A novel algorithm for classification of interatrial communications within the oval fossa in the newborn.

BACKGROUND: An interatrial communication is present in most neonates. The majority are considered the "normal" patency of the oval foramen, while a minority are abnormal atrial septal defects. Differentiation between the two with transthoracic echocardiography may be challenging, and no generally accepted method of classification is presently available. We aimed to develop and determine the reliability of a new classification of interatrial communications in newborns. METHODS AND RESULTS: An algorithm was developed based on echocardiographic criteria from 495 newborns (median age 11[8;13] days, 51.5% females). The algorithm defines three main categories: patency of the oval foramen, atrial septal defect, and no interatrial communication as well as several subtypes. We found an interatrial communication in 414 (83.6%) newborns. Of these, 386 (93.2%) were categorised as patency of the oval foramen and 28 (6.8%) as atrial septal defects.Echocardiograms from another 50 newborns (median age 11[8;13] days, 36.0% female), reviewed by eight experts in paediatric echocardiography, were used to assess the inter- and intraobserver variation of classification of interatrial communications into patency of the oval foramen and atrial septal defect, with and without the use of the algorithm. Review with the algorithm gave a substantial interobserver agreement (kappa = 0.66), and an almost perfect intraobserver agreement (kappa = 0.82). Without the use of the algorithm, the interobserver agreement between experienced paediatric cardiologists was low (kappa = 0.20). CONCLUSION: A new algorithm for echocardiographic classification of interatrial communications in newborns produced almost perfect intraobserver and substantial interobserver agreement. The algorithm may prove useful in both research and clinical practice.

National data on the early clinical use of non-invasive prenatal testing in public and private healthcare in Denmark 2013-2017.

INTRODUCTION: In Denmark, non-invasive prenatal testing (NIPT) has been used since 2013. We aimed to evaluate the early clinical use of NIPT in Danish public and private healthcare settings before NIPT became an integrated part of the national guidelines on prenatal screening and diagnosis in 2017. MATERIAL AND METHODS: NIPT data were collected between March 2013 and June 2017 from national public registries and private providers. Results from follow-up samples (chorionic villi, amniotic fluid, postnatal blood or fetal tissue) were included from The Danish Cytogenetics Central Registry and indications and outcome from The Danish Fetal Medicine Database. RESULTS: A total of 3936 NIPT results were included in the study from public hospitals (n = 3463, 88.0%) and private clinics (n = 473, 12.0%). The total number of prenatal tests was 19 713 during the study period: 20% were NIPT analyses (n = 3936) and 80% invasive procedures (n = 15 777). Twenty-five percent of NIPTs in the private clinics were performed before gestational week 11+0 , whereas NIPT in public settings was used only after combined first trimester screening (P < .001). Regardless of indication, the national public sensitivity was 96.9% (95% CI 82.0%-99.8%) for trisomy 21, 100% (95% CI 46.3%-100%) for trisomy 18, 100% (95% CI 5.5%-100%) for trisomy 13, and 87.0% (95% CI 74.5%-92.4%) for any fetal chromosomal aberration. Forty-seven true-positive NIPT results included cases of common aneuplodies (trisomy 21, n = 31; trisomy 18, n = 5; and trisomy 13, n = 1), sex chromosomal aberrations (n = 7) and atypical chromosomal aberrations (n = 3). One false-negative NIPT result occurred (trisomy 21). Of 47 cases, 21 (45%) cases with a true-positive NIPT result resulted in live births by choice; 11 of these children had Down and 4 had Edwards syndrome. CONCLUSIONS: The total number of NIPT analyses was low compared with the number of invasive procedures in the implementation period. In contrast to the generally high termination rate after a positive result following invasive testing in Denmark, a high proportion of true-positive NIPT results from the public setting resulted in live births. NIPT may be an important risk-free alternative to invasive testing for a minority of women in the public setting who wish to use prenatal genetic testing for information only and not for reproductive decision-making.

Why we succeed and fail in detecting fetal growth restriction: A population-based study.

INTRODUCTION: The objective of this study was to explore the association between detection of fetal growth restriction and maternal-, healthcare provider- and organizational factors. MATERIAL AND METHODS: A historical, observational, multicentre study. All women who gave birth to a child with a birthweight <2.3rd centile from 1 September 2012 to 31 August 2015 in Zealand, Denmark, were included. The population was identified through the Danish Fetal Medicine Database. Medical charts were reviewed to obtain data regarding maternal characteristics and information on the healthcare professionals. Date of authorization for the midwives and obstetricians involved was extracted from the Danish Health Authorization Registry. Multivariable Cox regression models were used to identify predictors of antenatal detection of fetal growth restriction, and analyses were adjusted for hospital, body mass index, parity, the presence of at least one risk factor and experience of the first midwife, number of midwife visits, number of visits to a doctor, the experience of the consultant midwife or the educational level of the doctor, the number of scans and gaps in continuity of midwife-care. Antenatal detection was defined as an ultrasound estimated fetal weight <2.3rd centile (corresponding to -2 standard deviations) prior to delivery. RESULTS: Among 78 544 pregnancies, 3069 (3.9%) had a fetal growth restriction. Detection occurred in 31% of fetal growth-restricted pregnancies. Clinical experience (defined as years since graduation) of the first consultation midwife was positively associated with detection, with a hazard ratio [HR] of 1.15, 95% confidence interval [CI] 1.03-1.28), for every 10 years of additional experience. The hazard of detection increased with the number of midwife consultations (HR 1.15, 95% CI 1.05-1.26) and with multiparity (HR 1.28, 95% CI 1.03-1.58). After adjusting for all covariates, an unexplained difference between hospitals (P = .01) remained. CONCLUSIONS: The low-risk nullipara may constitute an overlooked group of women at increased risk of antenatal non-detection of fetal growth restriction. Being screened by experienced midwives during early pregnancy and having access to multiple midwife consultations may improve future diagnosis.

Novel Clinical and Radiological Findings in a Family with Autosomal Recessive Omodysplasia.

Autosomal recessive omodysplasia (GPC6-related) is a rare short-limb skeletal dysplasia caused by biallelic mutations in the GPC6 gene. Affected individuals manifest with rhizomelic short stature, decreased mobility of elbow and knee joints as well as craniofacial anomalies. Both upper and lower limbs are severely affected. These manifestations contrast with normal height and limb shortening restricted to the arms in autosomal dominant omodysplasia (FZD2-related). Here, we report 2 affected brothers of Pakistani descent from Denmark with GPC6-related omodysplasia, aiming to highlight the clinical and radiological findings. A homozygous deletion of exon 6 in the GPC6 gene was detected. The pathognomonic radiological findings were distally tapered humeri and femora as well as severe proximal radioulnar diastasis. On close observations, we identified a recurrent and not previously described type of abnormal patterning in all long bones.

Fetal fraction of cell-free DNA in pregnancies after fresh or frozen embryo transfer following assisted reproductive technologies.

STUDY QUESTION: Is the fetal fraction (FF) of circulating cell-free DNA (cfDNA) affected in pregnancies following ART treatment with either fresh or frozen embryo transfer (ET) compared with natural conception? SUMMARY ANSWER: This study shows a significant reduction in the FF in ART patients compared with naturally conceived pregnancies, which seems to be more pronounced after fresh ET compared with frozen ET. WHAT IS KNOWN ALREADY: Non-invasive prenatal testing (NIPT) is based on cfDNA in maternal blood, of which about 10% is of placental origin and thus represents the fetal karyotype. Validation studies have demonstrated a high sensitivity, specificity and positive predictive value of NIPT for the detection of fetal trisomy 21, 18 and 13. Nevertheless, the FF of cfDNA is an important factor for NIPT test accuracy. Several studies have found a reduction in FF for pregnancies following ART in comparison with natural conception. However, knowledge on how the FF is affected in ART pregnancies after fresh ET compared with frozen ET is very limited. STUDY DESIGN, SIZE, DURATION: The study was designed as a case-control study. A total of 54 women with an ongoing pregnancy following ART treatment were included. After exclusion for different reasons, statistical analyses were based on 23 NIPT samples from pregnant women treated with fresh ET and 26 NIPT samples from pregnant women treated with frozen-thawed ET in a modified natural cycle. Women were included between February 2018 and November 2018. The results were compared with a control group of 238 naturally conceived pregnancies with a high-risk result from the combined first trimester screening (cFTS). PARTICIPANTS/MATERIALS, SETTING, METHODS: The study included women from the Fertility Clinics at Copenhagen University Hospital Hvidovre and Copenhagen University Hospital Rigshospitalet. Blood samples for NIPT analysis were drawn between 11 + 0 and 14 + 2 weeks of gestation and were all analyzed at the NIPT Center at Copenhagen University Hospital Hvidovre. The NIPT-test was performed by massive-parallel whole-genome sequencing. The FF was determined using the SeqFF algorithm. MAIN RESULTS AND THE ROLE OF CHANCE: We found a reduction in FF in ART patients compared with naturally conceived pregnancies, and the reduction was more pronounced for ART pregnancies after fresh ET (mean FF = 0.049) compared with frozen ET (mean FF = 0.063) (multivariate analysis adjusted for maternal BMI, P = 0.02). Another multivariate analysis, adjusted for BMI and multiples of median (MoM) values for pregnancy-associated plasma protein-A (PAPP-A), demonstrated a significantly reduced FF for ART pregnancies (mean FF = 0.056) compared with naturally conceived pregnancies (mean FF = 0.072) (P < 0.0001). We found that FF was significantly reduced with increasing maternal BMI (P < 0.0001) and with decreasing MoM values of PAPP-A (P = 0.003). LIMITATIONS, REASONS FOR CAUTION: A limitation of our study design was the relatively small sample size. Another limitation was that the control group was not matched with the ART-treated women. The majority of the women from the control group had a high risk from cFTS, thereby their biochemical markers were diverging. However, the biochemical markers for the ART-treated women with fresh or frozen ET were not divergent within the subgroups. WIDER IMPLICATIONS OF THE FINDINGS: Concurrent with other studies demonstrating a reduced FF for singleton pregnancies after ART treatment compared with naturally conceived pregnancies, we found a reduction in FF between the two groups. This is one of the first studies to examine FF in ART pregnancies after fresh ET compared with frozen ET, hence the existing knowledge is limited. We find that FF is even more reduced in pregnancies following fresh ET compared with frozen ET, which might possibly reflect the predisposition of being small for gestational age after fresh ET compared with natural cycle frozen ET. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by the A.P. Møller og Hustru Chastine Mc-Kinney Møllers Fond til almene Formaal (the A.P. Møller Foundation for General Purposes). All authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: NA.

Noninvasive prenatal testing and maternal obesity: A review.

Noninvasive prenatal testing (NIPT) has become a popular screening test for the most common fetal aneuploidies. The performance of NIPT is affected by several factors including maternal obesity, which results in a greater rate of no-calls for obese pregnant women. Guidelines regarding NIPT in prenatal screening have been published, but with few and divergent recommendations on the issue. We aimed to review the medical literature, guidelines from scientific societies and information material from commercial NIPT providers on no-calls and maternal obesity. We systematically identified medical literature and guidelines from scientific societies using the database MEDLINE. Information material from commercial NIPT providers was found via a systematic search on Google.com. Nine medical studies investigating the association between maternal obesity and NIPT no-calls were included. They all showed the same trend: increasing no-call rate with increasing maternal obesity. The no-call rate ranged from 0% to 4.2% for women with body mass index (BMI) 18.5-24.9 and from 5.4% to 70.1% for women BMI ≥40. We identified 17 scientific societies with guidelines and 13 commercial NIPT providers. All were checked for information material on no-calls and maternal obesity. To allow comparison, all guidelines were examined to answer the same three predefined questions. Of the 17 included scientific societies, 13 (76.5%) mentioned the association between maternal obesity and NIPT no-calls, two (11.8%) specified weight limits and three (17.6%) advised against NIPT for severely obese pregnant women. None of the 13 commercial NIPT providers provided specific recommendations, but four (30.8%) cite maternal obesity as a potential cause for a no-call. Because of the increasing number of patients in this group, we advocate updated recommendations to guide decision making in prenatal screening for obese pregnant women.

Targeted Rhesus immunoglobulin for RhD-negative women undergoing an induced abortion: A clinical pilot study.

INTRODUCTION: The aim of this clinical pilot study was to examine the accuracy of noninvasive fetal RHD genotyping in early pregnancy (8+0  to 11+6  weeks) and to clarify whether targeted administration of Rhesus immunoglobulin (RhIg) is possible for women undergoing an induced abortion such that unnecessary injections can be avoided. The study examines the correlation between gestational age and the amount of cell-free fetal DNA in maternal plasma, the fetal fraction of DNA and whether transportation time or body mass index affects these parameters. MATERIAL AND METHODS: Fifty-two RhD-negative women undergoing a surgically induced abortion were included. A maternal blood sample was collected prior to the abortion and a tissue sample was collected from the placental part of the abortion material after the intervention. Fetal RhD type was determined by PCR analysis of cell-free fetal DNA extracted from maternal plasma and on DNA from the tissue sample, with the latter providing a reference standard. Copies of RHD/mL were determined on RHD-positive samples and the fetal fraction of DNA was calculated. RESULTS: We demonstrated complete concordance between results from plasma and tissue, with 31 RhD-positive and 21 RhD-negative samples, corresponding to 40% being RhD-negative, specificity 100% [95% confidence interval (CI) 88.8-100] and sensitivity 100% (95% CI 83.9-100). We found no significant correlation between gestational age and the amount or the fraction of cell-free fetal DNA in maternal plasma, nor did we find that transportation time or BMI significantly affected these factors in this setup. CONCLUSIONS: Fetal RHD genotyping can be accurately performed from the 8th week of gestation and unnecessary injections of RhIg can be avoided for women undergoing an induced abortion. A larger study is needed to determine a more accurate sensitivity for the analysis early in pregnancy.

Maternal serum laeverin (aminopeptidase Q) measured in the first trimester of pregnancy does not predict preeclampsia.

Objective: The aim of this study was to compare the laeverin level in maternal serum from first trimester (11-14 weeks) of pregnancy between normal pregnancies and pregnancies that later developed preeclampsia (PE). Material and methods: This was a case-cohort study. The laeverin concentration was measured in cases with preterm PE (n = 55), term PE (n = 95), and a reference group of randomly selected women with normal pregnancy outcome (n = 200) in stored serum samples collected from the double-test as part of the combined first trimester trisomy 21 screening program. The samples were thawed and analyzed for laeverin. The median gestational age at blood sampling was 77 days (range 57-96 days). Multiple regression analysis was performed to establish a normal median. Concentrations were converted to multiples of the median (MoM) and groups were compared using the Mann-Whitney U-test. Results: In the reference group, laeverin was significantly correlated with gestational age (r = 0.18, p = .01) and its concentration ranged from 41-393 µg/L. No significant differences in the median laeverin MoM were found between the reference group (1.01 MoM) and cases with preterm PE (0.98 MoM) or term PE (0.96 MoM). Conclusions: First trimester maternal serum laeverin level cannot be used to predict preeclampsia.

Outcomes of monoamniotic twin pregnancies managed primarily in outpatient care-a Danish multicenter study.

INTRODUCTION: Monoamniotic twin pregnancies are high-risk pregnancies, and management by inpatient or frequent outpatient care is recommended. We report the outcomes of a national cohort of monoamniotic twin pregnancies managed primarily as outpatients. MATERIAL AND METHODS: We prospectively analyzed the recorded data from the Danish Fetal Medicine Database, local databases, and medical records of all monoamniotic twin pregnancies diagnosed at the first trimester scan or later, and managed at the six major fetal medicine centers in Denmark over a 10-year period. RESULTS: Sixty-one monoamniotic twin pregnancies were included. Thirteen pregnancies were terminated early. Of the remaining 48 pregnancies with a normal first trimester scan, there were 36 fetal losses (25 spontaneous miscarriages <22+0  weeks, 3 late terminations and 8 intrauterine deaths >22 weeks) and 60 liveborn children (62.5%), all of whom were delivered by cesarean delivery at a median gestational age of 33+0  weeks. Three children had minor malformations and there was 1 pregnancy with twin-to-twin transfusion syndrome. After 26+0  weeks, 78.8% were managed as outpatients. Intrauterine death occurred in 3.8% of outpatients and in 28.6% of inpatients (admitted due to complications). At weeks 32, 33 and 34, the prospective risk of intrauterine death was 6.9%, 4.2% and 5.9%, respectively. CONCLUSION: In this nationwide, unselected population, only 62.5% of fetuses with a normal first trimester scan were born alive. In contrast, the mortality was 3.8% after 26 weeks among the 78.8% of the cohort that was managed as outpatients. More knowledge is still needed to predict which pregnancies are at the highest risk of intrauterine death.

National screening guidelines and developments in prenatal diagnoses and live births of Down syndrome in 1973-2016 in Denmark.

INTRODUCTION: Denmark was the first country in the world to implement a national, free-for-all offer of prenatal screening for Down syndrome to all pregnant women. It has a high uptake (>90%) compared to other countries. Thus, Denmark offers an interesting case for investigating the consequences of implementing comprehensive, national prenatal screening guidelines. The aim of this study was to describe the historical developments in invasive procedures, pre-/postnatal diagnoses of Down syndrome and Down syndrome live births in the period 1973-2016 in Denmark. MATERIAL AND METHODS: Data on invasive procedures, pre- and postnatal Down syndrome diagnoses were retrieved from the Danish Cytogenetic Central Registry. RESULTS: From 1973 to 1993, screening based on maternal age and high-risk indications resulted in a constant increase in invasive procedures. After the introduction of the triple test in 1994, invasive procedures decreased for the first time in 20 years. Following the introduction of an offer of combined screening to all pregnant women in 2004, the number of invasive procedures decreased markedly, while there was a concurrent increase in prenatal diagnoses of Down syndrome. Additionally, the number of Down syndrome live births decreased suddenly and significantly, but subsequently stabilized at 23-35 annual live births. Of these, the majority were diagnosed postnatally. CONCLUSION: Though prenatal screening technologies constantly improve, it was the introduction of and adherence to national guidelines that resulted in marked shifts in screening procedures and outcome in Denmark.

The Danish Fetal Medicine Database: establishment, organization and quality assessment of the first trimester screening program for trisomy 21 in Denmark 2008-2012.

OBJECTIVE: To describe the establishment and organization of the Danish Fetal Medicine Database and to report national results of first-trimester combined screening for trisomy 21 in the 5-year period 2008-2012. DESIGN: National register study using prospectively collected first-trimester screening data from the Danish Fetal Medicine Database. POPULATION: Pregnant women in Denmark undergoing first-trimester screening for trisomy 21. METHODS: Data on maternal characteristics, biochemical and ultrasonic markers are continuously sent electronically from local fetal medicine databases (Astraia Gmbh software) to a central national database. Data are linked to outcome data from the National Birth Register, the National Patient Register and the National Cytogenetic Register via the mother's unique personal registration number. First-trimester screening data from 2008 to 2012 were retrieved. MAIN OUTCOME MEASURES: Screening performance was assessed for the years 2008-2012 by calculating detection rates and screen-positive rates. RESULTS: A total of 268 342 first-trimester risk assessments for trisomy 21 were performed in singleton pregnancies. Participation rate in first-trimester screening was >90%. The national screen-positive rate increased from 3.6% in 2008 to 4.7% in 2012. The national detection rate of trisomy 21 was reported to be between 82 and 90% in the 5-year period. CONCLUSION: A national fetal medicine database has been successfully established in Denmark. Results from the database have shown that at a national level first-trimester screening performance for trisomy 21 is high with a low screen-positive rate and a high detection rate.