9.8, 95% CI 1.4–71.6), but HCA/FIR− was not. The only neonatal outcome that MVM was associated with was low birthweight. Conclusion Placental histology provided important information when assessing the risk of adverse neonatal outcomes following EPT birth. publishedVersion

Introduction Isolated single umbilical artery (iSUA) refers to single umbilical artery cords with no other fetal malformations. The association of iSUA to adverse outcome of pregnancy has not been consistently reported, and whether iSUA carries increased risk of third stage of labor complications has not been studied. We aimed to investigate the risk of adverse perinatal outcome, third stage of labor complications, and associated placental and cord characteristics in pregnancies with iSUA. A further aim was to assess the risk of recurrence of iSUA and anomalous cord or placenta characteristics in Norway. Material and methods This was a population-based study of all singleton pregnancies with gestational age >16 weeks at birth using data from the Medical Birth Registry of Norway from 1999 to 2014 (n = 918 933). Odds ratios (OR) with 95% confidence intervals were calculated for adverse perinatal outcome (preterm birth, perinatal and intrauterine death, low Apgar score, transferral to neonatal intensive care ward, placental and cord characteristics [placental weight, cord length and knots, anomalous cord insertion, placental abruption and previa]), and third stage of labor complications (postpartum hemorrhage and the need for manual placental removal or curettage) in pregnancies with iSUA, and recurrence of iSUA using generalized estimating equations and logistic regression. Results Pregnancies with iSUA carried increased risk of adverse perinatal outcome (OR 5.06, 95% confidence interval [CI] 4.26-6.02) and perinatal and intrauterine death (OR 5.62, 95% CI 4.69-6.73), and a 73% and 55% increased risk of preterm birth and small-for-gestational-age neonate, respectively. The presence of iSUA also carried increased risk of a small placenta, placenta previa and abruption, anomalous cord insertion, long cord, cord knot and third stage of labor complications. Women with iSUA, long cord or anomalous cord insertion in one pregnancy carried increased risk of iSUA in the subsequent pregnancy. Conclusions The presence of ISUA was associated with a more than five times increased risk of intrauterine and perinatal death and with placental and cord complications. The high associated risk of adverse outcome justifies follow up with assessment of fetal wellbeing in the third trimester, intrapartum surveillance and preparedness for third stage of labor complications.

Purpose: Speckle tracking echocardiography is a promising method for assessment of myocardial function in fetal and neonatal hearts, but further studies are necessary to validate and optimize the settings for use in fetal cardiology. Previous studies have shown that the definition of the region of interest (ROI) affects strain values in adults. The aim of this study was to investigate how different widths of ROI influences measurements of four-chamber longitudinal systolic strain in fetuses late in pregnancy.Methods: Thirty-one singleton, healthy fetuses born to healthy mothers underwent an echocardiographic examination during gestational week 37. Speckle tracking was performed with two different settings for ROI width; the narrowest and second most narrow, provided both widths were assessed as suitable for the myocardial wall thickness of the fetus. Results: We found an inverse correlation between the ROI width and the strain values. Four-chamber longitudinal strain changed from -20.7 ± 3.6% to -18.0 ± 4.4% (pConclusions: Different widths of ROI influenced the strain measurements significantly in the fetal heart, comparable to what has been reported in adults. A standardization of the ROI setting could improve the interpretation, and reduce variability in fetal strain measurements.

The International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) is a scientific organization that encourages sound clinical practice, teaching and research related to diagnostic imaging in women's healthcare. The ISUOG Clinical Standards Committee (CSC) has a remit to develop Practice Guidelines and Consensus Statements as educational recommendations that provide healthcare practitioners with a consensus-based approach for diagnostic imaging. They are intended to reflect what is considered by ISUOG to be the best practice at the time at which they are issued. Although ISUOG has made every effort to ensure that Guidelines are accurate when issued, neither the Society nor any of its employees or members accepts any liability for the consequences of any inaccurate or misleading data, opinions or statements issued by the CSC. They are not intended to establish a legal standard of care because interpretation of the evidence that underpins the Guidelines may be influenced by individual circumstances and available resources. Approved Guidelines can be distributed freely with the permission of ISUOG (info@isuog.org).

Introduction Studies on the family aggregation of postpartum hemorrhage (PPH) are scarce and with inconsistent results, and to what extent current birthweight influences recurrence between relatives remains to be studied. Further, family aggregation of PPH has been studied from an individual, but not from a public heath perspective. We aimed to investigate family aggregation of PPH in Norway, how birthweight influences these effects, and to estimate the proportion of PPH cases attributable to a family history of PPH and current birthweight. Material and methods Using data from the Medical Birth Registry of Norway, Statistics Norway, and Central Population Registry of Norway we identified individuals as newborns, parents, grandparents, and full and half-siblings, and studied 1 002 687 mother–offspring, 841 164 father–offspring, and 761 011 both-parents–offspring pairs. We used multilevel logistic regression to calculate odds ratios (OR) with 95% CI. Results If the birth of the mother but not of the father involved PPH, then the OR of PPH (>500 mL) in the next generation was 1.44 (95% CI 1.39–1.49). If the birth of the father but not of the mother involved PPH, then OR was 1.12 (95% CI 1.08–1.16). These effects were stronger in severe PPH. Recurrence between siblings was highest between full sisters (OR 1.47, 95% CI 1.41–1.52), followed by maternal half-sisters, paternal half-sisters, and partners of full brothers. A family history of PPH or birthweight of 4000 g or more accounted for ≤5% and 15% of the total number of PPH cases, respectively. Conclusions A history of PPH in relatives influenced the recurrence risk of PPH in a dose–response pattern consistent with the anticipated proportion of shared genes. The recurrence was highest through the maternal line. publishedVersion

Women of reproductive age who present with abdominal pain and purulent vaginal discharge are commonly seen in primary health care and gynaecological outpatient clinics. Their symptoms are often caused by sexually transmitted infections and efficiently treated with empiric antibiotics. However, in some cases diagnostics are more challenging.We present the case history of a woman in her twenties with multiple sclerosis under rituximab treatment. She presented with a wide range of symptoms over twelve months, including upper and lower respiratory tract infections, urinary bladder urgency, chronic abdominal pain, diarrhoea, bloody stools, weight loss and fatigue. She underwent urological and gastroenterological examinations which yielded normal findings. After the onset of genital discomfort and copious amounts of vaginal discharge, gynaecological examination and routine microbiological testing of discharge were negative. Finally, she presented with septicaemia and progressive abdominal pain. Laparoscopy was performed due to absence of recovery after initial transvaginal ultrasound-guided aspiration of ovarian cysts. The microbe Ureaplasma urealyticum was detected in ovarian pus. Treatment with doxycycline resulted in full recovery.It is important to consider opportunistic microbes in immunocompromised patients, as they might pose a major diagnostic challenge and require the involvement of several specialties.

INTRODUCTION Despite adequate glycemic control, the risks of fetal macrosomia and perinatal complications are increased in diabetic pregnancies. Adjustments of the umbilical venous distribution, including increased ductus venosus shunting, can be important fetal compensatory mechanisms, but the impact of pregestational diabetes on umbilical venous and ductus venosus flow is not known. MATERIAL AND METHODS In this prospective study, 49 women with pregestational diabetes mellitus underwent monthly ultrasound examinations from gestational week 20 to 36. The blood velocity and the mean diameters of the umbilical vein and ductus venosus were used for calculating blood flow volumes. The development of the umbilical venous flow, ductus venosus flow and ductus venosus shunt fraction (% of umbilical venous blood shunted through the ductus venosus) was compared with a reference population, and the effect of HbA1c on the ductus venosus flow was assessed. RESULTS The umbilical venous flow was larger in pregnancies with pregestational diabetes mellitus than in low-risk pregnancies (p

Objective To assess whether parents who were born small for gestational age (below the 10th birthweight centile, SGA) have increased risk of severe or mild placental abruption. To assess whether a history of SGA in other family members modifies this intergenerational effect. Design Prospective population-based observational study. Setting The Medical Birth Registry of Norway. Population From 1967 to 2013, 785 333 mother–offspring pairs, 643 066 father–offspring pairs, 272 941 maternal tetrads (i.e. her offspring, sibling, and niece/nephew), and 265 505 paternal tetrads were identified. Methods Cohort study based on linked data from the Medical Birth Registry of Norway. Main outcome measures Relative risk (RR) of severe placental abruption (preterm birth, birthweight below the 10th centile, or perinatal death) and mild placental abruption (other cases) in families with SGA. Results Mothers who were born SGA had increased risk of severe placental abruption (RR 1.5; 95% confidence interval, 95% CI 1.3–1.8), but not mild abruption. The paternal effects were weaker. The combined effect of SGA in the mother and her sibling on severe abruption was twofold (RR 2.4; 95% CI 1.7–3.3) compared with birthweight centiles ≥10 for both. Similarly, the effect of adding an SGA niece/nephew was twofold (RR 2.3; 95% CI 1.3–3.9), whereas the combined effect of SGA in the mother, her sibling and her niece/nephew was fourfold (RR 3.6; 95% CI 1.9–6.8). Conclusions Women who were born SGA have an increased risk of severe placental abruption. The corresponding paternal effect was modest. A history of SGA in other family members increases the generational effect. Tweetable abstract Women born small for gestational age have excess risk of placental abruption.

This is the peer reviewed version of the following article: Acharya, G., Ebbing, C., Karlsen, H., Kiserud, T. & Rasmussen, S. (2019). Sex-specific reference ranges of cerebroplacental and umbilicocerebral ratios: A longitudinal study. Ultrasound in Obstetrics and Gynecology, 2019, which has been published in final form at https://doi.org/10.1002/uog.21870. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. Objectives - The ratio of middle cerebral artery (MCA) pulsatility index (PI) to umbilical artery (UA) PI, i.e. cerebro‐placental ratio (CPR), has been suggested as a measure of fetal “brain sparing” phenomenon reflecting redistribution of fetal cardiac output as a response to placental insufficiency. Observational studies have shown that low CPR values predict increased risk of adverse perinatal outcomes although evidence from randomized clinical trials is lacking. The inverse ratio, i.e. umbilico‐cerebral ratio (UCR), is preferred by some as it increases with increasing degree of fetal compromise. Monitoring fetal wellbeing requires serial assessment, and for this purpose, appropriate reference values should be based on data from longitudinal studies. However, longitudinal reference ranges for the UCR have not been established. Furthermore, the sex of the fetus influences its growth velocity, cord properties, in utero circadian rhythm, behavioral states and placental function, but whether gestational age‐dependent changes in CPR or UCR differ between male and female fetuses has not been studied. Thus, our objective was to investigate sex‐specific, gestational age‐associated serial changes in CPR and UCR during the second half of pregnancy and establish longitudinal reference ranges. Methods - This was a dual‐center prospective longitudinal study of singleton low risk pregnancies. Doppler blood flow velocity waveforms were obtained serially from the UA and MCA during 19‐41 weeks of gestation, and PIs were determined. CPR and UCR were calculated as the ratios, MCA PI/ UA PI and UA PI/ MCA PI, respectively. The course and outcome of pregnancies was recorded. Sex of the fetus was determined after delivery. Reference intervals were constructed using multilevel modelling and gestational age‐specific Z‐scores of male and female fetuses were compared. Results - Of a total of 299 pregnancies enrolled, 284 women and their fetuses (148 male and 136 female) were included in the final analysis, and 979 paired measurements of UA and MCA PIs were used to construct sex‐specific longitudinal reference intervals. Both CPR and UCR had U‐shaped curves of development during pregnancy, but with opposite directions. There was a small but significant (P=0.007) difference in z‐scores of CPR and UCR between male and female fetuses throughout the second half of pregnancy. Conclusions - We have established longitudinal reference ranges for CPR and UCR suitable for serial monitoring with possibilities to refine the assessment by fetal sex‐specific ranges and the conditioning by a previous measurement. The clinical significance of such refinements needs further evaluation.

Background Women of reproductive age who present with abdominal pain and purulent vaginal discharge are commonly seen in primary health care and gynaecological outpatient clinics. Their symptoms are often caused by sexually transmitted infections and efficiently treated with empiric antibiotics. However, in some cases diagnostics are more challenging. Case presentation We present the case history of a woman in her twenties with multiple sclerosis under rituximab treatment. She presented with a wide range of symptoms over twelve months, including upper and lower respiratory tract infections, urinary bladder urgency, chronic abdominal pain, diarrhoea, bloody stools, weight loss and fatigue. She underwent urological and gastroenterological examinations which yielded normal findings. After the onset of genital discomfort and copious amounts of vaginal discharge, gynaecological examination and routine microbiological testing of discharge were negative. Finally, she presented with septicaemia and progressive abdominal pain. Laparoscopy was performed due to absence of recovery after initial transvaginal ultrasound-guided aspiration of ovarian cysts. The microbe Ureaplasma urealyticum was detected in ovarian pus. Treatment with doxycycline resulted in full recovery. Interpretation It is important to consider opportunistic microbes in immunocompromised patients, as they might pose a major diagnostic challenge and require the involvement of several specialties.

Hypertensive disorders of pregnancy (HDP) tend to recur from one pregnancy to the next. The aims of the study were to assess the recurrence risk according to type of HDP defined by gestational age at birth and to examine whether recurrence is associated with the following additional risk factors for HDP: maternal age, smoking, inter delivery interval, diabetes, body mass index, as well as fetal growth restriction, and to assess temporal trends in these associations. All women with two singleton births in the Medical Birth Registry of Norway 1967-2012 (n= 742 980) were included in this population based cohort study. Logistic regression was used to calculate odds ratios for the risk of recurrent HDP according to type of HDP. The highest odds ratio of recurrence was observed for the same type of HDP based on gestational age at delivery. After gestational hypertension and term preeclampsia the risk increased tenfold for the same type to recur, whereas after late and early preterm preeclampsia, the risk increased 27 and 97 fold, respectively. The recurrence of early preterm preeclampsia was less influenced by additional risk factors than term HDP. Recurrence of early preterm HDP was significantly lower from 1993 onwards. Recurrent HDP tended to be of the same type as the previous HDP. Risk of recurrence associated with additional risk factors were observed particularly after term. The odds ratio of recurrence of early preterm HDP was significantly lower from 1993 onwards. This article is protected by copyright. All rights reserved.

Anomalous cord insertion is associated with increased risk of adverse maternal and perinatal outcome. Our aim was to study whether anomalous cord insertion is associated with prelabor rupture of membranes (PROM), preterm PROM (pPROM), long or short umbilical cord, and time trend of spontaneous preterm birth (SPTB) and anomalous cord insertion.A population-based register study using data from the Medical Birth Register of Norway including all singleton births (gestational age16 weeks and45 weeks) during 1999-2013 (n = 860 465) to calculate odds ratios (ORs) for PROM, pPROM, SPTB, and cord length (95th or5th centile) according to the cord insertion site by logistic regression with adjustment for possible confounders. We also assessed time trends of SPTB and anomalous cord insertion.Velamentous insertion of the cord was associated with an increased risk of PROM (OR 1.6, 95% CI 1.5-1.7), pPROM (OR 2.7, 95% CI 2.4-3.0), SPTB (OR 2.0, 95% CI 1.9-2.2), and a short cord (OR 1.7, 95% CI 1.5-1.8). Marginal insertion was to a lesser extent associated with these complications. Occurrences of SPTB and anomalous insertion declined. The decline in SPTB persisted after including an interaction term between anomalous insertion and time.Velamentous and, to a lesser extent, marginal cord insertions were associated with increased risk of PROM, pPROM, SPTB, and short cord. This suggests a common pathogenesis behind altered function of the membranes, cord, and placenta. The decline in SPTB could not be explained by the reduction in the occurrence of anomalous cord insertion.

Circadian rhythmicity is fundamental to human physiology, and is present even during fetal life in normal pregnancies. The impact of maternal endocrine disease on the fetal circadian rhythm is not well understood. The present study aimed to determine the fetal circadian rhythm in pregnancies complicated by pregestational diabetes mellitus (PGDM), compare it with a low-risk reference population, and identify the effects of maternal glycemic control and morning cortisol concentrations. Long-term fetal electrocardiogram recordings were made in 40 women with PGDM at 28 and 36 weeks of gestation. Two recordings were made in 18 of the women (45.0%) and one recording was made in 22 (55.0%). The mean fetal heart rate (fHR) and the fHR variation (root mean square of squared differences) were extracted in 1-min epochs, and circadian rhythmicity was detected by cosinor analysis. The study cohort was divided based on HbA1c levels and morning cortisol concentrations. Statistically, significant circadian rhythms in the fHR and the fHR variation were found in 45 (100%) and 44 (95.7%) of the 45 acceptable PGDM recordings, respectively. The rhythms were similar to those of the reference population. However, there was no statistically significant population-mean rhythm in the fHR among PGDM pregnancies at 36 weeks, indicating an increased interindividual variation. The group with higher HbA1c levels (6.0%) had no significant population-mean fHR rhythm at 28 or 36 weeks, and no significant fHR-variation rhythm at 36 weeks. Similarly, the group with a lower morning cortisol concentration (≤8.8 µg/dl) had no significant population-mean fHR-variation rhythm at 28 and 36 weeks. These findings indicate that individual fetal rhythmicity is present in pregnancies complicated by PGDM. However, suboptimal maternal glycemic control and a lower maternal morning cortisol concentration are associated with a less-well-synchronized circadian system of the fetus.

Background Pregestational diabetes is associated with fetal macrosomia, and umbilical perfusion of the fetal liver has a role in regulating fetal growth. We therefore hypothesized that pregestational diabetes alters fetal liver blood flow depending on degree of glycemic control. Methods In a prospective study, 49 women with pregestational diabetes underwent monthly ultrasound examinations during 24-36 gestational weeks. Blood flow was determined in the umbilical vein, ductus venosus and portal vein, and blood velocity was measured in the left portal vein, the latter reflecting the watershed between splanchnic and umbilical flow. The measurements were compared with reference values by z-score statistics, and the effect of HbA 1c assessed. Results The umbilical venous flow to the liver (z-score 0.36, p = 0.002), total venous liver flow (z-score 0.51, p1C . Conclusions In spite of increased umbilical blood distribution to the fetal liver, graded according to glycemic control, the total venous liver flow did not match third trimester fetal growth in pregnancies with pregestational diabetes, thus contributing towards increased perinatal risks and possibly altered liver function with long-term metabolic consequences.

INTRODUCTION Fetal biometry is used for determining gestational age and estimated date of delivery (EDD). However, the accuracy of the EDD depends on the assumed length of pregnancy included in the calculation. This study aimed at assessing the actual pregnancy length and accuracy of EDD prediction based on fetal head circumference measured at the second trimester. MATERIAL AND METHODS This was a population-based observational study with the following inclusion criteria: singleton pregnancy, head circumference dating in the second trimester, spontaneous onset or induction of delivery ≥ 294 days of gestation, live birth. The EDD was set anticipating a pregnancy length of 282 days. Bias in the prediction of EDD was defined as the difference between the actual date of birth and the EDD. RESULTS Head circumference measurements were available for 21 451 pregnancies. Ultrasound-dated pregnancies had a median pregnancy length of 283.03 days, corresponding to a method bias of 1.03 days (95% CI; 0.89-1.16). This bias was dependent on the head circumference at dating, ranging from -1.58 days (95% CI; -3.54 to 1.12) to 3.42 days (95% CI; 1.98-4.31). The median pregnancy length, based on the last menstrual period of women with a regular menstrual cycle (n = 12 985), was 283.15 days (95% CI; 282.91-283.31). A total of 5685 (22.9%, 95% CI; 22.4% to 23.4%) and 886 women (3.6%, 95% CI; 3.3%-3.8%) were still pregnant 7 and 14 days after the EDD, respectively. CONCLUSIONS Second trimester head circumference measurements can be safely used to predict EDD. A revision of the pregnancy length to 283 days will reduce the bias of EDD prediction to a level comparable with other methods.

To assess whether anomalous cord insertion is associated with risk of complications in the third stage of labor.A population-based study.Norwegian Medical Birth Register.All singleton births (gestational age16 weeks and45 weeks) during the period 1999-2011 (n = 738,443 singletons). Deliveries by cesarean were excluded, leaving 628,680 vaginal singleton deliveries for the analyses.Calculation of odds ratios for complications in the third stage of labor (postpartum hemorrhage, manual delivery of the placenta, curettage) in velamentous and marginal cord insertion by logistic regression with adjustment for confounders.Complications in the third stage of labor, postpartum hemorrhage, manual placental removal and curettage.Anomalous cord insertion was associated with an increased risk of complications in the third stage of labor, the risk being higher for velamentous than for marginal insertion. The risks persisted after adjusting for possible confounding factors. Velamentous cord insertion carried a 5.6% risk of a need for manual removal of the placenta, compared with the risk of 1.1% for nonvelamentous insertion (odds ratio = 5.21, 95% confidence interval 4.71-5.76) in vaginal delivery, and we found increased risks of curettage (odds ratio = 3.29, 95% confidence interval 2.87-3.77) and postpartum hemorrhage (odds ratio = 2.06, 95% confidence interval 1.77-2.39).Marginal and especially velamentous cord insertion is associated with an increased risk of hemorrhage in the third stage of labor, need for manual removal of the placenta and curettage. Anomalous cord insertion can be identified prenatally and so possibly influence obstetric management.

Objectives To determine risk factors for short and long umbilical cord, entanglement and knot. Explore their associated risks of adverse maternal and perinatal outcome, including risk of recurrence in a subsequent pregnancy. To provide population based gestational age and sex and parity specific reference ranges for cord length. Design Population based registry study. Setting Medical Birth Registry of Norway 1999–2013. Population All singleton births (gestational age>22weeks

Congenital heart block (CHB) may develop in the fetus of Ro/SSA autoantibody-positive women. A population-based recurrence rate of only 12% however suggests that factors other than maternal autoantibodies influence the risk of developing CHB.1 In the present study, we aimed to identify genetic contribution to the disease by analysing HLA associations in European families with a Ro/SSA antibody-positive mother and at least one child affected by CHB. HLA allele genotypes were imputed for 173 families comprising 635 individuals (291 parents, 173 cases and 167 unaffected siblings) from Sweden, Norway, Finland and Italy (online supplementary table 1) based on 5636 tag SNPs. Parental HLA allele transmission frequencies to patients with CHB were assessed and OR and significance of the association with CHB calculated. We considered nominal P values

Introduction A validation of data regarding the placenta, cord and membranes in Medical Birth Registry of Norway (MBRN) is lacking. Here we investigate the inter- and intra-observer agreement of observations regarding the placenta, cord and membranes to the MBRN in two institutions. Material and methods We conducted a dual center validation study of data regarding placenta, cord and membranes. In the inter-observer study, 196 placentas in two institutions were examined by the attending midwife and a blinded colleague, whereas in the intra-observer study registrations by the attending midwife on 195 placentas were compared with her own registrations to the MBRN. In a separate sample consisting of 51 placental pathology reports, midwives’ registrations to the MBRN were compared with the pathology report. For categorical and continuous variables, agreement was assessed by kappa value and paired sample t-test, respectively. Results Inter-observer agreement between two midwives for cord insertion site and bi-placenta, cord knots and vessel anomalies were good (kappa values >0.79 and >0.96, respectively). The inter- and intra-observer study showed no significant differences regarding placental weight and cord length (p = 0.31 and 0.28, p = 0.71 and 0.39, respectively). The inter-observer agreement between the pathology reports and midwives’ registrations was good for gross placental and cord variants (kappa 0.73–1.0), but there were significant differences in placental weight and cord length (p < 0.0001). Conclusions The results suggest that the validity of data regarding placenta and cord in the MBRN is sufficiently high to justify future large-scale epidemiologic research based on this database.

After birth, the hepatic artery buffer response helps to maintain liver perfusion. Here, the authors establish a Doppler technique to measure fetal hepatic artery flow velocity and test the hypothesis that the buffer response also operates prenatally. Women with low-risk pregnancies were recruited to a longitudinal study (N = 161). Measurement techniques and reference ranges for hepatic artery velocities and pulsatility index (PI) were established. Ductus venosus peak velocity (V(DVps)) represented the portocaval pressure gradient, and umbilical venous flow (Q(UV)) represented portal flow. Reference ranges were established for the more accessible left hepatic artery branch. Hepatic artery PI was lower in fetuses with V(DVps)10th centile (P.05) and in those with Q(UV)10th centile ( P.0001). Conversely, hepatic artery PI was higher in those with Q(UV)90th centile (P.0001). The authors establish a method for measuring fetal hepatic arterial blood velocity, provide reference ranges, and show that the hepatic artery buffer response operates prenatally.

Introduction. Centiles of middle cerebral artery pulsatility index and cerebroplacental ratio are useful for predicting adverse perinatal outcomes. A ‘conditional centile’ is conditioned by a previous measurement reflecting degree of individual change over time. Here we test whether such centiles are independent predictors and whether their combination improves prediction. Material and methods. This prospective longitudinal study included 220 pregnant women diagnosed with or at risk of having a small-for-gestational-age fetus. Serial Doppler measurements of the umbilical artery and middle cerebral artery pulsatility indexs were used to calculate cerebroplacental ratio. Preterm birth, operative delivery due to fetal distress, admission to neonatal intensive care unit, 5-min Apgar score